What is Atypical Depression?

Introduction

Atypical depression as it has been known in the DSM IV, is depression that shares many of the typical symptoms of the psychiatric syndromes of major depression or dysthymia but is characterised by improved mood in response to positive events.

In contrast to atypical depression, people with melancholic depression generally do not experience an improved mood in response to normally pleasurable events. Atypical depression also features significant weight gain or an increased appetite, hypersomnia, a heavy sensation in the limbs, and interpersonal rejection sensitivity that results in significant social or occupational impairment.

Despite its name, “atypical” depression does not mean it is uncommon or unusual. The reason for its name is twofold: it was identified with its “unique” symptoms subsequent to the identification of melancholic depression and its responses to the two different classes of antidepressants that were available at the time were different from melancholic depression (i.e. monoamine oxidase inhibitors (MAOIs) had clinically significant benefits for atypical depression, while tricyclics did not).

Atypical depression is four times more common in females than in males. Individuals with atypical features tend to report an earlier age of onset (e.g. while in high school) of their depressive episodes, which also tend to be more chronic and only have partial remission between episodes. Younger individuals may be more likely to have atypical features, whereas older individuals may more often have episodes with melancholic features. Atypical depression has high comorbidity of anxiety disorders, carries more risk of suicidal behaviour, and has distinct personality psychopathology and biological traits.

Atypical depression is more common in individuals with bipolar I, bipolar II, cyclothymia and seasonal affective disorder. Depressive episodes in bipolar disorder tend to have atypical features, as does depression with seasonal patterns.

Refer to Masked Depression and Treatment-Resistant Depression.

Pathophysiology

Significant overlap between atypical and other forms of depression have been observed, though studies suggest there are differentiating factors within the various pathophysiological models of depression. In the endocrine model, evidence suggests the HPA axis is hyperactive in melancholic depression, and hypoactive in atypical depression. Atypical depression can be differentiated from melancholic depression via verbal fluency tests and psychomotor speed tests. Although both show impairment in several areas such as visuospatial memory and verbal fluency, melancholic patients tend to show more impairment than atypical depressed patients.

Furthermore, regarding the inflammatory theory of depression, inflammatory blood markers (cytokines) appear to be more elevated in atypical depression when compared to non-atypical depression.

Diagnosis

The diagnosis of atypical depression is based on the criteria stated in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The DSM-5 defines atypical depression as a subtype of major depressive disorder that presents with “atypical features”, characterised by:

  • Mood reactivity (i.e., mood brightens in response to actual or potential positive events)
  • At least two of the following:
    • Significant weight gain or increase in appetite (hyperphagia);
    • Hypersomnia (sleeping too much, as opposed to the insomnia present in melancholic depression);
    • Leaden paralysis (i.e., heavy feeling resulting in difficulty moving the arms or legs);
    • Long-standing pattern of interpersonal rejection sensitivity (not limited to episodes of mood disturbance) that results in significant social or occupational impairment.

Criteria are not met for With Melancholic Features or With Catatonic Features during the same episode.

Treatment

Due to the differences in clinical presentation between atypical depression and melancholic depression, studies were conducted in the 1980s and 1990s to assess the therapeutic responsiveness of the available antidepressant pharmacotherapy in this subset of patients. Currently, antidepressants such as SSRIs, SNRIs, NRIs, and mirtazapine are considered the best medications to treat atypical depression due to efficacy and fewer side effects than previous treatments. Bupropion, a norepinephrine reuptake inhibitor, may be uniquely suited to treat the atypical depression symptoms of lethargy and increased appetite in adults. Modafinil is sometimes used successfully as an off-label treatment option.

Before the year 2000, monoamine oxidase inhibitors (MAOIs) were shown to be of superior efficacy compared to other antidepressants for the treatment of atypical depression, and were used as first-line treatment for this clinical presentation. This class of medication fell in popularity with the advent of the aforementioned selective agents, due to concerns of interaction with tyramine-rich foods (such as some aged cheese, certain types of wine, tap beer and fava beans) causing a hypertensive crisis and some – but not all – sympathomimetic drugs, as well as the risk of serotonin syndrome when concomitantly used with serotonin reuptake agents. Despite these concerns, they are still used in treatment-resistant cases, when other options have been exhausted, and usually show greater rates of remission compared to previous pharmacotherapies. They are also generally better tolerated by many patients. There are also newer selective and reversible MAOIs, such as moclobemide, which carry a much lower risk of tyramine potentiation and have fewer interactions with other drugs.

Tricyclic antidepressants (TCAs) were also used prior to the year 2000 for atypical depression, but were not as efficacious as MAOIs, and have fallen out of favour with prescribers due to the less tolerable side effects of TCAs and more adequate therapies being available.

Some evidence supports that psychotherapy such as cognitive behavioural therapy (CBT) has equal efficacy to MAOI. These are talk therapy sessions with psychiatrists to help the individual identify troubling thoughts or experiences that may have affected their mental state, and develop corresponding coping mechanisms for each identified issue.

No robust guidelines for the treatment of atypical depression currently exist.

Epidemiology

True prevalence of atypical depression is difficult to determine. Several studies conducted in patients diagnosed with a depressive disorder show that about 40% exhibit atypical symptoms, with four times more instances found in female patients. Research also supports that atypical depression tends to have an earlier onset, with teenagers and young adults more likely to exhibit atypical depression than older patients. Patients with atypical depression have shown to have higher rates of neglect and abuse in their childhood as well as alcohol and drug disorders in their family. Overall, rejection sensitivity is the most common symptom, and due to some studies forgoing this criterion, there is concern for underestimation of prevalence.

Research

In general, atypical depression tends to cause greater functional impairment than other forms of depression. Atypical depression is a chronic syndrome that tends to begin earlier in life than other forms of depression – usually beginning in the teenage years. Similarly, patients with atypical depression are more likely to suffer from personality disorders and anxiety disorders such as borderline personality disorder, avoidant personality disorder, generalised anxiety disorder, obsessive-compulsive disorder, and bipolar disorder.

Recent research suggests that young people are more likely to suffer from hypersomnia while older people are more likely to suffer from polyphagia.

Medication response differs between chronic atypical depression and acute melancholic depression. Some studies suggest that the older class of antidepressants, MAOIs, may be more effective at treating atypical depression. While the more modern SSRIs and SNRIs are usually quite effective in this illness, the tricyclic antidepressants typically are not. The wakefulness-promoting agent modafinil has shown considerable effect in combating atypical depression, maintaining this effect even after discontinuation of treatment. Antidepressant response can often be enhanced with supplemental medications, such as buspirone, bupropion, or aripiprazole. Psychotherapy, whether alone or in combination with medication, is also an effective treatment in individual and group settings.

Reviewing the Understanding of the Treatment Guidelines for Schizophrenia & Major Depressive Disorder

Research Paper Title

Improvements in the degree of understanding of the treatment guidelines for schizophrenia and major depressive disorder in a nationwide dissemination and implementation study.

Background

To implement clinical practice guidelines (CPGs), it is necessary for psychiatrists to deepen their understanding of the CPGs. The Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project is a nationwide dissemination and implementation study of two sets of CPGs for schizophrenia and major depressive disorder (MDD).

Methods

A total of 413 psychiatrists (n = 212 in 2016; n = 201 in 2017) learned the two CPGs in the education program of the EGUIDE project, and clinical knowledge of these CPGs was evaluated at baseline and after the programs. To improve the correct answer rate for clinical knowledge after the programs, we revised the lecture materials associated with items that had a low correct answer rate in 2016 and used the revised lecture materials with the CPGs in 2017. The rates of correct answers after the programmes between the 2016 and 2017 groups were compared.

Results

The correct answer rate of one item on the schizophrenia CPG and one item on the MDD CPG tended to be improved (S-D5 and D-C6) and that of one on the MDD CPG was significantly improved (D-D3, P = 0.0008) in the 2017 group compared to those in the 2016 group.

Conclusions

The researchers reported improvements in clinical knowledge of CPGs after the EGUIDE program in the 2017 group following revision of the lecture materials based on results from the 2016 group. These attempts to improve the degree of understanding of CPGs may facilitate the successful dissemination and implementation of psychiatric guidelines in everyday practice.

Reference

Numata, S., Nakataki, M., Hasegawa, N., Takaesu, Y., Takeshima, M., Onitsuka, T., Nakamura, T., Edagawa, R., do, H., Miura, K., Matsumoto, J., Yasui-Fiurukori, N., Kishimoto, T., Hori, H., Tsuboi, T., Yasuda, Y., Furihata, R., Muraoka, H., Ochi, S., Nagasawa, T., Kyou, Y., Murata, A., Katsumoto, E., Ohi, K., Hishimoto, A., Inada, K., Watanabe, K. & Hashimoto, R. (2021) Improvements in the degree of understanding the treatment guidelines for schizophrenia and major depressive disorder in a nationwide dissemination and implementation study. Neuropsychopharmacology Reports. doi: 10.1002/npr2.12173. Online ahead of print.

What is Melancholic Depression?

Introduction

Melancholic depression, or depression with melancholic features, is a DSM-IV and DSM-5 subtype of clinical depression.

Refer to Melancholia.

Signs and Symptoms

Requiring at least one of the following symptoms:

  • Anhedonia (the inability to find pleasure in positive things).
  • Lack of mood reactivity (i.e. mood does not improve in response to positive events).

And at least three of the following:

  • Depression that is subjectively different from grief or loss.
  • Severe weight loss or loss of appetite.
  • Psychomotor agitation or retardation.
  • Early morning awakening.
  • Guilt that is excessive.
  • Worse mood in the morning.

Melancholic features apply to an episode of depression that occurs as part of either major depressive disorder or bipolar disorder I or II.

Causes

The causes of melancholic-type major depressive disorder are believed to be mostly biological factors; some may have inherited the disorder from their parents. Sometimes stressful situations can trigger episodes of melancholic depression, though this is a contributing cause rather than a necessary or sufficient cause. People with psychotic symptoms are also thought to be more susceptible to this disorder. It is frequent in old age and often unnoticed by some physicians who perceive the symptoms to be a part of dementia. Major depressive disorder, melancholic or otherwise, is a separate condition that can be comorbid with dementia in the elderly.

Treatment

Melancholic depression is often considered to be a biologically based and particularly severe form of depression. Treatment involves antidepressants, electroconvulsive therapy, or other empirically supported treatments such as cognitive behavioural therapy and interpersonal therapy for depression. A 2008 analysis of a large study of patients with unipolar major depression found a rate of 23.5% for melancholic features. It was the first form of depression extensively studied, and many of the early symptom checklists for depression reflect this.

Incidence

The incidence of melancholic depression has been found to increase when the temperature and/or sunlight are low. According to the DSM-IV, the “melancholic features” specifier may be applied to the following only:

  • Major depressive episode, single episode.
  • Major depressive episode, recurrent episode.
  • Bipolar I disorder, most recent episode depressed.
  • Bipolar II disorder, most recent episode depressed.

What is a Major Depressive Episode?

Introduction

A major depressive episode (MDE) is a period characterised by the symptoms of major depressive disorder.

Sufferers primarily have a depressed mood for two weeks or more, and a loss of interest or pleasure in everyday activities, accompanied by other symptoms such as feelings of emptiness, hopelessness, anxiety, worthlessness, guilt and irritability, changes in appetite, problems concentrating, remembering details or making decisions, and thoughts of suicide. Insomnia or hypersomnia, aches, pains, or digestive problems that are resistant to treatment may also be present. The description has been formalized in psychiatric diagnostic criteria such as the DSM-5 and ICD-10.

Biological, psychological, and social factors are believed to be involved in the cause of depression, although it is still not well understood. Factors like socioeconomic status, life experience, and personality tendencies play a role in the development of depression and may represent increases in risk for developing a MDE. There are many theories as to how depression occurs. One interpretation is that neurotransmitters in the brain are out of balance, and this results in feelings of worthlessness and despair. Magnetic resonance imaging shows that brains of people who have depression look different than the brains of people not exhibiting signs of depression. A family history of depression increases the chance of being diagnosed.

Emotional pain and economic costs are associated with depression. In the United States and Canada, the costs associated with major depression are comparable to those related to heart disease, diabetes, and back problems and are greater than the costs of hypertension. According to the Nordic Journal of Psychiatry, there is a direct correlation between major depressive episode and unemployment.

Treatments for a major depressive episode include psychotherapy and antidepressants, although in more serious cases, hospitalization or intensive outpatient treatment may be required.

Signs and Symptoms

The criteria below are based on the formal DSM-V criteria for a major depressive episode. A diagnosis of major depressive episode requires that the patient has experienced five or more of the symptoms below, and one of the symptoms must be either depressed mood or loss of interest or pleasure (although both are frequently present). These symptoms must be present for at least 2 weeks and represent a change from the patient’s normal behaviour.

Depressed Mood and Loss of Interest (Anhedonia)

Either depressed mood or a loss of interest or pleasure must be present for the diagnosis of a MDE. Depressed mood is the most common symptom seen in major depressive episodes. Interest or pleasure in everyday activities can be decreased; this is referred to as anhedonia. These feelings must be present on an everyday basis for two weeks or longer to meet DSM-V criteria for a MDE. In addition, the person may experience one or more of the following emotions: sadness, emptiness, hopelessness, indifference, anxiety, tearfulness, pessimism, emotional numbness, or irritability. In children and adolescents, a depressed mood often appears more irritable in nature. There may be a loss of interest in or desire for sex, or other activities once found to be pleasant. Friends and family of the depressed person may notice that they have withdrawn from friends, or neglected or quit doing activities that were once a source of enjoyment.

Sleep

Nearly every day, the person may sleep excessively, known as hypersomnia, or not enough, known as insomnia. Insomnia is the most common type of sleep disturbance for people who are clinically depressed. Symptoms of insomnia include trouble falling asleep, trouble staying asleep, or waking up too early in the morning. Hypersomnia is a less common type of sleep disturbance. It may include sleeping for prolonged periods at night or increased sleeping during the daytime. The sleep may not be restful, and the person may feel sluggish despite many hours of sleep, which may amplify their depressive symptoms and interfere with other aspects of their lives. Hypersomnia is often associated with an atypical depression, as well as seasonal affective disorder.

Feelings of Guilt or Worthlessness

Depressed people may have feelings of guilt that go beyond a normal level or are delusional. These feelings of guilt and/or worthlessness are excessive and inappropriate. MDE’s are notable for a significant, often unrealistic, drop in self-esteem. The guilt and worthlessness experienced in a MDE can range from subtle feelings of guilt to frank delusions or to shame and humiliation. Additionally, self-loathing is common in clinical depression, and can lead to a downward spiral when combined with other symptoms.

Loss of Energy

Persons going through a MDE often have a general lack of energy, as well as fatigue and tiredness, nearly every day for at least 2 weeks. A person may feel tired without having engaged in any physical activity, and day-to-day tasks become increasingly difficult. Job tasks or housework become very tiring, and the patient finds that their work begins to suffer.

Decreased Concentration

Nearly every day, the person may be indecisive or have trouble thinking or concentrating. These issues cause significant difficulty in functioning for those involved in intellectually demanding activities, such as school and work, especially in difficult fields. Depressed people often describe a slowing of thought, inability to concentrate and make decisions, and being easily distracted. In the elderly, the decreased concentration caused by a MDE may present as deficits in memory. This is referred to as pseudodementia and often goes away with treatment. Decreased concentration may be reported by the patient or observed by others.

Change in Eating, Appetite, or Weight

In a major depressive episode, appetite is most often decreased, although a small percentage of people experience an increase in appetite. A person experiencing a depressive episode may have a marked loss or gain of weight (5% of their body weight in one month). A decrease in appetite may result in weight loss that is unintentional or when a person is not dieting. Some people experience an increase in appetite and may gain significant amounts of weight. They may crave certain types of food, such as sweets or carbohydrates. In children, failure to make expected weight gains may be counted towards this criteria. Overeating is often associated with atypical depression.

Motor Activity

Nearly every day, others may see that the person’s activity level is not normal. People suffering from depression may be overly active (psychomotor agitation) or be very lethargic (psychomotor retardation). Psychomotor agitation is marked by an increase in body activity which may result in restlessness, an inability to sit still, pacing, hand wringing, or fidgeting with clothes or objects. Psychomotor retardation results in a decrease in body activity or thinking. In this case, a depressed person may demonstrate a slowing of thinking, speaking, or body movement. They may speak more softly or say less than usual. To meet diagnostic criteria, changes in motor activity must be so abnormal that it can be observed by others. Personal reports of feeling restless or feeling slow do not count towards the diagnostic criteria.

Thoughts of Death and Suicide

A person going through a MDE may have repeated thoughts about death (other than the fear of dying) or suicide (with or without a plan), or may have made a suicide attempt. The frequency and intensity of thoughts about suicide can range from believing that friends and family would be better off if one were dead, to frequent thoughts about committing suicide (generally related to wishing to stop the emotional pain), to detailed plans about how the suicide would be carried out. Those who are more severely suicidal may have made specific plans and decided upon a day and location for the suicide attempt.

Comorbid Disorders

MDE’s may show comorbidity (association) with other physical and mental health problems. About 20-25% of individuals with a chronic general medical condition will develop major depression. Common comorbid disorders include: eating disorders, substance-related disorders, panic disorder, and obsessive-compulsive disorder. Up to 25% of people who experience a major depressive episode have a pre-existing dysthymic disorder.

Some persons who have a fatal illness or are at the end of their life may experience depression, although this is not universal.

Causes

The cause of a MDE is not well understood. However, the mechanism is believed to be a combination of biological, psychological, and social factors. A MDE can often follow an acute stress in someone’s life. Evidence suggests that psychosocial stressors play a larger role in the first 1-2 depressive episodes, while having less influence in later episodes. People who experience a major depressive episode often have other mental health issues.

Other risk factors for a depressive episode include:

  • Family history of a mood disorder;
  • Recent negative life events;
  • Personality (insecure, worried, stress-sensitive, obsessive, unassertive, dependent);
  • Early childhood trauma;
  • Postpartum; and
  • Lack of interpersonal relationships.

One gene by itself has not been linked to depression. Studies show that depression can be passed down in families, but this is believed to be due to a combined effect of genetic and environmental factors. Other medical conditions, like hypothyroidism for example, may cause someone to experience similar symptoms as a MDE, however this would be considered a mood disorder due to a general medical condition, according to the DSM-V.

Diagnosis

Criteria

The two main symptoms in a major depressive episode are a depressed mood or a loss of interest or pleasure. From the list below, one bold symptom and four other symptoms must be present for a diagnosis of MDE. These symptoms must be present for at least 2 weeks and must be causing significant distress or impairment in functioning.

  • Depressed mood.
  • Loss of interest or pleasure.
  • Change in appetite.
  • Change in sleep.
  • Change in body activity (psychomotor changes).
  • Loss of energy.
  • Feelings of worthlessness and excessive or inappropriate guilt.
  • Indecisiveness or a decrease in concentration.
  • Suicidal ideation.

To diagnose a major depressive episode, a trained healthcare provider must make sure that:

  • The symptoms do not meet the criteria for a mixed episode.
  • The symptoms must cause considerable distress or impair functioning at work, in social settings or in other important areas in order to qualify as an episode.
  • The symptoms are not due to the direct physiological effects of a substance (e.g. abuse of a drug or medication) or a general medical condition (e.g. hypothyroidism).

Workup

No labs are diagnostic of a depressive episode. But some labs can help rule out general medical conditions that may mimic the symptoms of a depressive episode. Healthcare providers may order some routine blood work, including routine blood chemistry, CBC with differential, thyroid function studies, and Vitamin B12 levels, before making a diagnosis.

Differential Diagnosis

There are other mental health disorders or medical conditions to consider before diagnosing a MDE:

  • Bipolar disorder.
  • Cyclothymic disorder.
  • Disruptive mood dysregulation disorder.
  • Persistent depressive disorder.
  • Anxiety disorder (Generalised anxiety, PTSD, obsessive compulsive disorder).
  • Substance abuse or Substance Use Disorder.
  • Personality disorder with depressive symptoms.
  • Adjustment disorder.
  • Depression due to a general medical condition.
  • Premenstrual dysphoric disorder.

Screening

Healthcare providers may screen patients in the general population for depression using a screening tool, such as the Patient Healthcare Questionnaire-2 (PHQ-2). If the PHQ-2 screening is positive for depression, a provider may then administer the PHQ-9. The Geriatric Depression Scale is a screening tool that can be used in the elderly population.

Treatment

Depression is a treatable illness. Treatments for a MDE may be provided by mental health specialists (i.e. psychologist, psychiatrists, social workers, counsellors, etc.), mental health centres or organisations, hospitals, outpatient clinics, social service agencies, private clinics, peer support groups, clergy, and employee assistance programmes. The treatment plan could include psychotherapy alone, antidepressant medications alone, or a combination of medication and psychotherapy.

For major depressive episodes of severe intensity (multiple symptoms, minimal mood reactivity, severe functional impairment), combined psychotherapy and antidepressant medications are more effective than psychotherapy alone. Meta-analyses suggest that the combination of psychotherapy and antidepressant medications is more effective in treating mild and moderate forms of depression as well, compared to either type of treatment alone. Patients with severe symptoms may require outpatient treatment or hospitalisation.

The treatment of a major depressive episode can be split into 3 phases:

  • Acute phase: the goal of this phase is to resolve the current major depressive episode.
  • Continuation: this phase continues the same treatment from the acute phase for 4-8 months after the depressive episode has resolved and the goal is to prevent relapse.
  • Maintenance: this phase is not necessary for every patient but is often used for patients who have experienced 2-3 or more MDE’s.
    • Treatment may be maintained indefinitely to prevent the occurrence and severity of future episodes.

Therapy

Psychotherapy, also known as talk therapy, counselling, or psychosocial therapy, is characterised by a patient talking about their condition and mental health issues with a trained therapist. Different types of psychotherapy are used as a treatment for depression. These include cognitive behavioural therapy, interpersonal therapy, dialectical behaviour therapy, acceptance and commitment therapy, and mindfulness techniques. Evidence shows that cognitive behavioural therapy can be as effective as medication in the treatment of a MDE.

Psychotherapy may be the first treatment used for mild to moderate depression, especially when psychosocial stressors are playing a large role. Psychotherapy alone may not be as effective for more severe forms of depression.

Some of the main forms of psychotherapies used for treatment of a major depressive episode along with what makes them unique are included below:

  • Cognitive psychotherapy: focus on patterns of thinking.
  • Interpersonal psychotherapy: focus on relationships, losses, and conflict resolution.
  • Problem-solving psychotherapy: focus on situations and strategies for problem-solving.
  • Psychodynamic psychotherapy: focus on defence mechanisms and coping strategies.

Medication

Medications used to treat depression include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and atypical antidepressants such as mirtazapine, which do not fit neatly into any of the other categories. Different antidepressants work better for different individuals. It is often necessary to try several before finding one that works best for a specific patient. Some people may find it necessary to combine medications, which could mean two antidepressants or an antipsychotic medication in addition to an antidepressant. If a person’s close relative has responded well to a certain medication, that treatment will likely work well for him or her. Antidepressant medications are effective in the acute, continuation, and maintenance phases of treatment, as described above.

The treatment benefits of antidepressant medications are often not seen until 1-2 weeks into treatment, with maximum benefits being reached around 4-6 weeks. Most healthcare providers will monitor patients more closely during the acute phase of treatment and continue to monitor at longer intervals in the continuation and maintenance phases.

Sometimes, people stop taking antidepressant medications due to side effects, although side effects often become less severe over time. Suddenly stopping treatment or missing several doses may cause withdrawal-like symptoms. Some studies have shown that antidepressants may increase short-term suicidal thoughts or actions, especially in children, adolescents, and young adults. However, antidepressants are more likely to reduce a person’s risk of suicide in the long run.

Below are listed the main classes of antidepressant medications, some of the most common drugs in each category, and their major side effects:

  • Selective serotonin reuptake inhibitors (citalopram, escitalopram, paroxetine, fluoxetine, sertraline): major side effects include nausea, diarrhoea, and sexual dysfunction.
  • Serotonin and norepinephrine reuptake inhibitors (duloxetine, venlafaxine, desvenlafaxine): major side effects include nausea, diarrhoea, increased heart rate, increased blood pressure, and tremor.
  • Tricyclic antidepressants (amitryptiline, desipramine, doxepin, imipramine, nortriptyline): major side effects include sedation, low blood pressure when moving from sitting to standing (orthostatic hypotension), tremor, and heart issues like conduction delays or arrhythmias.
  • Monoamine oxidase inhibitors (isocarboxazid, phenelzine, selegiline): major side effects include high blood pressure (emergency) if eaten with foods rich in tyramine (e.g. cheeses, some meats, and home-brewed beer), sedation, tremor, and orthostatic hypotension.

Alternative Treatments

There are several treatment options that exist for people who have experienced several episodes of major depression or have not responded to several treatments.

Electroconvulsive therapy is a treatment in which a generalised seizure is induced by means of electrical current. The mechanism of action of the treatment is not clearly understood but has been show to be most effective in the most severely depressed patients. For this reason, electroconvulsive therapy is preferred for the most severe forms of depression or depression that has not responded to other treatments, known as refractory depression.

Vagus nerve stimulation is another alternative treatment that has been proven to be effective in the treatment of depression, especially people that have been resistant to four or more treatments. Some of the unique benefits of vagus nerve stimulation include improved neurocognitive function and a sustained clinical response.

Transcranial magnetic stimulation is also an alternative treatment for a major depressive episode. It is a non-invasive treatment that is easily tolerated and shows an antidepressant effect, especially in more typical depression and younger adults.

Prognosis

If left untreated, a typical MDE may last for several months. About 20% of these episodes can last two years or more. About half of depressive episodes end spontaneously. However, even after the MDE is over, 20% to 30% of patients have residual symptoms, which can be distressing and associated with disability. 50% of people will have another major depressive episode after the first. However, the risk of relapse is decreased by taking antidepressant medications for more than 6 months.

Symptoms completely improve in six to eight weeks in 60%-70% of patients. The combination of therapy and antidepressant medications has been shown to improve resolution of symptoms and outcomes of treatment.

Suicide is the 8th leading cause of death in the United States. The risk of suicide is increased during a MDE. However, the risk is even more elevated during the first two phases of treatment. There are several factors associated with an increased risk of suicide, listed below:

  • Greater than 45 years of age;
  • Male;
  • History of suicide attempt or self-injurious behaviours;
  • Family history of suicide or mental illness;
  • Recent severe loss;
  • Poor health;
  • Detailed plan;
  • Inability to accept help;
  • Lack of social support
  • Psychotic features (auditory or visual hallucinations, disorganisation of speech, behaviour, or thought);
  • Alcohol or drug use or comorbid psychiatric disorder; and/or
  • Severe depression.

Epidemiology

Estimates of the numbers of people suffering from MDE’s and major depressive disorder (MDD) vary significantly. Overall, 13-20% of people will experience significant depressive symptoms at some point in their life. The overall prevalence of MDD is slightly lower ranging from 3.7-6.7% of people. In their lifetime, 20% to 25% of women, and 7% to 12% of men will suffer a MDE. The peak period of development is between the ages of 25 and 44 years. Onset of major depressive episodes or MDD often occurs to people in their mid-20s, and less often to those over 65. The prevalence of depressive symptoms in the elderly is around 1-2%. Elderly persons in nursing homes may have increased rates, up to 15-25%. African-Americans have higher rates of depressive symptoms compared to other races. Prepubescent girls are affected at a slightly higher rate than prepubescent boys.

In a National Institute of Mental Health study, researchers found that more than 40% of people with post-traumatic stress disorder suffered from depression four months after the traumatic event they experienced.

Women who have recently given birth may be at increased risk for having a major depressive episode. This is referred to as postpartum depression and is a different health condition than the baby blues, a low mood that resolves within 10 days after delivery.

What is Generalised Anxiety Disorder (GAD)?

Introduction

Generalised anxiety disorder (GAD) is an anxiety disorder characterised by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning, and sufferers are overly concerned about everyday matters such as health, finances, death, family, relationship concerns, or work difficulties. Symptoms may include excessive worry, restlessness, trouble sleeping, exhaustion, irritability, sweating, and trembling.

Symptoms must be consistent and ongoing, persisting at least six months, for a formal diagnosis of GAD. Individuals with GAD often suffer from other disorders including other psychiatric disorders (e.g. major depressive disorder), substance use disorder, obesity, and may have a history of trauma or family with GAD. Clinicians use screening tools such as the GAD-7 and GAD-2 questionnaires to determine if individuals may have GAD and warrant formal evaluation for the disorder. Additionally, sometimes screening tools may enable clinicians to evaluate the severity of GAD symptoms.

GAD is believed to have a hereditary or genetic basis (e.g. first-degree relatives of an individual who has GAD are themselves more likely to have GAD) but the exact nature of this relationship is not fully appreciated. Genetic studies of individuals who have anxiety disorders (including GAD) suggest that the hereditary contribution to developing anxiety disorders is only approximately 30-40%, which suggests that environmental factors may be more important to determining whether an individual develops GAD.

The pathophysiology of GAD implicates several regions of the brain that mediate the processing of stimuli associated with fear, anxiety, memory, and emotion (i.e. the amygdala, insula and the frontal cortex). It has been suggested that individuals with GAD have greater amygdala and medial prefrontal cortex (mPFC) activity in response to stimuli than individuals who do not have GAD. However, the relationship between GAD and activity levels in other parts of the frontal cortex is the subject of ongoing research with some literature suggesting greater activation in specific regions for individuals who have GAD but where other research suggests decreased activation levels in individuals who have GAD as compared to individuals who do not have GAD.

Traditional treatment modalities include variations on psychotherapy (e.g. cognitive-behavioural therapy (CBT)) and pharmacological intervention (e.g. citalopram, escitalopram, sertraline, duloxetine, and venlafaxine). CBT and selective serotonin reuptake inhibitors (SSRIs) are the respectively predominant psychological and pharmacological treatment modalities; other treatments (e.g. selective norepinephrine reuptake inhibitors (SNRIs)) are often considered depending on individual response to therapy. Areas of active investigation include the usefulness of complementary and alternative medications (CAMs), exercise, therapeutic massage and other interventions that have been proposed for study.

Estimates regarding prevalence of GAD or lifetime risk (i.e. lifetime morbid risk (LMR)) for GAD vary depending upon which criteria are used for diagnosing GAD (e.g. DSM-5 vs ICD-10) although estimates do not vary widely between diagnostic criteria. In general, ICD-10 is more inclusive than DSM-5, so estimates regarding prevalence and lifetime risk tend to be greater using ICD-10. In regard to prevalence, in a given year, about two (2%) percent of adults in the United States and Europe have been suggested to suffer GAD. However, the risk of developing GAD at any point in life has been estimated at 9.0%. Although it is possible to experience a single episode of GAD during one’s life, most people who experience GAD experience it repeatedly over the course of their lives as a chronic or ongoing condition. GAD is diagnosed twice as frequently in women as in men.

Diagnosis

DSM-5 Criteria

The diagnostic criteria for GAD as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013), published by the American Psychiatric Association, are paraphrased as follows:

  1. “Excessive anxiety or worry” experienced most days over at least six (6) month and which involve a plurality of concerns.
  2. Inability to manage worry.
  3. At least three (3) of the following occur:
    • Restlessness.
    • Fatigability.
    • Problems concentrating.
    • Irritability.
    • Muscle tension.
    • Difficulty with sleep.
    • Note that in children, only one (1) of the above items is required.
  4. One experiences significant distress in functioning (e.g. work, school, social life).
  5. Symptoms are not due to drug abuse, prescription medication or other medical condition(s).
  6. Symptoms do not fit better with another psychiatric condition such as panic disorder.

No major changes to GAD have occurred since publication of the Diagnostic and Statistical Manual of Mental Disorders (2004); minor changes include wording of diagnostic criteria.

ICD-10 Criteria

The 10th revision of the International Statistical Classification of Disease (ICD-10) provides a different set of diagnostic criteria for GAD than the DSM-5 criteria described above. In particular, ICD-10 allows diagnosis of GAD as follows:

  • A period of at least six months with prominent tension, worry, and feelings of apprehension, about everyday events and problems.
  • At least four symptoms out of the following list of items must be present, of which at least one from items (1) to (4).
    • Autonomic arousal symptoms:
      • (1) Palpitations or pounding heart, or accelerated heart rate.
      • (2) Sweating.
      • (3) Trembling or shaking.
      • (4) Dry mouth (not due to medication or dehydration).
    • Symptoms concerning chest and abdomen:
      • (5) Difficulty breathing.
      • (6) Feeling of choking.
      • (7) Chest pain or discomfort.
      • (8) Nausea or abdominal distress (e.g. churning in the stomach).
    • Symptoms concerning brain and mind:
      • (9) Feeling dizzy, unsteady, faint or light-headed.
      • (10) Feelings that objects are unreal (derealization), or that one’s self is distant or “not really here” (depersonalization).
      • (11) Fear of losing control, going crazy, or passing out.
      • (12) Fear of dying.
    • General symptoms:
      • (13) Hot flashes or cold chills.
      • (14) Numbness or tingling sensations.
    • Symptoms of tension:
      • (15) Muscle tension or aches and pains.
      • (16) Restlessness and inability to relax.
      • (17) Feeling keyed up, or on edge, or of mental tension.
      • (18) A sensation of a lump in the throat or difficulty with swallowing.
    • Other non-specific symptoms:
      • (19) Exaggerated response to minor surprises or being startled.
      • (20) Difficulty in concentrating or mind going blank, because of worrying or anxiety.
      • (21) Persistent irritability.
      • (22) Difficulty getting to sleep because of worrying.
  • The disorder does not meet the criteria for panic disorder (F41.0), phobic anxiety disorders (F40.-), obsessive-compulsive disorder (F42.-) or hypochondriacal disorder (F45.2).
  • Most commonly used exclusion criteria: not sustained by a physical disorder, such as hyperthyroidism, an organic mental disorder (F0) or psychoactive substance-related disorder (F1), such as excess consumption of amphetamine-like substances, or withdrawal from benzodiazepines.[21]

See ICD-10 F41.1

Note: For children different ICD-10 criteria may be applied for diagnosing GAD (see F93.80).

History of Diagnostic Criteria

The American Psychiatric Association introduced GAD as a diagnosis in the DSM-III in 1980, when anxiety neurosis was split into GAD and panic disorder. The definition in the DSM-III required uncontrollable and diffuse anxiety or worry that is excessive and unrealistic and persists for 1 month or longer. High rates in comorbidity of GAD and major depression led many commentators to suggest that GAD would be better conceptualised as an aspect of major depression instead of an independent disorder. Many critics stated that the diagnostic features of this disorder were not well established until the DSM-III-R. Since comorbidity of GAD and other disorders decreased with time, the DSM-III-R changed the time requirement for a GAD diagnosis to 6 months or longer. The DSM-IV changed the definition of excessive worry and the number of associated psychophysiological symptoms required for a diagnosis. Another aspect of the diagnosis the DSM-IV clarified was what constitutes a symptom as occurring “often”. The DSM-IV also required difficulty controlling the worry to be diagnosed with GAD. The DSM-5 emphasized that excessive worrying had to occur more days than not and on a number of different topics. It has been stated that the constant changes in the diagnostic features of the disorder have made assessing epidemiological statistics such as prevalence and incidence difficult, as well as increasing the difficulty for researchers in identifying the biological and psychological underpinnings of the disorder. Consequently, making specialized medications for the disorder is more difficult as well. This has led to the continuation of GAD being medicated heavily with SSRIs.

Risk Factors

Genetics, Family and Environment

The relationship between genetics and anxiety disorders is an ongoing area of research. It is broadly understood that there exists an hereditary basis for GAD, but the exact nature of this hereditary basis is not fully appreciated. While investigators have identified several genetic loci that are regions of interest for further study, there is no singular gene or set of genes that have been identified as causing GAD. Nevertheless, genetic factors may play a role in determining whether an individual is at greater risk for developing GAD, structural changes in the brain related to GAD, or whether an individual is more or less likely to respond to a particular treatment modality. Genetic factors that may play a role in development of GAD are usually discussed in view of environmental factors (e.g. life experience or ongoing stress) that might also play a role in development of GAD. The traditional methods of investigating the possible hereditary basis of GAD include using family studies and twin studies (there are no known adoption studies of individuals who suffer anxiety disorders, including GAD). Meta-analysis of family and twin studies suggests that there is strong evidence of a hereditary basis for GAD in that GAD is more likely to occur in first-degree relatives of individuals who have GAD than in non-related individuals in the same population. Twin studies also suggest that there may be a genetic linkage between GAD and major depressive disorder (MDD), which may explain the common occurrence of MDD in individuals who suffer GAD (e.g. comorbidity of MDD in individuals with GAD has been estimated at approximately 60%). When GAD is considered among all anxiety disorders (e.g. panic disorder, social anxiety disorder), genetic studies suggest that hereditary contribution to the development of anxiety disorders amounts to only approximately 30-40%, which suggests that environmental factors are likely more important to determining whether an individual may develop GAD. In regard to environmental influences in the development of GAD, it has been suggested that parenting behaviour may be an important influence since parents potentially model anxiety-related behaviours. It has also been suggested that individuals who suffer GAD have experienced a greater number of minor stress-related events in life and that the number of stress-related events may be important in development of GAD (irrespective of other individual characteristics).

Studies of possible genetic contributions to the development of GAD have examined relationships between genes implicated in brain structures involved in identifying potential threats (e.g. in the amygdala) and also implicated in neurotransmitters and neurotransmitter receptors known to be involved in anxiety disorders. More specifically, genes studied for their relationship to development of GAD or demonstrated to have had a relationship to treatment response include:

  • PACAP (A54G polymorphism): remission after 6 month treatment with Venlafaxine suggested to have a significant relationship with the A54G polymorphism (Cooper et al. (2013)).
  • HTR2A gene (rs7997012 SNP G allele): HTR2A allele suggested to be implicated in a significant decrease in anxiety symptoms associated with response to 6 months of Venlafaxine treatment (Lohoff et al. (2013)).
  • SLC6A4 promoter region (5-HTTLPR): Serotonin transporter gene suggested to be implicated in significant reduction in anxiety symptoms in response to 6 months of Venlafaxine treatment (Lohoff et al. (2013)).

Pathophysiology

The pathophysiology of GAD is an active and ongoing area of research often involving the intersection of genetics and neurological structures. GAD has been linked to changes in functional connectivity of the amygdala and its processing of fear and anxiety. Sensory information enters the amygdala through the nuclei of the basolateral complex (consisting of lateral, basal and accessory basal nuclei). The basolateral complex processes the sensory-related fear memories and communicates information regarding threat importance to memory and sensory processing elsewhere in the brain, such as the medial prefrontal cortex and sensory cortices. Neurological structures traditionally appreciated for their roles in anxiety include the amygdala, insula and orbitofrontal cortex (OFC). It is broadly postulated that changes in one or more of these neurological structures are believed to allow greater amygdala response to emotional stimuli in individuals who have GAD as compared to individuals who do not have GAD.

Individuals who GAD have been suggested to have greater amygdala and medial prefrontal cortex (mPFC) activation in response to stimuli than individuals who do not have GAD. However, the exact relationship between the amygdala and the frontal cortex (e.g. prefrontal cortex or the orbitofrontal cortex (OFC)) is not fully understood because there are studies that suggest increased or decreased activity in the frontal cortex in individuals who have GAD. Consequently, because of the tenuous understanding of the frontal cortex as it relates to the amygdala in individuals who have GAD, it’s an open question as to whether individuals who have GAD bear an amygdala that is more sensitive than an amygdala in an individual without GAD or whether frontal cortex hyperactivity is responsible for changes in amygdala responsiveness to various stimuli. Recent studies have attempted to identify specific regions of the frontal cortex (e.g. dorsomedial prefrontal cortex (dmPFC)) that may be more or less reactive in individuals who have GAD or specific networks that may be differentially implicated in individuals who have GAD. Other lines of study investigate whether activation patterns vary in individuals who have GAD at different ages with respect to individuals who do not have GAD at the same age (e.g. amygdala activation in adolescents with GAD).

Treatment

Traditional treatment modalities broadly fall into two (2) categories:

  • Psychotherapeutic; and
  • Pharmacological intervention.

In addition to these two conventional therapeutic approaches, areas of active investigation include complementary and alternative medications (CAMs), brain stimulation, exercise, therapeutic massage and other interventions that have been proposed for further study. Treatment modalities can, and often are utilised concurrently so that an individual may pursue psychological therapy (i.e. psychotherapy) and pharmacological therapy. Both cognitive behavioural therapy (CBT) and medications (such as SSRIs) have been shown to be effective in reducing anxiety. A combination of both CBT and medication is generally seen as the most desirable approach to treatment. Use of medication to lower extreme anxiety levels can be important in enabling patients to engage effectively in CBT.

Psychotherapy

Psychotherapeutic interventions include a plurality of therapy types that vary based upon their specific methodologies for enabling individuals to gain insight into the working of the conscious and subconscious mind and which sometimes focus on the relationship between cognition and behaviour. Cognitive behavioural therapy (CBT) is widely regarded as the first-line psychological therapy for treating GAD. Additionally, many of these psychological interventions may be delivered in an individual or group therapy setting. While individual and group settings are broadly both considered effective for treating GAD, individual therapy tends to promote longer-lasting engagement in therapy (i.e. lower attrition over time).

Psychodynamic Therapy

Psychodynamic therapy is a type of therapy premised upon Freudian psychology in which a psychologist enables an individual explore various elements in their subconscious mind to resolve conflicts that may exist between the conscious and subconscious elements of the mind. In the context of GAD, the psychodynamic theory of anxiety suggests that the unconscious mind engages in worry as a defence mechanism to avoid feelings of anger or hostility because such feelings might cause social isolation or other negative attribution toward oneself. Accordingly, the various psychodynamic therapies attempt to explore the nature of worry as it functions in GAD in order to enable individuals to alter the subconscious practice of using worry as a defence mechanism and to thereby diminish GAD symptoms. Variations of psychotherapy include a near-term version of therapy, “short-term anxiety-provoking psychotherapy (STAPP).

Behavioural Therapy

Behavioural therapy is therapeutic intervention premised upon the concept that anxiety is learned through classical conditioning (e.g., in view of one or more negative experiences) and maintained through operant conditioning (e.g. one finds that by avoiding a feared experience that one avoids anxiety). Thus, behavioural therapy enables an individual to re-learn conditioned responses (behaviours) and to thereby challenge behaviours that have become conditioned responses to fear and anxiety, and which have previously given rise to further maladaptive behaviours.

Cognitive Therapy

Cognitive therapy (CT) is premised upon the idea that anxiety is the result of maladaptive beliefs and methods of thinking. Thus, CT involves assisting individuals to identify more rational ways of thinking and to replace maladaptive thinking patterns (i.e. cognitive distortions) with healthier thinking patterns (e.g. replacing the cognitive distortion of catastrophising with a more productive pattern of thinking). Individuals in CT learn how to identify objective evidence, test hypotheses, and ultimately identify maladaptive thinking patterns so that these patterns can be challenged and replaced.

Acceptance and Commitment Therapy

Acceptance and commitment therapy (ACT) is a behavioural treatment based on acceptance-based models. ACT is designed with the purpose to target three therapeutic goals:

  1. Reduce the use of avoiding strategies intended to avoid feelings, thoughts, memories, and sensations;
  2. Decreasing a person’s literal response to their thoughts (e.g., understanding that thinking “I’m hopeless” does not mean that the person’s life is truly hopeless); and
  3. Increasing the person’s ability to keep commitments to changing their behaviours.

These goals are attained by switching the person’s attempt to control events to working towards changing their behaviour and focusing on valued directions and goals in their lives as well as committing to behaviours that help the individual accomplish those personal goals. This psychological therapy teaches mindfulness (paying attention on purpose, in the present, and in a non-judgemental manner) and acceptance (openness and willingness to sustain contact) skills for responding to uncontrollable events and therefore manifesting behaviours that enact personal values. Like many other psychological therapies, ACT works best in combination with pharmacology treatments.

Intolerance of Uncertainty Therapy

Intolerance of uncertainty (IU) refers to a consistent negative reaction to uncertain and ambiguous events regardless of their likelihood of occurrence. Intolerance of uncertainty therapy (IUT) is used as a stand-alone treatment for GAD patients. Thus, IUT focuses on helping patients in developing the ability to tolerate, cope with and accept uncertainty in their life in order to reduce anxiety. IUT is based on the psychological components of psychoeducation, awareness of worry, problem-solving training, re-evaluation of the usefulness of worry, imagining virtual exposure, recognition of uncertainty, and behavioural exposure. Studies have shown support for the efficacy of this therapy with GAD patients with continued improvements in follow-up periods.

Motivational Interviewing

A promising innovative approach to improving recovery rates for the treatment of GAD is to combine CBT with motivational interviewing (MI). Motivational interviewing is a strategy centred on the patient that aims to increase intrinsic motivation and decrease ambivalence about change due to the treatment. MI contains four key elements:

  • Express empathy;
  • Heighten dissonance between behaviours that are not desired and values that are not consistent with those behaviours;
  • Move with resistance rather than direct confrontation; and
  • Encourage self-efficacy.

It is based on asking open-ended questions and listening carefully and reflectively to patients’ answers, eliciting “change talk”, and talking with patients about the pros and cons of change. Some studies have shown the combination of CBT with MI to be more effective than CBT alone.

Cognitive Behavioural Therapy

Cognitive behavioural therapy (CBT) is an evidence-based type of psychotherapy that demonstrates efficacy in treating GAD and which integrates the cognitive and behavioural therapeutic approaches. The objective of CBT is to enable individuals to identify irrational thoughts that cause anxiety and to challenge dysfunctional thinking patterns by engaging in awareness techniques such as hypothesis testing and journaling. Because CBT involves the practice of worry and anxiety management, CBT includes a plurality of intervention techniques that enable individuals to explore worry, anxiety and automatic negative thinking patterns. These interventions include anxiety management training, cognitive restructuring, progressive relaxation, situational exposure and self-controlled desensitisation.

Other forms of psychological therapy include:

  • Relaxation techniques (e.g. relaxing imagery, meditational relaxation).
  • Metacognitive Therapy (MCT):
    • The objective of MCT is to alter thinking patterns regarding worry so that worry is no longer used as a coping strategy.
  • Mindfulness based stress reduction (MBSR).
  • Mindfulness based cognitive therapy (MBCT).
  • Supportive therapy:
    • This is a Rogerian method of therapy in which subjects experience empathy and acceptance from their therapist to facilitate increasing awareness.
    • Variations of active supportive therapy include Gestalt therapy, Transactional analysis and Counselling.

Pharmacotherapy

Historically, benzodiazepines (BZs) were used prominently to treat anxiety starting in the 1970s but support for this use attenuated in view of the risk for dependence and tolerance to the medication. BZs can have a plurality of effects that made them a seemingly desirable option for treating anxiety – i.e. BZs have anxiolytic, hypnotic (induce sleep), myorelaxant (relax muscles), anticonvulsant and amnestic (impair short-term memory) properties. While BZs are well appreciated for their ability to alleviate anxiety (i.e. their anxiolytic properties) shortly after administration, they are also known for their ability to promote dependence and are frequently abused. Current recommendations for using BZs to treat anxiety in GAD allow no more than 2-4 weeks of BZ exposure. Antidepressants (e.g. SSRIs/SNRIs) have become a mainstay in treating GAD in adults. First-line mediations from any drug category often include drugs that have been approved by the US Food and Drug Administration (FDA) for treating GAD because these medications have been proven safe and effective for treating GAD.

FDA-Approved Medications for Treating GAD

FDA-approved medications for treating GAD include:

  • SSRIs:
    • Paroxetine.
    • Escitalopram.
  • SNRIs:
    • Venlafaxine.
    • Duloxetine.
  • Benzodiazepines (BZs):
    • Alprazolam: Alprazolam is the only FDA-approved BZ for treating GAD.
  • Azapirones:
    • Buspirone.

Non-FDA Approved Medications

While certain medications are not specifically FDA approved for treatment of GAD, there are a number of medications that historically have been used or studied for treating GAD. Other medications that have been used or evaluated for treating GAD include:

  • SSRIs (antidepressants):
    • Citalopram.
    • Fluoxetine.
    • Sertraline.
    • Fluvoxamine (SSRI).
  • Benzodiazepines:
    • Clonazepam.
    • Lorazepam.
    • Diazepam.
  • GABA analogs:
    • Pregabalin (atypical anxiolytic, GABA analog).
    • Tiagabine.
  • Second-generation antipsychotics (SGAs):
    • Olanzapine (evidence of effectiveness is merely a trend).
    • Ziprasidone.
    • Risperidone.
    • Aripiprazole (studied as an adjunctive measure in concert with other treatment).
    • Quetiapine (atypical antipsychotic studied as an adjunctive measure in adults and geriatric patients).
  • Antihistamines:
    • Hydroxyzine (H1 receptor antagonist).
  • Vilazodone (atypical antidepressant).
  • Agomelatine (antidepressant, MT1/2 receptor agonist, 5HT2c antagonist).
  • Clonidine (noted to cause decreased blood pressure and other AEs).
  • Guanfacine (a2A receptor agonist, studied in paediatric patients with GAD).
  • Mirtazapine (atypical antidepressant having 5HT2A and 5HT2c receptor affinity).
  • Vortioxetine (multimodal antidepressant).
  • Eszopiclone (non-benzodiazepine hypnotic).
  • Tricyclic antidepressants:
    • Amitriptyline.
    • Clomipramine.
    • Doxepin.
    • Imipramine.
    • Trimipramine.
    • Desipramine.
    • Nortriptyline.
    • Protriptyline.
  • Opipramol (atypical TCA).]
  • Trazodone.
  • Monamine oxidase inhibitors (MAOIs):
    • Tranylcypromine.
    • Phenelzine.
  • Homeopathic preparations (discussed below, see complementary and alternative medications (CAMs))

Selective Serotonin Reuptake Inhibitors

Pharmaceutical treatments for GAD include selective serotonin reuptake inhibitors (SSRIs).[50] SSRIs increase serotonin levels through inhibition of serotonin reuptake receptors.

FDA approved SSRIs used for this purpose include escitalopram and paroxetine. However, guidelines suggest using sertraline first due to its cost-effectiveness compared to other SSRIs used for GAD and a lower risk of withdrawal compared to SNRIs. If sertraline is found to be ineffective, then it is recommended to try another SSRI or SNRI.

Common side effects include nausea, sexual dysfunction, headache, diarrhoea, constipation, restlessness, increased risk of suicide in young adults and adolescents, among others. Sexual side effects, weight gain, and higher risk of withdrawal are more common in paroxetine than escitalopram and sertraline. In older populations or those taking concomitant medications that increase risk of bleeding, SSRIs may further increase the risk of bleeding. Overdose of an SSRI or concomitant use with another agent that causes increased levels of serotonin can result in serotonin syndrome, which can be life-threatening.

Serotonin Norepinephrine Reuptake Inhibitors

First line pharmaceutical treatments for GAD also include serotonin-norepinephrine reuptake inhibitors (SNRIs). These inhibit the reuptake of serotonin and noradrenaline to increase their levels in the CNS.

FDA approved SNRIs used for this purpose include duloxetine (Cymbalta) and venlafaxine (Effexor). While SNRIs have similar efficacy as SSRIs, many psychiatrists prefer to use SSRIs first in the treatment of GAD The slightly higher preference for SSRIs over SNRIs as a first choice for treatment of anxiety disorders may have been influenced by the observation of poorer tolerability of the SNRIs in comparison to SSRIs in systematic reviews of studies of depressed patients.

Side effects common to both SNRIs include anxiety, restlessness, nausea, weight loss, insomnia, dizziness, drowsiness, sweating, dry mouth, sexual dysfunction and weakness. In comparison to SSRIs, the SNRIs have a higher prevalence of the side effects of insomnia, dry mouth, nausea and high blood pressure. Both SNRIs have the potential for discontinuation syndrome after abrupt cessation, which can precipitate symptoms including motor disturbances and anxiety and may require tapering. Like other serotonergic agents, SNRIs have the potential to cause serotonin syndrome, a potentially fatal systemic response to serotonergic excess that causes symptoms including agitation, restlessness, confusion, tachycardia, hypertension, mydriasis, ataxia, myoclonus, muscle rigidity, diaphoresis, diarrhoea, headache, shivering, goose bumps, high fever, seizures, arrhythmia and unconsciousness. SNRIs like SSRIs carry a black box warning for suicidal ideation, but it is generally considered that the risk of suicide in untreated depression is far higher than the risk of suicide when depression is properly treated.

Pregabalin and Gabapentin

Pregabalin (Lyrica) acts on the voltage-dependent calcium channel to decrease the release of neurotransmitters such as glutamate, norepinephrine and substance P. Its therapeutic effect appears after 1 week of use and is similar in effectiveness to lorazepam, alprazolam and venlafaxine but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychic and somatic anxiety symptoms. Long-term trials have shown continued effectiveness without the development of tolerance and additionally, unlike benzodiazepines, it does not disrupt sleep architecture and produces less severe cognitive and psychomotor impairment. It also has a low potential for abuse and dependency and may be preferred over the benzodiazepines for these reasons. The anxiolytic effects of pregabalin appear to persist for at least six months continuous use, suggesting tolerance is less of a concern; this gives pregabalin an advantage over certain anxiolytic medications such as benzodiazepines.

Gabapentin (Neurontin), a closely related medication to pregabalin with the same mechanism of action, has also demonstrated effectiveness in the treatment of GAD, though unlike pregabalin, it has not been approved specifically for this indication. Nonetheless, it is likely to be of similar usefulness in the management of this condition, and by virtue of being off-patent, it has the advantage of being significantly less expensive in comparison. In accordance, gabapentin is frequently prescribed off-label to treat GAD.

Complementary and Alternative Medicines Studied for Potential in Treating GAD

Complementary and alternative medicines (CAMs) are widely used by individuals who suffer GAD despite having no evidence or varied evidence regarding efficacy. Efficacy trials for CAM medications often suffer from various types of bias and low quality reporting in regard to safety. In regard to efficacy, critics point out that CAM trials sometimes predicate claims of efficacy based on a comparison of a CAM against a known drug after which no difference in subjects is found by investigators and which is used to suggest an equivalence between a CAM and a drug. Because this equates a lack of evidence with the positive assertion of efficacy, a “lack of difference” assertion is not a proper claim for efficacy. Moreover, an absence of strict definitions and standards for CAM compounds further burdens the literature regarding CAM efficacy in treating GAD. CAMs academically studied for their potential in treating GAD or GAD symptoms along with a summary of academic findings are given below. What follows is a summary of academic findings. Accordingly, none of the following should be taken as offering medical guidance or an opinion as to the safety or efficacy of any of the following CAMs.

  • Kava Kava (Piper methysticum) extracts:
    • Meta analysis does not suggest efficacy of Kava Kava extracts due to few data available yielding inconclusive results or non-statistically significant results.
    • Nearly a quarter (25.8%) of subjects experienced adverse effects (AEs) from Kava Kava extracts during six (6) trials.
    • Kava Kava may cause liver toxicity.
  • Lavender (Lavandula angustifolia) extracts:
    • Small and varied studies may suggest some level of efficacy as compared to placebo or other medication; claims of efficacy are regarded as needing further evaluation.
    • Silexan is an oil derivative of Lavender studied in paediatric patients with GAD.
    • Concern exists regarding the question as to whether Silexan may cause unopposed oestrogen exposure in boys due to disruption of steroid signalling.
  • Galphimia glauca extracts:
    • While Galphima glauca extracts have been the subject of two (2) randomised controlled trials (RCTs) comparing Galphima glauca extracts to lorazepam, efficacy claims are regarded as “highly uncertain.”
  • Chamomile (Matricaria chamomilla) extracts:
    • Poor quality trials have trends that may suggest efficacy but further study is needed to establish any claim of efficacy.
  • Crataegus oxycantha and Eschscholtzia californica extracts combined with magnesium:
    • A single12-week trial of Crataegus oxycantha and Eschscholtzia californica compared to placebo has been used to suggest efficacy.
    • However, efficacy claims require confirmation studies.
    • For the minority of subjects who experienced AEs from extracts, most AEs implicated gastrointestinal tract (GIT) intolerance.
  • Echium amoneum extract:
    • A single, small trial used this extract as a supplement to fluoxetine (vs using a placebo to supplement fluoxetine); larger studies are needed to substantiate efficacy claims.
  • Gamisoyo-San:
    • Small trials of this herbal mixture compared to placebo have suggested no efficacy of the herbal mixture over placebo but further study is necessary to allow definitive conclusion of a lack of efficacy.
  • Passiflora incarnata extract:
    • Claims of efficacy or benzodiazepam equivalence are regarded as “highly uncertain.”
  • Valeriana extract:
    • A single 4-week trial suggests no effect of Valeriana extract on GAD but is regarded as “uninformative” on the topic of efficacy in view of its finding that the benzodiazepine diazepam also had no effect.
    • Further study may be warranted.

Other Possible Modalities Discussed in Literature for Potential in Treating GAD

Other modalities that have been academically studied for their potential in treating GAD or symptoms of GAD are summarised below. What follows is a summary of academic findings. Accordingly, none of the following should be taken as offering medical guidance or an opinion as to the safety or efficacy of any of the following modalities.

  • Acupuncture:
    • A single, very small trial revealed a trend toward efficacy but flaws in the trial design suggest uncertainty regarding efficacy.
  • Balneotherapy:
    • Data from a single non-blinded study suggested possible efficacy of balneotherapy as compared to paroxetine.
    • However, efficacy claims need confirmation.
  • Therapeutic massage:
    • A single, small, possibly biased study revealed inconclusive results.
  • Resistance and aerobic exercise:
    • When compared to no treatment, a single, small, potentially unrepresentative trial suggested a trend toward GAD remission and reduction of worry.
  • Chinese bloodletting:
    • When added to paroxetine, a single, small, imprecise trial that lacked a sham procedure for comparison suggested efficacy at 4-weeks.
    • However, larger trials are needed to evaluate this technique as compared to a sham procedure.
  • Floating in water:
    • When compared to no treatment, a single, imprecise, non-blinded trial suggested a trend toward efficacy (findings were statistically insignificant).
  • Swedish massage:
    • When compared to a sham procedure, a single trial showed a trend toward efficacy (i.e. findings were statistically insignificant).
  • Ayurvedic medications:
    • A single non-blinded trial was inconclusive as to whether Ayurvedic medications were effective in treating GAD.
  • Multi-faith spiritually-based intervention:
    • A single, small, non-blinded study was inconclusive regarding efficacy.

Lifestyle

Lifestyle factors including: stress management, stress reduction, relaxation, exercise, sleep hygiene, and caffeine and alcohol reduction can influence anxiety levels. Physical activity has shown to have a positive impact whereas low physical activity may be a risk factor for anxiety disorders.

Substances and Anxiety in GAD

While there are no substances that are known to cause GAD, certain substances or the withdrawal from certain substances have been implicated in promoting the experience of anxiety. For example, even while benzodiazepines may afford individuals with GAD relief from anxiety, withdrawal from benzodiazepines is associated with the experience of anxiety among other adverse events like sweating and tremor.

Tobacco withdrawal symptoms may provoke anxiety in smokers and excessive caffeine use has been linked to aggravating and maintaining anxiety.

Comorbidity

Depression

In the National Comorbidity Survey (2005), 58% of patients diagnosed with major depression were found to have an anxiety disorder; among these patients, the rate of comorbidity with GAD was 17.2%, and with panic disorder, 9.9%. Patients with a diagnosed anxiety disorder also had high rates of comorbid depression, including 22.4% of patients with social phobia, 9.4% with agoraphobia, and 2.3% with panic disorder. A longitudinal cohort study found 12% of the 972 participants had GAD comorbid with MDD. Accumulating evidence indicates that patients with comorbid depression and anxiety tend to have greater illness severity and a lower treatment response than those with either disorder alone. In addition, social function and quality of life are more greatly impaired.

For many, the symptoms of both depression and anxiety are not severe enough (i.e. are subsyndromal) to justify a primary diagnosis of either major depressive disorder (MDD) or an anxiety disorder. However, dysthymia is the most prevalent comorbid diagnosis of GAD clients. Patients can also be categorised as having mixed anxiety-depressive disorder, and they are at significantly increased risk of developing full-blown depression or anxiety.

Various explanations for the high comorbidity between GAD and depressive disorders have been suggested, including genetic pleiotropy, meaning that GAD and nonbipolar depression might represent different phenotypic expressions of a common aetiology.

Comorbidity and Treatment

Therapy has been shown to have equal efficacy in patients with GAD and patients with GAD and comorbid disorders. Patients with comorbid disorders have more severe symptoms when starting therapy but demonstrated a greater improvement than patients with simple GAD.

Pharmacological approaches i.e. the use of antidepressants must be adapted for different comorbidities. For example, serotonin reuptake inhibitors and short acting benzodiazepines (BZDs) are used for depression and anxiety. However, for patients with anxiety and substance abuse, BZDs should be avoided due to their abuse liability. CBT has been found an effective treatment since it improves symptoms of GAD and substance abuse.

Compared to the general population, patients with internalising disorders such as depression, GAD and post-traumatic stress disorder (PTSD) have higher mortality rates, but die of the same age-related diseases as the population, such as heart disease, cerebrovascular disease and cancer.

GAD often coexists with conditions associated with stress, such as muscle tension and irritable bowel syndrome.

Patients with GAD can sometimes present with symptoms such as insomnia or headaches as well as pain and interpersonal problems.

Further research suggests that about 20% to 40% of individuals with attention deficit hyperactivity disorder have comorbid anxiety disorders, with GAD being the most prevalent.

Those with GAD have a lifetime comorbidity prevalence of 30% to 35% with alcohol use disorder and 25% to 30% for another substance use disorder. People with both GAD and a substance use disorder also have a higher lifetime prevalence for other comorbidities. A study found that GAD was the primary disorder in slightly more than half of the 18 participants that were comorbid with alcohol use disorder.

Epidemiology

GAD is often estimated to affect approximately 3-6% of adults and 5% of children and adolescents. Although estimates have varied to suggest a GAD prevalence of 3% in children and 10.8% in adolescents. When GAD manifests in children and adolescents, it typically begins around 8 to 9 years of age.

Estimates regarding prevalence of GAD or lifetime risk (i.e. lifetime morbid risk (LMR)) for GAD vary depending upon which criteria are used for diagnosing GAD (e.g. DSM-5 vs ICD-10) although estimates do not vary widely between diagnostic criteria. In general, ICD-10 is more inclusive than DSM-5, so estimates regarding prevalence and lifetime risk tend to be greater using ICD-10. In regard to prevalence, in a given year, about two (2%) percent of adults in the United States and Europe have been suggested to suffer GAD. However, the risk of developing GAD at any point in life has been estimated at 9.0%. Although it is possible to experience a single episode of GAD during one’s life, most people who experience GAD experience it repeatedly over the course of their lives as a chronic or ongoing condition. GAD is diagnosed twice as frequently in women as in men and is more often diagnosed in those who are separated, divorced, unemployed, widowed or have low levels of education, and among those with low socioeconomic status. African Americans have higher odds of having GAD and the disorder often manifests itself in different patterns. It has been suggested that greater prevalence of GAD in women may be because women are more likely than men to live in poverty, are more frequently the subject of discrimination, and be sexually and physically abused more often than men. In regard to the first incidence of GAD in an individual’s life course, a first manifestation of GAD usually occurs between the late teenage years and the early twenties with the median age of onset being approximately 31 and mean age of onset being 32.7. However, GAD can begin or reoccur at any point in life. Indeed, GAD is common in the elderly population.

  • US: Approximately 3.1% of people age 18 and over in a given year (9.5 million).
  • UK: 5.9% of adults were affected by GAD in 2019.
  • Australia: 3% of adults
  • Canada: 2.5%.
  • Italy: 2.9%
  • Taiwan: 0.4%.

What is Major Depressive Disorder?

Introduction

Major depressive disorder (MDD), also known simply as depression, is a mental disorder characterised by at least two weeks of pervasive low mood. Low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause are common symptoms. Those affected may also occasionally have delusions or hallucinations. Some people have periods of depression separated by years, while others nearly always have symptoms present. Major depression is more severe and lasts longer than sadness, which is a normal part of life.

The diagnosis of MDD is based on the person’s reported experiences and a mental status examination. There is no laboratory test for the disorder, but testing may be done to rule out physical conditions that can cause similar symptoms. Those with MDD are typically treated with counselling and antidepressant medication. Medication appears to be effective, but the effect may only be significant in the most severely depressed. Types of counselling used include cognitive behavioural therapy (CBT) and interpersonal therapy, and electroconvulsive therapy (ECT) may be considered if other measures are not effective. Hospitalisation may be necessary in cases with a risk of harm to self and may occasionally occur against a person’s wishes.

The most common time of onset is in a person’s 20s and 30s, with females affected about twice as often as males. MDD affected approximately 163 million people (2% of the world’s population) in 2017. The percentage of people who are affected at one point in their life varies from 7% in Japan to 21% in France. Lifetime rates are higher in the developed world (15%) compared to the developing world (11%). The disorder causes the second-most years lived with disability, after lower back pain.

The term MDD was introduced by a group of US clinicians in the mid-1970s. The cause of MDD is believed to be a combination of genetic, environmental, and psychological factors, with about 40% of the risk related to genetics. Risk factors include a family history of the condition, major life changes, certain medications, chronic health problems, and substance abuse. It can negatively affect a person’s personal life, work life, or education as well as sleeping, eating habits, and general health. Those currently or previously affected with the disorder may be stigmatised.

Not to be confused with Depression (Mood).

Brief History

The Ancient Greek physician Hippocrates described a syndrome of melancholia as a distinct disease with particular mental and physical symptoms; he characterised all “fears and despondencies, if they last a long time” as being symptomatic of the ailment. It was a similar but far broader concept than today’s depression; prominence was given to a clustering of the symptoms of sadness, dejection, and despondency, and often fear, anger, delusions and obsessions were included.

The term depression itself was derived from the Latin verb deprimere, “to press down”. From the 14th century, “to depress” meant to subjugate or to bring down in spirits. It was used in 1665 in English author Richard Baker’s Chronicle to refer to someone having “a great depression of spirit”, and by English author Samuel Johnson in a similar sense in 1753. The term also came into use in physiology and economics. An early usage referring to a psychiatric symptom was by French psychiatrist Louis Delasiauve in 1856, and by the 1860s it was appearing in medical dictionaries to refer to a physiological and metaphorical lowering of emotional function. Since Aristotle, melancholia had been associated with men of learning and intellectual brilliance, a hazard of contemplation and creativity. The newer concept abandoned these associations and through the 19th century, became more associated with women.

Although melancholia remained the dominant diagnostic term, depression gained increasing currency in medical treatises and was a synonym by the end of the century; German psychiatrist Emil Kraepelin may have been the first to use it as the overarching term, referring to different kinds of melancholia as depressive states.

Sigmund Freud likened the state of melancholia to mourning in his 1917 paper Mourning and Melancholia. He theorized that objective loss, such as the loss of a valued relationship through death or a romantic break-up, results in subjective loss as well; the depressed individual has identified with the object of affection through an unconscious, narcissistic process called the libidinal cathexis of the ego. Such loss results in severe melancholic symptoms more profound than mourning; not only is the outside world viewed negatively but the ego itself is compromised. The patient’s decline of self-perception is revealed in his belief of his own blame, inferiority, and unworthiness. He also emphasized early life experiences as a predisposing factor. Adolf Meyer put forward a mixed social and biological framework emphasizing reactions in the context of an individual’s life, and argued that the term depression should be used instead of melancholia. The first version of the DSM (DSM-I, 1952) contained depressive reaction and the DSM-II (1968) depressive neurosis, defined as an excessive reaction to internal conflict or an identifiable event, and also included a depressive type of manic-depressive psychosis within Major affective disorders.

In the mid-20th century, researchers theorised that depression was caused by a chemical imbalance in neurotransmitters in the brain, a theory based on observations made in the 1950s of the effects of reserpine and isoniazid in altering monoamine neurotransmitter levels and affecting depressive symptoms. The chemical imbalance theory has never been proven.

The term unipolar (along with the related term bipolar) was coined by the neurologist and psychiatrist Karl Kleist, and subsequently used by his disciples Edda Neele and Karl Leonhard.

The term Major depressive disorder was introduced by a group of US clinicians in the mid-1970s as part of proposals for diagnostic criteria based on patterns of symptoms (called the “Research Diagnostic Criteria”, building on earlier Feighner Criteria), and was incorporated into the DSM-III in 1980. The American Psychiatric Association added “major depressive disorder” to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), as a split of the previous depressive neurosis in the DSM-II, which also encompassed the conditions now known as dysthymia and adjustment disorder with depressed mood. To maintain consistency the ICD-10 used the same criteria, with only minor alterations, but using the DSM diagnostic threshold to mark a mild depressive episode, adding higher threshold categories for moderate and severe episodes. The ancient idea of melancholia still survives in the notion of a melancholic subtype.

The new definitions of depression were widely accepted, albeit with some conflicting findings and views. There have been some continued empirically based arguments for a return to the diagnosis of melancholia. There has been some criticism of the expansion of coverage of the diagnosis, related to the development and promotion of antidepressants and the biological model since the late 1950s.

Epidemiology

MDD affected approximately 163 million people in 2017 (2% of the global population). The percentage of people who are affected at one point in their life varies from 7% in Japan to 21% in France. In most countries the number of people who have depression during their lives falls within an 8-18% range. In North America, the probability of having a major depressive episode within a year-long period is 3-5% for males and 8-10% for females. Major depression is about twice as common in women as in men, although it is unclear why this is so, and whether factors unaccounted for are contributing to this. The relative increase in occurrence is related to pubertal development rather than chronological age, reaches adult ratios between the ages of 15 and 18, and appears associated with psychosocial more than hormonal factors. As of 2017, depression is the third most common worldwide cause of disability among both sexes, following low back pain and headache.

People are most likely to develop their first depressive episode between the ages of 30 and 40, and there is a second, smaller peak of incidence between ages 50 and 60. The risk of major depression is increased with neurological conditions such as stroke, Parkinson’s disease, or multiple sclerosis, and during the first year after childbirth. It is also more common after cardiovascular illnesses, and is related more to those with a poor cardiac disease outcome than to a better one. Studies conflict on the prevalence of depression in the elderly, but most data suggest there is a reduction in this age group. Depressive disorders are more common in urban populations than in rural ones and the prevalence is increased in groups with poorer socioeconomic factors, e.g. homelessness.

Signs and Symptoms

Major depression significantly affects a person’s family and personal relationships, work or school life, sleeping and eating habits, and general health. Its impact on functioning and well-being has been compared to that of other chronic medical conditions, such as diabetes.

A person having a major depressive episode usually exhibits a low mood, which pervades all aspects of life, and an inability to experience pleasure in previously enjoyable activities. Depressed people may be preoccupied with – or ruminate over – thoughts and feelings of worthlessness, inappropriate guilt or regret, helplessness or hopelessness. In severe cases, depressed people may have symptoms of psychosis. These symptoms include delusions or, less commonly, hallucinations, usually unpleasant. Other symptoms of depression include poor concentration and memory (especially in those with melancholic or psychotic features), withdrawal from social situations and activities, reduced sex drive, irritability, and thoughts of death or suicide. Insomnia is common among the depressed. In the typical pattern, a person wakes very early and cannot get back to sleep. Hypersomnia, or oversleeping, can also happen. Some antidepressants may also cause insomnia due to their stimulating effect.

A depressed person may report multiple physical symptoms such as fatigue, headaches, or digestive problems; physical complaints are the most common presenting problem in developing countries, according to the World Health Organisation’s (WHO’s) criteria for depression. Appetite often decreases, with resulting weight loss, although increased appetite and weight gain occasionally occur. Family and friends may notice that the person’s behaviour is either agitated or lethargic. Older depressed people may have cognitive symptoms of recent onset, such as forgetfulness, and a more noticeable slowing of movements.

Depressed children may often display an irritable mood rather than a depressed one, and show varying symptoms depending on age and situation. Most lose interest in school and show a decline in academic performance. They may be described as clingy, demanding, dependent, or insecure. Diagnosis may be delayed or missed when symptoms are interpreted as “normal moodiness.”

Associated Conditions

Major depression frequently co-occurs with other psychiatric problems. The 1990-1992 National Comorbidity Survey (US) reports that half of those with major depression also have lifetime anxiety and its associated disorders such as generalised anxiety disorder. Anxiety symptoms can have a major impact on the course of a depressive illness, with delayed recovery, increased risk of relapse, greater disability and increased suicide attempts. There are increased rates of alcohol and drug abuse and particularly dependence, and around a third of individuals diagnosed with attention deficit hyperactivity disorder (ADHD) develop comorbid depression. Post-traumatic stress disorder and depression often co-occur. Depression may also coexist with ADHD, complicating the diagnosis and treatment of both. Depression is also frequently comorbid with alcohol abuse and personality disorders. Depression can also be exacerbated during particular months (usually winter) for those with seasonal affective disorder. While overuse of digital media has been associated with depressive symptoms, digital media may also be utilised in some situations to improve mood.

Depression and pain often co-occur. One or more pain symptoms are present in 65% of depressed patients, and anywhere from 5 to 85% of patients with pain will be suffering from depression, depending on the setting; there is a lower prevalence in general practice, and higher in specialty clinics. The diagnosis of depression is often delayed or missed, and the outcome can worsen if the depression is noticed but completely misunderstood.

Depression is also associated with a 1.5- to 2-fold increased risk of cardiovascular disease, independent of other known risk factors, and is itself linked directly or indirectly to risk factors such as smoking and obesity. People with major depression are less likely to follow medical recommendations for treating and preventing cardiovascular disorders, which further increases their risk of medical complications. In addition, cardiologists may not recognise underlying depression that complicates a cardiovascular problem under their care.

Depression often coexists with physical disorders common among the elderly, such as stroke, other cardiovascular diseases, Parkinson’s disease, and chronic obstructive pulmonary disease.

Cause(s)

The biopsychosocial model proposes that biological, psychological, and social factors all play a role in causing depression. The diathesis-stress model specifies that depression results when a pre-existing vulnerability, or diathesis, is activated by stressful life events. The pre-existing vulnerability can be either genetic, implying an interaction between nature and nurture, or schematic, resulting from views of the world learned in childhood.

Childhood abuse, either physical, sexual or psychological, are all risk factors for depression, among other psychiatric issues that co-occur such as anxiety and drug abuse. Childhood trauma also correlates with severity of depression, lack of response to treatment and length of illness. However, some are more susceptible to developing mental illness such as depression after trauma, and various genes have been suggested to control susceptibility.

Genetics

Family and twin studies find that nearly 40% of individual differences in risk for major depressive disorder can be explained by genetic factors. Like most psychiatric disorders, major depressive disorder is likely to be influenced by many individual genetic changes. In 2018, a genome-wide association study discovered 44 variants in the genome linked to risk for major depression. This was followed by a 2019 study that found 102 variants in the genome linked to depression.

The 5-HTTLPR, or serotonin transporter promoter gene’s short allele has been associated with increased risk of depression. However, since the 1990s, results have been inconsistent, with three recent reviews finding an effect and two finding none. Other genes that have been linked to a gene-environment interaction include CRHR1, FKBP5 and BDNF, the first two of which are related to the stress reaction of the HPA axis, and the latter of which is involved in neurogenesis. There is no conclusive effects of candidate gene on depression, either alone or in combination with life stress. Research focusing on specific candidate genes has been criticised for its tendency to generate false positive findings. There are also other efforts to examine interactions between life stress and polygenic risk for depression.

Other Health Problems

Depression may also come secondary to a chronic or terminal medical condition, such as HIV/AIDS or asthma, and may be labelled “secondary depression.” It is unknown whether the underlying diseases induce depression through effect on quality of life, of through shared aetiologies (such as degeneration of the basal ganglia in Parkinson’s disease or immune dysregulation in asthma). Depression may also be iatrogenic (the result of healthcare), such as drug-induced depression. Therapies associated with depression include interferons, beta-blockers, isotretinoin, contraceptives, cardiac agents, anticonvulsants, antimigraine drugs, antipsychotics, and hormonal agents such as gonadotropin-releasing hormone agonist. Drug abuse in early age is also associated with increased risk of developing depression later in life. Depression that occurs as a result of pregnancy is called postpartum depression, and is thought to be the result of hormonal changes associated with pregnancy. Seasonal affective disorder, a type of depression associated with seasonal changes in sunlight, is thought to be the result of decreased sunlight.

Pathophysiology

The pathophysiology of depression is not yet understood, but the current theories centre around monoaminergic systems, the circadian rhythm, immunological dysfunction, HPA axis dysfunction and structural or functional abnormalities of emotional circuits.

The monoamine theory, derived from the efficacy of monoaminergic drugs in treating depression, was the dominant theory until recently. The theory postulates that insufficient activity of monoamine neurotransmitters is the primary cause of depression. Evidence for the monoamine theory comes from multiple areas. Firstly, acute depletion of tryptophan, a necessary precursor of serotonin, a monoamine, can cause depression in those in remission or relatives of depressed patients; this suggests that decreased serotonergic neurotransmission is important in depression. Secondly, the correlation between depression risk and polymorphisms in the 5-HTTLPR gene, which codes for serotonin receptors, suggests a link. Third, decreased size of the locus coeruleus, decreased activity of tyrosine hydroxylase, increased density of alpha-2 adrenergic receptor, and evidence from rat models suggest decreased adrenergic neurotransmission in depression. Furthermore, decreased levels of homovanillic acid, altered response to dextroamphetamine, responses of depressive symptoms to dopamine receptor agonists, decreased dopamine receptor D1 binding in the striatum, and polymorphism of dopamine receptor genes implicate dopamine, another monoamine, in depression. Lastly, increased activity of monoamine oxidase, which degrades monoamines, has been associated with depression. However, this theory is inconsistent with the fact that serotonin depletion does not cause depression in healthy persons, the fact that antidepressants instantly increase levels of monoamines but take weeks to work, and the existence of atypical antidepressants which can be effective despite not targeting this pathway. One proposed explanation for the therapeutic lag, and further support for the deficiency of monoamines, is a desensitisation of self-inhibition in raphe nuclei by the increased serotonin mediated by antidepressants. However, disinhibition of the dorsal raphe has been proposed to occur as a result of decreased serotonergic activity in tryptophan depletion, resulting in a depressed state mediated by increased serotonin. Further countering the monoamine hypothesis is the fact that rats with lesions of the dorsal raphe are not more depressive than controls, the finding of increased jugular 5-HIAA in depressed patients that normalised with SSRI treatment, and the preference for carbohydrates in depressed patients. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.

Immune system abnormalities have been observed, including increased levels of cytokines involved in generating sickness behaviour (which shares overlap with depression). The effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine inhibitors in treating depression, and normalization of cytokine levels after successful treatment further suggest immune system abnormalities in depression.

HPA axis abnormalities have been suggested in depression given the association of CRHR1 with depression and the increased frequency of dexamethasone test non-suppression in depressed patients. However, this abnormality is not adequate as a diagnosis tool, because its sensitivity is only 44%. These stress-related abnormalities have been hypothesized to be the cause of hippocampal volume reductions seen in depressed patients. Furthermore, a meta-analysis yielded decreased dexamethasone suppression, and increased response to psychological stressors. Further abnormal results have been obscured with the cortisol awakening response, with increased response being associated with depression.

Theories unifying neuroimaging findings have been proposed. The first model proposed is the “Limbic Cortical Model”, which involves hyperactivity of the ventral paralimbic regions and hypoactivity of frontal regulatory regions in emotional processing. Another model, the “Corito-Striatal model”, suggests that abnormalities of the prefrontal cortex in regulating striatal and subcortical structures results in depression. Another model proposes hyperactivity of salience structures in identifying negative stimuli, and hypoactivity of cortical regulatory structures resulting in a negative emotional bias and depression, consistent with emotional bias studies.

Diagnosis

Clinical Assessment

A diagnostic assessment may be conducted by a suitably trained general practitioner, or by a psychiatrist or psychologist, who records the person’s current circumstances, biographical history, current symptoms, family history, and alcohol and drug use. The assessment also includes a mental state examination, which is an assessment of the person’s current mood and thought content, in particular the presence of themes of hopelessness or pessimism, self-harm or suicide, and an absence of positive thoughts or plans. Specialist mental health services are rare in rural areas, and thus diagnosis and management is left largely to primary-care clinicians. This issue is even more marked in developing countries. Rating scales are not used to diagnose depression, but they provide an indication of the severity of symptoms for a time period, so a person who scores above a given cut-off point can be more thoroughly evaluated for a depressive disorder diagnosis. Several rating scales are used for this purpose; these include the Hamilton Rating Scale for Depression, the Beck Depression Inventory[90] or the Suicide Behaviours Questionnaire-Revised.

Primary-care physicians and other non-psychiatrist physicians have more difficulty with under-recognition and undertreatment of depression compared to psychiatric physicians, in part because of the physical symptoms that often accompany depression, in addition to many potential patient, provider, and system barriers. A review found that non-psychiatrist physicians miss about two-thirds of cases, though this has improved somewhat in more recent studies.

Before diagnosing major depressive disorder, a doctor generally performs a medical examination and selected investigations to rule out other causes of symptoms. These include blood tests measuring TSH and thyroxine to exclude hypothyroidism; basic electrolytes and serum calcium to rule out a metabolic disturbance; and a full blood count including ESR to rule out a systemic infection or chronic disease. Adverse affective reactions to medications or alcohol misuse are often ruled out, as well. Testosterone levels may be evaluated to diagnose hypogonadism, a cause of depression in men. Vitamin D levels might be evaluated, as low levels of vitamin D have been associated with greater risk for depression.

Subjective cognitive complaints appear in older depressed people, but they can also be indicative of the onset of a dementing disorder, such as Alzheimer’s disease. Cognitive testing and brain imaging can help distinguish depression from dementia. A CT scan can exclude brain pathology in those with psychotic, rapid-onset or otherwise unusual symptoms. No biological tests confirm major depression. In general, investigations are not repeated for a subsequent episode unless there is a medical indication.

DSM and ICD Criteria

The most widely used criteria for diagnosing depressive conditions are found in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM) and the WHO’s International Statistical Classification of Diseases and Related Health Problems (ICD) which uses the name depressive episode for a single episode and recurrent depressive disorder for repeated episodes. The latter system is typically used in European countries, while the former is used in the US and many other non-European nations, and the authors of both have worked towards conforming one with the other.

Both DSM-5 and ICD-10 mark out typical (main) depressive symptoms. ICD-10 defines three typical depressive symptoms (depressed mood, anhedonia, and reduced energy), two of which should be present to determine the depressive disorder diagnosis. According to DSM-5, there are two main depressive symptoms- a depressed mood and loss of interest/pleasure in activities (anhedonia). These symptoms, as well as five out of the nine more specific symptoms listed, must frequently occur for more than two weeks (to the extent in which it impairs functioning) for the diagnosis.

MDD is classified as a mood disorder in DSM-5. The diagnosis hinges on the presence of single or recurrent major depressive episodes. Further qualifiers are used to classify both the episode itself and the course of the disorder. The category Unspecified Depressive Disorder is diagnosed if the depressive episode’s manifestation does not meet the criteria for a major depressive episode. The ICD-10 system does not use the term major depressive disorder but lists very similar criteria for the diagnosis of a depressive episode (mild, moderate or severe); the term recurrent may be added if there have been multiple episodes without mania.

Major Depressive Episode

A major depressive episode (MDE) is characterised by the presence of a severely depressed mood that persists for at least two weeks.

Episodes may be isolated or recurrent and are categorised as mild (few symptoms in excess of minimum criteria), moderate, or severe (marked impact on social or occupational functioning). An episode with psychotic features – commonly referred to as psychotic depression – is automatically rated as severe. If the patient has had an episode of mania or markedly elevated mood, a diagnosis of bipolar disorder is made instead. Depression without mania is sometimes referred to as unipolar because the mood remains at one emotional state or “pole”.

DSM-IV-TR excludes cases where the symptoms are a result of bereavement, although it is possible for normal bereavement to evolve into a depressive episode if the mood persists and the characteristic features of a MDE develop. The criteria were criticised because they do not take into account any other aspects of the personal and social context in which depression can occur. In addition, some studies have found little empirical support for the DSM-IV cut-off criteria, indicating they are a diagnostic convention imposed on a continuum of depressive symptoms of varying severity and duration. Bereavement is no longer an exclusion criterion in DSM-5, and it is now up to the clinician to distinguish between normal reactions to a loss and MDD. Excluded are a range of related diagnoses, including:

  • Dysthymia, which involves a chronic but milder mood disturbance;
  • Recurrent brief depression, consisting of briefer depressive episodes;
  • Minor depressive disorder, whereby only some symptoms of major depression are present; and
  • Adjustment disorder with depressed mood, which denotes low mood resulting from a psychological response to an identifiable event or stressor.

Three new depressive disorders were added to the DSM-5:

  • Disruptive mood dysregulation disorder, classified by significant childhood irritability and tantrums;
  • Premenstrual dysphoric disorder (PMDD), causing periods of anxiety, depression, or irritability in the week or two before a woman’s menstruation, and
  • Persistent depressive disorder.

Subtypes

The DSM-5 recognises six further subtypes of MDD, called specifiers, in addition to noting the length, severity and presence of psychotic features:

  • Melancholic depression:
    • This is characterised by a loss of pleasure in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early-morning waking, psychomotor retardation, excessive weight loss (not to be confused with anorexia nervosa), or excessive guilt.
  • Atypical depression:
    • This is characterised by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite (comfort eating), excessive sleep or sleepiness (hypersomnia), a sensation of heaviness in limbs known as leaden paralysis, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.
  • Catatonic depression:
    • This is a rare and severe form of major depression involving disturbances of motor behaviour and other symptoms.
    • Here, the person is mute and almost stuporous, and either remains immobile or exhibits purposeless or even bizarre movements.
    • Catatonic symptoms also occur in schizophrenia or in manic episodes, or may be caused by neuroleptic malignant syndrome.
  • Depression with anxious distress:
    • This was added into the DSM-V as a means to emphasize the common co-occurrence between depression or mania and anxiety, as well as the risk of suicide of depressed individuals with anxiety.
    • Specifying in such a way can also help with the prognosis of those diagnosed with a depressive or bipolar disorder.
  • Depression with peri-partum onset:
    • This refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth or while a woman is pregnant.
    • DSM-IV-TR used the classification “postpartum depression,” but this was changed in order to not exclude cases of depressed woman during pregnancy.
    • Depression with peripartum onset has an incidence rate of 10-15% among new mothers.
    • The DSM-V mandates that, in order to qualify as depression with peripartum onset, onset occur during pregnancy or within one month of delivery.
    • It has been said that postpartum depression can last as long as three months.
  • Seasonal affective disorder (SAD):
    • This is a form of depression in which depressive episodes come on in the autumn or winter, and resolve in spring.
    • The diagnosis is made if at least two episodes have occurred in colder months with none at other times, over a two-year period or longer.

Differential Diagnosis

Refer to Differential Diagnoses of Depression.

To confirm MDD as the most likely diagnosis, other potential diagnoses must be considered, including dysthymia, adjustment disorder with depressed mood, or bipolar disorder. Dysthymia is a chronic, milder mood disturbance in which a person reports a low mood almost daily over a span of at least two years. The symptoms are not as severe as those for major depression, although people with dysthymia are vulnerable to secondary episodes of major depression (sometimes referred to as double depression). Adjustment disorder with depressed mood is a mood disturbance appearing as a psychological response to an identifiable event or stressor, in which the resulting emotional or behavioural symptoms are significant but do not meet the criteria for a MDE. Bipolar disorder, also known as manic–depressive disorder, is a condition in which depressive phases alternate with periods of mania or hypomania. Although depression is currently categorised as a separate disorder, there is ongoing debate because individuals diagnosed with major depression often experience some hypomanic symptoms, indicating a mood disorder continuum. Further differential diagnoses involve chronic fatigue syndrome.

Other disorders need to be ruled out before diagnosing major depressive disorder. They include depressions due to physical illness, medications, and substance abuse. Depression due to physical illness is diagnosed as a mood disorder due to a general medical condition. This condition is determined based on history, laboratory findings, or physical examination. When the depression is caused by a medication, drug of abuse, or exposure to a toxin, it is then diagnosed as a specific mood disorder (previously called substance-induced mood disorder in the DSM-IV-TR).

Screening and Prevention

Since 2016, the United States Preventive Services Task Force (USPSTF) has recommended screening for depression among those over the age 12; a 2005 Cochrane review found that the routine use of screening questionnaires has little effect on detection or treatment.

Preventive efforts may result in decreases in rates of the condition of between 22 and 38%. Eating large amounts of fish may also reduce the risk.

Behavioural interventions, such as interpersonal therapy and cognitive-behavioural therapy, are effective at preventing new onset depression. Because such interventions appear to be most effective when delivered to individuals or small groups, it has been suggested that they may be able to reach their large target audience most efficiently through the Internet.

However, an earlier meta-analysis found preventive programmes with a competence-enhancing component to be superior to behaviour-oriented programmes overall, and found behavioural programmes to be particularly unhelpful for older people, for whom social support programmes were uniquely beneficial. In addition, the programs that best prevented depression comprised more than eight sessions, each lasting between 60 and 90 minutes, were provided by a combination of lay and professional workers, had a high-quality research design, reported attrition rates, and had a well-defined intervention.

The Netherlands mental health care system provides preventive interventions, such as the “Coping with Depression” course (CWD) for people with sub-threshold depression. The course is claimed to be the most successful of psychoeducational interventions for the treatment and prevention of depression (both for its adaptability to various populations and its results), with a risk reduction of 38% in major depression and an efficacy as a treatment comparing favourably to other psychotherapies.

Management

The three most common treatments for depression are psychotherapy, medication, and electroconvulsive therapy. Psychotherapy is the treatment of choice (over medication) for people under 18. The UK National Institute for Health and Care Excellence (NICE) 2004 guidelines indicate that antidepressants should not be used for the initial treatment of mild depression because the risk-benefit ratio is poor. The guidelines recommend that antidepressants treatment in combination with psychosocial interventions should be considered for:

  • People with a history of moderate or severe depression.
  • Those with mild depression that has been present for a long period.
  • As a second line treatment for mild depression that persists after other interventions.
  • As a first line treatment for moderate or severe depression.

The guidelines further note that antidepressant treatment should be continued for at least six months to reduce the risk of relapse, and that SSRIs are better tolerated than tricyclic antidepressants.

American Psychiatric Association treatment guidelines recommend that initial treatment should be individually tailored based on factors including severity of symptoms, co-existing disorders, prior treatment experience, and patient preference. Options may include pharmacotherapy, psychotherapy, exercise, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or light therapy. Antidepressant medication is recommended as an initial treatment choice in people with mild, moderate, or severe major depression, and should be given to all patients with severe depression unless ECT is planned. There is evidence that collaborative care by a team of health care practitioners produces better results than routine single-practitioner care.

Treatment options are much more limited in developing countries, where access to mental health staff, medication, and psychotherapy is often difficult. Development of mental health services is minimal in many countries; depression is viewed as a phenomenon of the developed world despite evidence to the contrary, and not as an inherently life-threatening condition. A 2014 Cochrane review found insufficient evidence to determine the effectiveness of psychological versus medical therapy in children.

Lifestyle

Physical exercise is recommended for management of mild depression, and has a moderate effect on symptoms. Exercise has also been found to be effective for (unipolar) major depression. It is equivalent to the use of medications or psychological therapies in most people. In older people it does appear to decrease depression. Exercise may be recommended to people who are willing, motivated, and physically healthy enough to participate in an exercise programme as treatment.

There is a small amount of evidence that skipping a night’s sleep may improve depressive symptoms, with the effects usually showing up within a day. This effect is usually temporary. Besides sleepiness, this method can cause a side effect of mania or hypomania.

In observational studies, smoking cessation has benefits in depression as large as or larger than those of medications.

Besides exercise, sleep and diet may play a role in depression, and interventions in these areas may be an effective add-on to conventional methods.

Talking Therapies

Talking therapy (psychotherapy) can be delivered to individuals, groups, or families by mental health professionals. A 2017 review found that cognitive behavioural therapy appears to be similar to antidepressant medication in terms of effect. A 2012 review found psychotherapy to be better than no treatment but not other treatments. With more complex and chronic forms of depression, a combination of medication and psychotherapy may be used. There is moderate-quality evidence that psychological therapies are a useful addition to standard antidepressant treatment of treatment-resistant depression in the short term.

Psychotherapy has been shown to be effective in older people. Successful psychotherapy appears to reduce the recurrence of depression even after it has been stopped or replaced by occasional booster sessions.

Cognitive Behavioural Therapy

Cognitive behavioural therapy (CBT) currently has the most research evidence for the treatment of depression in children and adolescents, and CBT and interpersonal psychotherapy (IPT) are preferred therapies for adolescent depression. In people under 18, according to the National Institute for Health and Clinical Excellence, medication should be offered only in conjunction with a psychological therapy, such as CBT, interpersonal therapy, or family therapy. CBT has also been shown to reduce the number of sick days taken by people with depression, when used in conjunction with primary care.

The most-studied form of psychotherapy for depression is CBT, which teaches clients to challenge self-defeating, but enduring ways of thinking (cognitions) and change counter-productive behaviours. Research beginning in the mid-1990s suggested that CBT could perform as well as or better than antidepressants in patients with moderate to severe depression. CBT may be effective in depressed adolescents, although its effects on severe episodes are not definitively known. Several variables predict success for cognitive behavioural therapy in adolescents: higher levels of rational thoughts, less hopelessness, fewer negative thoughts, and fewer cognitive distortions. CBT is particularly beneficial in preventing relapse.

CBT and occupational programmes (including modification of work activities and assistance) have been shown to be effective in reducing sick days taken by workers with depression.

Variants

Several variants of CBT have been used in those with depression, the most notable being rational emotive behaviour therapy (REBT), and mindfulness-based cognitive therapy. Mindfulness-based stress reduction programmes may reduce depression symptoms. Mindfulness programmes also appear to be a promising intervention in youth.

Psychoanalysis

Psychoanalysis is a school of thought, founded by Sigmund Freud, which emphasizes the resolution of unconscious mental conflicts. Psychoanalytic techniques are used by some practitioners to treat clients presenting with major depression. A more widely practiced therapy, called psychodynamic psychotherapy, is in the tradition of psychoanalysis but less intensive, meeting once or twice a week. It also tends to focus more on the person’s immediate problems, and has an additional social and interpersonal focus. In a meta-analysis of three controlled trials of Short Psychodynamic Supportive Psychotherapy, this modification was found to be as effective as medication for mild to moderate depression.

Antidepressants

Conflicting results have arisen from studies that look at the effectiveness of antidepressants in people with acute, mild to moderate depression. Stronger evidence supports the usefulness of antidepressants in the treatment of depression that is chronic (dysthymia) or severe.

While small benefits were found, researchers Irving Kirsch and Thomas Moore state they may be due to issues with the trials rather than a true effect of the medication. In a later publication, Kirsch concluded that the overall effect of new-generation antidepressant medication is below recommended criteria for clinical significance. Similar results were obtained in a meta-analysis by Fornier.

A review commissioned by the National Institute for Health and Care Excellence (UK) concluded that there is strong evidence that selective serotonin reuptake inhibitors (SSRIs), such as escitalopram, paroxetine, and sertraline, have greater efficacy than placebo on achieving a 50% reduction in depression scores in moderate and severe major depression, and that there is some evidence for a similar effect in mild depression. Similarly, a Cochrane systematic review of clinical trials of the generic tricyclic antidepressant amitriptyline concluded that there is strong evidence that its efficacy is superior to placebo.

A 2019 Cochrane review on the combined use of antidepressants plus benzodiazepines demonstrated improved effectiveness when compared to antidepressants alone; however, these effects were not maintained in the acute or continuous phase. The benefits of adding a benzodiazepine should be balanced against possible harms and other alternative treatment strategies when antidepressant mono-therapy is considered inadequate.

In 2014, the US Food and Drug Administration published a systematic review of all antidepressant maintenance trials submitted to the agency between 1985 and 2012. The authors concluded that maintenance treatment reduced the risk of relapse by 52% compared to placebo, and that this effect was primarily due to recurrent depression in the placebo group rather than a drug withdrawal effect.

To find the most effective antidepressant medication with minimal side-effects, the dosages can be adjusted, and if necessary, combinations of different classes of antidepressants can be tried. Response rates to the first antidepressant administered range from 50 to 75%, and it can take at least six to eight weeks from the start of medication to improvement. Antidepressant medication treatment is usually continued for 16 to 20 weeks after remission, to minimise the chance of recurrence, and even up to one year of continuation is recommended. People with chronic depression may need to take medication indefinitely to avoid relapse.

SSRIs are the primary medications prescribed, owing to their relatively mild side-effects, and because they are less toxic in overdose than other antidepressants. People who do not respond to one SSRI can be switched to another antidepressant, and this results in improvement in almost 50% of cases. Another option is to switch to the atypical antidepressant bupropion. Venlafaxine, an antidepressant with a different mechanism of action, may be modestly more effective than SSRIs. However, venlafaxine is not recommended in the UK as a first-line treatment because of evidence suggesting its risks may outweigh benefits, and it is specifically discouraged in children and adolescents.

For children, some research has supported the use of the SSRI antidepressant fluoxetine. The benefit however appears to be slight in children, while other antidepressants have not been shown to be effective. Medications are not recommended in children with mild disease. There is also insufficient evidence to determine effectiveness in those with depression complicated by dementia. Any antidepressant can cause low blood sodium levels; nevertheless, it has been reported more often with SSRIs. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating atypical antidepressant mirtazapine can be used in such cases.

Irreversible monoamine oxidase inhibitors, an older class of antidepressants, have been plagued by potentially life-threatening dietary and drug interactions. They are still used only rarely, although newer and better-tolerated agents of this class have been developed. The safety profile is different with reversible monoamine oxidase inhibitors, such as moclobemide, where the risk of serious dietary interactions is negligible and dietary restrictions are less strict.

It is unclear whether antidepressants affect a person’s risk of suicide. For children, adolescents, and probably young adults between 18 and 24 years old, there is a higher risk of both suicidal ideations and suicidal behaviour in those treated with SSRIs. For adults, it is unclear whether SSRIs affect the risk of suicidality. One review found no connection; another an increased risk; and a third no risk in those 25-65 years old and a decreased risk in those more than 65. A black box warning was introduced in the United States in 2007 on SSRIs and other antidepressant medications due to the increased risk of suicide in patients younger than 24 years old. Similar precautionary notice revisions were implemented by the Japanese Ministry of Health.

Other Medications

There is some evidence that omega-3 fatty acids fish oil supplements containing high levels of eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) are effective in the treatment of, but not the prevention of major depression. However, a Cochrane review determined there was insufficient high quality evidence to suggest omega-3 fatty acids were effective in depression. There is limited evidence that vitamin D supplementation is of value in alleviating the symptoms of depression in individuals who are vitamin D-deficient. There is some preliminary evidence that COX-2 inhibitors, such as celecoxib, have a beneficial effect on major depression. Lithium appears effective at lowering the risk of suicide in those with bipolar disorder and unipolar depression to nearly the same levels as the general population. There is a narrow range of effective and safe dosages of lithium thus close monitoring may be needed. Low-dose thyroid hormone may be added to existing antidepressants to treat persistent depression symptoms in people who have tried multiple courses of medication. Limited evidence suggests stimulants, such as amphetamine and modafinil, may be effective in the short term, or as adjuvant therapy. Also, it is suggested that folate supplements may have a role in depression management. There is tentative evidence for benefit from testosterone in males.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is a standard psychiatric treatment in which seizures are electrically induced in patients to provide relief from psychiatric illnesses. ECT is used with informed consent as a last line of intervention for major depressive disorder.

A round of ECT is effective for about 50% of people with treatment-resistant major depressive disorder, whether it is unipolar or bipolar. Follow-up treatment is still poorly studied, but about half of people who respond relapse within twelve months.

Aside from effects in the brain, the general physical risks of ECT are similar to those of brief general anaesthesia. Immediately following treatment, the most common adverse effects are confusion and memory loss. ECT is considered one of the least harmful treatment options available for severely depressed pregnant women.

A usual course of ECT involves multiple administrations, typically given two or three times per week, until the patient is no longer suffering symptoms. ECT is administered under anaesthesia with a muscle relaxant. Electroconvulsive therapy can differ in its application in three ways: electrode placement, frequency of treatments, and the electrical waveform of the stimulus. These three forms of application have significant differences in both adverse side effects and symptom remission. After treatment, drug therapy is usually continued, and some patients receive maintenance ECT.

ECT appears to work in the short term via an anticonvulsant effect mostly in the frontal lobes, and longer term via neurotrophic effects primarily in the medial temporal lobe.

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) or deep transcranial magnetic stimulation is a non-invasive method used to stimulate small regions of the brain. TMS was approved by the FDA for treatment-resistant major depressive disorder (trMDD) in 2008 and as of 2014 evidence supports that it is probably effective. The American Psychiatric Association the Canadian Network for Mood and Anxiety Disorders, and the Royal Australia and New Zealand College of Psychiatrists have endorsed TMS for trMDD.

Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is another non-invasive method used to stimulate small regions of the brain with the help of a weak electric current. Increasing evidence has been gathered for its efficiency as a depression treatment. A meta-analysis was published in 2020 summarising results across nine studies (572 participants) concluded that active tDCS was significantly superior to sham for response (30.9% vs. 18.9%, respectively), remission (19.9% vs. 11.7%) and depression improvement. According to a 2016 meta analysis, 34% of tDCS-treated patients showed at least 50% symptom reduction compared to 19% sham-treated across 6 randomised controlled trials.

Light Therapy

Bright light therapy reduces depression symptom severity, with benefit for both seasonal affective disorder and for non-seasonal depression, and an effect similar to those for conventional antidepressants. For non-seasonal depression, adding light therapy to the standard antidepressant treatment was not effective. For non-seasonal depression, where light was used mostly in combination with antidepressants or wake therapy, a moderate effect was found, with response better than control treatment in high-quality studies, in studies that applied morning light treatment, and with people who respond to total or partial sleep deprivation. Both analyses noted poor quality, short duration, and small size of most of the reviewed studies.

Other

There is insufficient evidence for Reiki and dance movement therapy in depression.

As of 2019 cannabis is specifically not recommended as a treatment.

Prognosis

Major depressive episodes often resolve over time whether or not they are treated. Outpatients on a waiting list show a 10-15% reduction in symptoms within a few months, with approximately 20% no longer meeting the full criteria for a depressive disorder. The median duration of an episode has been estimated to be 23 weeks, with the highest rate of recovery in the first three months.

Studies have shown that 80% of those suffering from their first major depressive episode will have at least one more depression during their life, with a lifetime average of 4 episodes. Other general population studies indicate that around half those who have an episode recover (whether treated or not) and remain well, while the other half will have at least one more, and around 15% of those experience chronic recurrence. Studies recruiting from selective inpatient sources suggest lower recovery and higher chronicity, while studies of mostly outpatients show that nearly all recover, with a median episode duration of 11 months. Around 90% of those with severe or psychotic depression, most of whom also meet criteria for other mental disorders, experience recurrence.

A high proportion of people who experience full symptomatic remission still have at least one not fully resolved symptom after treatment. Recurrence or chronicity is more likely if symptoms have not fully resolved with treatment. Current guidelines recommend continuing antidepressants for four to six months after remission to prevent relapse. Evidence from many randomised controlled trials indicate continuing antidepressant medications after recovery can reduce the chance of relapse by 70% (41% on placebo vs. 18% on antidepressant). The preventive effect probably lasts for at least the first 36 months of use.

People experiencing repeated episodes of depression require ongoing treatment in order to prevent more severe, long-term depression. In some cases, people must take medications for the rest of their lives.

Cases when outcome is poor are associated with inappropriate treatment, severe initial symptoms including psychosis, early age of onset, previous episodes, incomplete recovery after one year of treatment, pre-existing severe mental or medical disorder, and family dysfunction.

Depressed individuals have a shorter life expectancy than those without depression, in part because depressed patients are at risk of dying of suicide. They also have a higher rate of dying from other causes, being more susceptible to medical conditions such as heart disease. Up to 60% of people who die of suicide have a mood disorder such as major depression, and the risk is especially high if a person has a marked sense of hopelessness or has both depression and borderline personality disorder. About 2-8% of adults with major depression die by suicide, and about 50% of people who die by suicide had depression or another mood disorder. The lifetime risk of suicide associated with a diagnosis of major depression in the US is estimated at 3.4%, which averages two highly disparate figures of almost 7% for men and 1% for women (although suicide attempts are more frequent in women). The estimate is substantially lower than a previously accepted figure of 15%, which had been derived from older studies of hospitalised patients.

Major depression is currently the leading cause of disease burden in North America and other high-income countries, and the fourth-leading cause worldwide. In the year 2030, it is predicted to be the second-leading cause of disease burden worldwide after HIV, according to the WHO. Delay or failure in seeking treatment after relapse and the failure of health professionals to provide treatment are two barriers to reducing disability.

Depression may affect people’s ability to work. The combination of usual clinical care and support with return to work (like working less hours or changing tasks) probably reduces sick leave by 15%, and leads to fewer depressive symptoms and improved work capacity, reducing sick leave by an annual average of 25 days per year. Helping depressed people return to work without a connection to clinical care has not been shown to have an effect on sick leave days. Additional psychological interventions (such as online CBT) leads to fewer sick days compared to standard management only. Streamlining care or adding specific providers for depression care may help to reduce sick leave.

Society and Culture

Terminology

The term “depression” is used in a number of different ways. It is often used to mean this syndrome but may refer to other mood disorders or simply to a low mood. People’s conceptualisations of depression vary widely, both within and among cultures. “Because of the lack of scientific certainty,” one commentator has observed, “the debate over depression turns on questions of language. What we call it – ‘disease,’ ‘disorder,’ ‘state of mind’ – affects how we view, diagnose, and treat it.” There are cultural differences in the extent to which serious depression is considered an illness requiring personal professional treatment, or is an indicator of something else, such as the need to address social or moral problems, the result of biological imbalances, or a reflection of individual differences in the understanding of distress that may reinforce feelings of powerlessness, and emotional struggle.

The diagnosis is less common in some countries, such as China. It has been argued that the Chinese traditionally deny or somatise emotional depression (although since the early 1980s, the Chinese denial of depression may have modified). Alternatively, it may be that Western cultures reframe and elevate some expressions of human distress to disorder status. Australian professor Gordon Parker and others have argued that the Western concept of depression “medicalises” sadness or misery. Similarly, Hungarian-American psychiatrist Thomas Szasz and others argue that depression is a metaphorical illness that is inappropriately regarded as an actual disease. There has also been concern that the DSM, as well as the field of descriptive psychiatry that employs it, tends to reify abstract phenomena such as depression, which may in fact be social constructs. American archetypal psychologist James Hillman writes that depression can be healthy for the soul, insofar as “it brings refuge, limitation, focus, gravity, weight, and humble powerlessness.” Hillman argues that therapeutic attempts to eliminate depression echo the Christian theme of resurrection, but have the unfortunate effect of demonising a soulful state of being.

Stigma

Historical figures were often reluctant to discuss or seek treatment for depression due to social stigma about the condition, or due to ignorance of diagnosis or treatments. Nevertheless, analysis or interpretation of letters, journals, artwork, writings, or statements of family and friends of some historical personalities has led to the presumption that they may have had some form of depression. People who may have had depression include English author Mary Shelley, American-British writer Henry James, and American president Abraham Lincoln. Some well-known contemporary people with possible depression include Canadian songwriter Leonard Cohen and American playwright and novelist Tennessee Williams. Some pioneering psychologists, such as Americans William James and John B. Watson, dealt with their own depression.

There has been a continuing discussion of whether neurological disorders and mood disorders may be linked to creativity, a discussion that goes back to Aristotelian times. British literature gives many examples of reflections on depression. English philosopher John Stuart Mill experienced a several-months-long period of what he called “a dull state of nerves”, when one is “unsusceptible to enjoyment or pleasurable excitement; one of those moods when what is pleasure at other times, becomes insipid or indifferent”. He quoted English poet Samuel Taylor Coleridge’s “Dejection” as a perfect description of his case: “A grief without a pang, void, dark and drear, / A drowsy, stifled, unimpassioned grief, / Which finds no natural outlet or relief / In word, or sigh, or tear.” English writer Samuel Johnson used the term “the black dog” in the 1780s to describe his own depression, and it was subsequently popularised by depression sufferer former British Prime Minister Sir Winston Churchill.

Social stigma of major depression is widespread, and contact with mental health services reduces this only slightly. Public opinions on treatment differ markedly to those of health professionals; alternative treatments are held to be more helpful than pharmacological ones, which are viewed poorly. In the UK, the Royal College of Psychiatrists and the Royal College of General Practitioners conducted a joint Five-year Defeat Depression campaign to educate and reduce stigma from 1992 to 1996; a MORI study conducted afterwards showed a small positive change in public attitudes to depression and treatment.

Elderly

Depression is especially common among those over 65 years of age and increases in frequency beyond this age. In addition, the risk of depression increases in relation to the frailty of the individual. Depression is one of the most important factors which negatively impact quality of life in adults, as well as the elderly. Both symptoms and treatment among the elderly differ from those of the rest of the population.

As with many other diseases, it is common among the elderly not to present with classical depressive symptoms. Diagnosis and treatment is further complicated in that the elderly are often simultaneously treated with a number of other drugs, and often have other concurrent diseases. Treatment differs in that studies of SSRIs have shown lesser and often inadequate effects among the elderly, while other drugs, such as duloxetine (a serotonin-norepinephrine reuptake inhibitor), with more clear effects have adverse effects, such as dizziness, dryness of the mouth, diarrhoea and constipation, which can be especially difficult to handle among the elderly.

Problem solving therapy was, as of 2015, the only psychological therapy with proven effect, and can be likened to a simpler form of CBT. However, elderly with depression are seldom offered any psychological treatment, and the evidence proving other treatments effective is incomplete. ECT has been used in the elderly, and register-studies suggest it is effective, although less so as compared to the rest of the population. The risks involved with treatment of depression among the elderly as opposed to benefits are not entirely clear.

Research

MRI scans of patients with depression have revealed a number of differences in brain structure compared to those who are not depressed. Meta-analyses of neuroimaging studies in major depression reported that, compared to controls, depressed patients had increased volume of the lateral ventricles and adrenal gland and smaller volumes of the basal ganglia, thalamus, hippocampus, and frontal lobe (including the orbitofrontal cortex and gyrus rectus). Hyperintensities have been associated with patients with a late age of onset, and have led to the development of the theory of vascular depression.

Trials are looking at the effects of botulinum toxins on depression. The idea is that the drug is used to make the person look less frowning and that this stops the negative facial feedback from the face. In 2015 results showed, however, that the partly positive effects that had been observed until then could have been due to placebo effects.

In 2018-2019, the US Food and Drug Administration (FDA) granted Breakthrough therapy designation to Compass Pathways and, separately, Usona Institute. Compass is a for-profit company studying psilocybin for treatment-resistant depression; Usona is a non-profit organisation studying psilocybin for major depressive disorder more broadly.

Animals Models

Models of depression in animals for the purpose of study include iatrogenic depression models (such as drug-induced), forced swim tests, tail suspension test, and learned helplessness models. Criteria frequently used to assess depression in animals include expression of despair, neurovegetative changes, and anhedonia, as many other criteria for depression are untestable in animals, such as guilt and suicidality.

What is Mood Disorder?

Introduction

Mood disorder, also known as mood affective disorders, is a group of conditions where a disturbance in the person’s mood is the main underlying feature. The classification is in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD).

Mood disorders fall into the basic groups of elevated mood, such as mania or hypomania; depressed mood, of which the best-known and most researched is major depressive disorder (MDD) (commonly called clinical depression, unipolar depression, or major depression); and moods which cycle between mania and depression, known as bipolar disorder (BD) (formerly known as manic depression). There are several sub-types of depressive disorders or psychiatric syndromes featuring less severe symptoms such as dysthymic disorder (similar to but milder than MDD) and cyclothymic disorder (similar to but milder than BD). Mood disorders may also be substance induced or occur in response to a medical condition.

English psychiatrist Henry Maudsley proposed an overarching category of affective disorder. The term was then replaced by mood-disorder, as the latter term refers to the underlying or longitudinal emotional state, whereas the former refers to the external expression observed by others.

Refer to Depression (Mood).

Epidemiology

According to a substantial amount of epidemiology studies conducted, women are twice as likely to develop certain mood disorders, such as major depression. Although there is an equal number of men and women diagnosed with bipolar II disorder, women have a slightly higher frequency of the disorder.

The prevalence of depressive symptoms has increased over the years with recent generations reporting a 6% increase in symptoms of depression compared to individuals from older generations.

In 2011, mood disorders were the most common reason for hospitalization among children aged 1-17 years in the United States, with approximately 112,000 stays. Mood disorders were top principal diagnosis for Medicaid super-utilisers in the United States in 2012. Further, a study of 18 States found that mood disorders accounted for the highest number of hospital readmissions among Medicaid patients and the uninsured, with 41,600 Medicaid patients and 12,200 uninsured patients being readmitted within 30 days of their index stay – a readmission rate of 19.8 per 100 admissions and 12.7 per 100 admissions, respectively. In 2012, mood and other behavioural health disorders were the most common diagnoses for Medicaid-covered and uninsured hospital stays in the United States (6.1% of Medicaid stays and 5.2% of uninsured stays).

A study conducted in 1988 to 1994 amongst young American adults involved a selection of demographic and health characteristics. A population-based sample of 8,602 men and women ages 17-39 years participated. Lifetime prevalence were estimated based on six mood measures:

  • Major depressive episode (MDE) 8.6%.
  • Major depressive disorder with severity (MDE-s) 7.7%.
  • Dysthymia 6.2%.
  • MDE-s with dysthymia 3.4%.
  • Any bipolar disorder 1.6%.
  • Any mood disorder 11.5%.

Classification

Depressive Disorders

  • Major depressive disorder (MDD):
    • Commonly called major depression, unipolar depression, or clinical depression, wherein a person has one or more major depressive episodes.
    • After a single episode, Major Depressive Disorder (single episode) would be diagnosed.
    • After more than one episode, the diagnosis becomes Major Depressive Disorder (Recurrent).
    • Depression without periods of mania is sometimes referred to as unipolar depression because the mood remains at the bottom “pole” and does not climb to the higher, manic “pole” as in bipolar disorder.
  • Individuals with a major depressive episode or major depressive disorder are at increased risk for suicide.
  • Seeking help and treatment from a health professional dramatically reduces the individual’s risk for suicide.
  • Studies have demonstrated that asking if a depressed friend or family member has thought of committing suicide is an effective way of identifying those at risk, and it does not “plant” the idea or increase an individual’s risk for suicide in any way.
  • Epidemiological studies carried out in Europe suggest that, at this moment, roughly 8.5% of the world’s population have a depressive disorder. No age group seems to be exempt from depression, and studies have found that depression appears in infants as young as 6 months old who have been separated from their mothers.
  • Depressive disorder is frequent in primary care and general hospital practice but is often undetected.
  • Unrecognised depressive disorder may slow recovery and worsen prognosis in physical illness, therefore it is important that all doctors be able to recognise the condition, treat the less severe cases, and identify those requiring specialist care.

Diagnosticians recognise several subtypes or course specifiers:

  • Atypical depression (AD):
    • This is characterised by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite (“comfort eating”), excessive sleep or somnolence (hypersomnia), a sensation of heaviness in limbs known as leaden paralysis, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.
    • Difficulties in measuring this subtype have led to questions of its validity and prevalence.
  • Melancholic depression:
    • This is characterised by a loss of pleasure (anhedonia) in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early-morning waking, psychomotor retardation, excessive weight loss (not to be confused with anorexia nervosa), or excessive guilt.
  • Psychotic major depression (PMD):
    • Or simply psychotic depression, is the term for a major depressive episode, in particular of melancholic nature, wherein the patient experiences psychotic symptoms such as delusions or, less commonly, hallucinations.
    • These are most commonly mood-congruent (content coincident with depressive themes).
  • Catatonic depression:
    • This is a rare and severe form of major depression involving disturbances of motor behaviour and other symptoms.
    • Here, the person is mute and almost stuporose, and either is immobile or exhibits purposeless or even bizarre movements.
    • Catatonic symptoms can also occur in schizophrenia or a manic episode, or can be due to neuroleptic malignant syndrome.
  • Postpartum depression (PPD)
    • This is listed as a course specifier in DSM-IV-TR; it refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth.
    • Postpartum depression, which affects 10-15% of women, typically sets in within three months of labour, and lasts as long as three months.
    • It is quite common for women to experience a short-term feeling of tiredness and sadness in the first few weeks after giving birth; however, postpartum depression is different because it can cause significant hardship and impaired functioning at home, work, or school as well as, possibly, difficulty in relationships with family members, spouses, or friends, or even problems bonding with the newborn.
    • In the treatment of postpartum major depressive disorders and other unipolar depressions in women who are breastfeeding, nortriptyline, paroxetine (Paxil), and sertraline (Zoloft) are in general considered to be the preferred medications.
    • Women with personal or family histories of mood disorders are at particularly high risk of developing postpartum depression.
  • Premenstrual dysphoric disorder (PMDD):
    • This is a severe and disabling form of premenstrual syndrome affecting 3-8% of menstruating women.
    • The disorder consists of a “cluster of affective, behavioural and somatic symptoms” that recur monthly during the luteal phase of the menstrual cycle.
    • PMDD was added to the list of depressive disorders in the Diagnostic and Statistical Manual of Mental Disorders in 2013.
    • The exact pathogenesis of the disorder is still unclear and is an active research topic. Treatment of PMDD relies largely on antidepressants that modulate serotonin levels in the brain via serotonin reuptake inhibitors as well as ovulation suppression using contraception.
  • Seasonal affective disorder (SAD):
    • Also known as “winter depression” or “winter blues”, is a specifier.
    • Some people have a seasonal pattern, with depressive episodes coming on in the autumn or winter, and resolving in spring.
    • The diagnosis is made if at least two episodes have occurred in colder months with none at other times over a two-year period or longer.
    • It is commonly hypothesised that people who live at higher latitudes tend to have less sunlight exposure in the winter and therefore experience higher rates of SAD, but the epidemiological support for this proposition is not strong (and latitude is not the only determinant of the amount of sunlight reaching the eyes in winter).
    • It is said that this disorder can be treated by light therapy.
    • SAD is also more prevalent in people who are younger and typically affects more females than males.
  • Dysthymia:
    • This is a condition related to unipolar depression, where the same physical and cognitive problems are evident, but they are not as severe and tend to last longer (usually at least 2 years).
    • The treatment of dysthymia is largely the same as for major depression, including antidepressant medications and psychotherapy.
  • Double depression:
    • Can be defined as a fairly depressed mood (dysthymia) that lasts for at least two years and is punctuated by periods of major depression.
  • Depressive Disorder Not Otherwise Specified (DD-NOS):
    • This is designated by the code 311 for depressive disorders that are impairing but do not fit any of the officially specified diagnoses.
    • According to the DSM-IV, DD-NOS encompasses “any depressive disorder that does not meet the criteria for a specific disorder.”
    • It includes the research diagnoses of recurrent brief depression, and minor depressive disorder listed below.
  • Depressive personality disorder (DPD)
    • This is a controversial psychiatric diagnosis that denotes a personality disorder with depressive features.
    • Originally included in the DSM-II, depressive personality disorder was removed from the DSM-III and DSM-III-R.
    • Recently, it has been reconsidered for reinstatement as a diagnosis. Depressive personality disorder is currently described in Appendix B in the DSM-IV-TR as worthy of further study.
  • Recurrent brief depression (RBD):
    • Distinguished from major depressive disorder primarily by differences in duration.
    • Individuals with RBD have depressive episodes about once per month, with individual episodes lasting less than two weeks and typically less than 2-3 days.
    • Diagnosis of RBD requires that the episodes occur over the span of at least one year and, in female patients, independently of the menstrual cycle.
    • Individuals with clinical depression can develop RBD, and vice versa, and both illnesses have similar risks.
  • Minor depressive disorder:
    • Or simply minor depression, which refers to a depression that does not meet full criteria for major depression but in which at least two symptoms are present for two weeks.

Bipolar Disorders

Bipolar disorder (BD) (also called “manic depression” or “manic-depressive disorder”), an unstable emotional condition characterised by cycles of abnormal, persistent high mood (mania) and low mood (depression), which was formerly known as “manic depression” (and in some cases rapid cycling, mixed states, and psychotic symptoms). Subtypes include:

  • Bipolar I:
    • This is distinguished by the presence or history of one or more manic episodes or mixed episodes with or without major depressive episodes.
    • A depressive episode is not required for the diagnosis of Bipolar I Disorder, but depressive episodes are usually part of the course of the illness.
  • Bipolar II :
    • Consisting of recurrent intermittent hypomanic and depressive episodes or mixed episodes.
  • Cyclothymia:
    • This is a form of bipolar disorder, consisting of recurrent hypomanic and dysthymic episodes, but no full manic episodes or full major depressive episodes.
  • Bipolar disorder not otherwise specified (BD-NOS):
    • Sometimes called “sub-threshold” bipolar, indicates that the patient has some symptoms in the bipolar spectrum (e.g. manic and depressive symptoms) but does not fully qualify for any of the three formal bipolar DSM-IV diagnoses mentioned above.

It is estimated that roughly 1% of the adult population has bipolar I, a further 1% has bipolar II or cyclothymia, and somewhere between 2% and 5% percent have “sub-threshold” forms of bipolar disorder. Furthermore, the possibility of getting bipolar disorder when one parent is diagnosed with it is 15-30%. Risk, when both parents have it, is 50-75%. Also, while with bipolar siblings the risk is 15-25%, with identical twins it is about 70%.

A minority of people with bipolar disorder have high creativity, artistry or a particular gifted talent. Before the mania phase becomes too extreme, its energy, ambition, enthusiasm and grandiosity often bring people with this type of mood disorder life’s masterpieces.[29]

Substance-induced

A mood disorder can be classified as substance-induced if its aetiology can be traced to the direct physiologic effects of a psychoactive drug or other chemical substance, or if the development of the mood disorder occurred contemporaneously with substance intoxication or withdrawal. Also, an individual may have a mood disorder coexisting with a substance abuse disorder. Substance-induced mood disorders can have features of a manic, hypomanic, mixed, or depressive episode. Most substances can induce a variety of mood disorders. For example, stimulants such as amphetamine, methamphetamine, and cocaine can cause manic, hypomanic, mixed, and depressive episodes.

Alcohol-Induced

High rates of major depressive disorder occur in heavy drinkers and those with alcoholism. Controversy has previously surrounded whether those who abused alcohol and developed depression were self-medicating their pre-existing depression. But recent research has concluded that, while this may be true in some cases, alcohol misuse directly causes the development of depression in a significant number of heavy drinkers. Participants studied were also assessed during stressful events in their lives and measured on a Feeling Bad Scale. Likewise, they were also assessed on their affiliation with deviant peers, unemployment, and their partner’s substance use and criminal offending. High rates of suicide also occur in those who have alcohol-related problems. It is usually possible to differentiate between alcohol-related depression and depression that is not related to alcohol intake by taking a careful history of the patient. Depression and other mental health problems associated with alcohol misuse may be due to distortion of brain chemistry, as they tend to improve on their own after a period of abstinence.

Benzodiazepine-induced

Benzodiazepines, such as alprazolam, clonazepam, lorazepam and diazepam, can cause both depression and mania.

Benzodiazepines are a class of medication commonly used to treat anxiety, panic attacks and insomnia, and are also commonly misused and abused. Those with anxiety, panic and sleep problems commonly have negative emotions and thoughts, depression, suicidal ideations, and often have comorbid depressive disorders. While the anxiolytic and hypnotic effects of benzodiazepines disappear as tolerance develops, depression and impulsivity with high suicidal risk commonly persist. These symptoms are “often interpreted as an exacerbation or as a natural evolution of previous disorders and the chronic use of sedatives is overlooked”. Benzodiazepines do not prevent the development of depression, can exacerbate pre-existing depression, can cause depression in those with no history of it, and can lead to suicide attempts. Risk factors for attempted and completed suicide while using benzodiazepines include high dose prescriptions (even in those not misusing the medications), benzodiazepine intoxication, and underlying depression.

The long-term use of benzodiazepines may have a similar effect on the brain as alcohol, and are also implicated in depression. As with alcohol, the effects of benzodiazepine on neurochemistry, such as decreased levels of serotonin and norepinephrine, are believed to be responsible for the increased depression. Additionally, benzodiazepines can indirectly worsen mood by worsening sleep (i.e. benzodiazepine-induced sleep disorder). Like alcohol, benzodiazepines can put people to sleep but, while asleep, they disrupt sleep architecture: decreasing sleep time, delaying time to REM sleep, and decreasing deep sleep (the most restorative part of sleep for both energy and mood). Just as some antidepressants can cause or worsen anxiety in some patients due to being activating, benzodiazepines can cause or worsen depression due to being a central nervous system depressant – worsening thinking, concentration and problem solving (i.e. benzodiazepine-induced neurocognitive disorder). However, unlike antidepressants, in which the activating effects usually improve with continued treatment, benzodiazepine-induced depression is unlikely to improve until after stopping the medication.

In a long-term follow-up study of patients dependent on benzodiazepines, it was found that 10 people (20%) had taken drug overdoses while on chronic benzodiazepine medication despite only two people ever having had any pre-existing depressive disorder. A year after a gradual withdrawal programme, no patients had taken any further overdoses.

Just as with intoxication and chronic use, benzodiazepine withdrawal can also cause depression. While benzodiazepine-induced depressive disorder may be exacerbated immediately after discontinuation of benzodiazepines, evidence suggests that mood significantly improves after the acute withdrawal period to levels better than during use. Depression resulting from withdrawal from benzodiazepines usually subsides after a few months but in some cases may persist for 6-12 months.

Due to Another Medical Condition

“Mood disorder due to a general medical condition” is used to describe manic or depressive episodes which occur secondary to a medical condition. There are many medical conditions that can trigger mood episodes, including neurological disorders (e.g. dementias), metabolic disorders (e.g. electrolyte disturbances), gastrointestinal diseases (e.g. cirrhosis), endocrine disease (e.g. thyroid abnormalities), cardiovascular disease (e.g. heart attack), pulmonary disease (e.g. chronic obstructive pulmonary disease), cancer, and autoimmune diseases (e.g. multiple sclerosis).

Not Otherwise Specified

Mood disorder not otherwise specified (MD-NOS) is a mood disorder that is impairing but does not fit in with any of the other officially specified diagnoses. In the DSM-IV MD-NOS is described as “any mood disorder that does not meet the criteria for a specific disorder.” MD-NOS is not used as a clinical description but as a statistical concept for filing purposes.

Most cases of MD-NOS represent hybrids between mood and anxiety disorders, such as mixed anxiety-depressive disorder or atypical depression. An example of an instance of MD-NOS is being in minor depression frequently during various intervals, such as once every month or once in three days. There is a risk for MD-NOS not to get noticed, and for that reason not to get treated.

Causes

Meta-analyses show that high scores on the personality domain neuroticism are a strong predictor for the development of mood disorders. A number of authors have also suggested that mood disorders are an evolutionary adaptation. A low or depressed mood can increase an individual’s ability to cope with situations in which the effort to pursue a major goal could result in danger, loss, or wasted effort. In such situations, low motivation may give an advantage by inhibiting certain actions. This theory helps to explain why negative life incidents precede depression in around 80% of cases, and why they so often strike people during their peak reproductive years. These characteristics would be difficult to understand if depression were a dysfunction.

A depressed mood is a predictable response to certain types of life occurrences, such as loss of status, divorce, or death of a child or spouse. These are events that signal a loss of reproductive ability or potential, or that did so in humans’ ancestral environment. A depressed mood can be seen as an adaptive response, in the sense that it causes an individual to turn away from the earlier (and reproductively unsuccessful) modes of behaviour.

A depressed mood is common during illnesses, such as influenza. It has been argued that this is an evolved mechanism that assists the individual in recovering by limiting his/her physical activity. The occurrence of low-level depression during the winter months, or seasonal affective disorder, may have been adaptive in the past, by limiting physical activity at times when food was scarce. It is argued that humans have retained the instinct to experience low mood during the winter months, even if the availability of food is no longer determined by the weather.

Much of what is known about the genetic influence of clinical depression is based upon research that has been done with identical twins. Identical twins have exactly the same genetic code. It has been found that when one identical twin becomes depressed the other will also develop clinical depression approximately 76% of the time. When identical twins are raised apart from each other, they will both become depressed about 67% of the time. Because both twins become depressed at such a high rate, the implication is that there is a strong genetic influence. If it happened that when one twin becomes clinically depressed the other always develops depression, then clinical depression would likely be entirely genetic.

Bipolar disorder is also considered a mood disorder and it is hypothesized that it might be caused by mitochondrial dysfunction.

Sex Differences

Mood disorders, specifically stress-related mood disorders such as anxiety and depression, have been shown to have differing rates of diagnosis based on sex. In the United States, women are two times more likely than men to be diagnosed with a stress-related mood disorder. Underlying these sex differences, studies have shown a dysregulation of stress-responsive neuroendocrine function causing an increase in the likelihood of developing these affective disorders. Overactivation of the hypothalamic-pituitary-adrenal (HPA) axis could provide potential insight into how these sex differences arise. Neuropeptide corticotropin-releasing factor (CRF) is released from the paraventricular nucleus (PVN) of the hypothalamus, stimulating adrenocorticotropic hormone (ACTH) release into the blood stream. From here ACTH triggers the release of glucocorticoids such as cortisol from the adrenal cortex. Cortisol, known as the main stress hormone, creates a negative feedback loop back to the hypothalamus to deactivate the stress response. When a constant stressor is present, the HPA axis remains overactivated and cortisol is constantly produced. This chronic stress is associated with sustained CRF release, resulting in the increased production of anxiety- and depressive-like behaviours and serving as a potential mechanism for differences in prevalence between men and women.

Diagnosis

DSM-5

The DSM-5, released in May 2013, separates the mood disorder chapter from the DSM-TR-IV into two sections: Depressive and related disorders and bipolar and related disorders. Bipolar disorders falls in between depressive disorders and schizophrenia spectrum and related disorders “in recognition of their place as a bridge between the two diagnostic classes in terms of symptomatology, family history and genetics” (Ref. 1, p 123). Bipolar disorders underwent a few changes in the DSM-5, most notably the addition of more specific symptomology related to hypomanic and mixed manic states. Depressive disorders underwent the most changes, the addition of three new disorders: disruptive mood dysregulation disorder, persistent depressive disorder (previously dysthymia), and premenstrual dysphoric disorder (previously in appendix B, the section for disorders needing further research). Disruptive mood dysregulation disorder is meant as a diagnosis for children and adolescents who would normally be diagnosed with bipolar disorder as a way to limit the bipolar diagnosis in this age cohort. Major depressive disorder (MDD) also underwent a notable change, in that the bereavement clause has been removed. Those previously exempt from a diagnosis of MDD due to bereavement are now candidates for the MDD diagnosis.

Treatment

There are different types of treatments available for mood disorders, such as therapy and medications. Behaviour therapy, cognitive behaviour therapy and interpersonal therapy have all shown to be potentially beneficial in depression. Major depressive disorder medications usually include antidepressants; a combination of antidepressants and cognitive behavioural therapy has shown to be more effective than one treatment alone. Bipolar disorder medications can consist of antipsychotics, mood stabilisers, anticonvulsants and/or lithium. Lithium specifically has been proven to reduce suicide and all causes of mortality in people with mood disorders. If mitochondrial dysfunction or mitochondrial diseases are the cause of mood disorders like bipolar disorder, then it has been hypothesized that N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin could be potential treatment options. In determining treatment, there are many types of depression scales that are used.

  • One of the depression scales is a self-report scale called Beck Depression Inventory (BDI).
  • Another scale is the Hamilton Depression Rating Scale (HAMD).
    • HAMD is a clinical rating scale in which the patient is rated based on clinician observation.
  • The Centre for Epidemiologic Studies Depression Scale (CES-D) is a scale for depression symptoms that applies to the general population.
    • This scale is typically used in research and not for self-reports.
  • The PHQ-9 which stands for Patient-Health Questionnaire-9 questions, is a self-report as well.
  • Finally, the Mood Disorder Questionnaire (MDQ) evaluates bipolar disorder.

Research

Kay Redfield Jamison and others have explored the possible links between mood disorders – especially bipolar disorder – and creativity. It has been proposed that a “ruminating personality type may contribute to both [mood disorders] and art.”

Jane Collingwood notes an Oregon State University study that:

“…looked at the occupational status of a large group of typical patients and found that ‘those with bipolar illness appear to be disproportionately concentrated in the most creative occupational category.’ They also found that the likelihood of ‘engaging in creative activities on the job’ is significantly higher for bipolar than nonbipolar workers”.

In Liz Paterek’s article “Bipolar Disorder and the Creative Mind” she wrote:

“Memory and creativity are related to mania. Clinical studies have shown that those in a manic state will rhyme, find synonyms, and use alliteration more than controls. This mental fluidity could contribute to an increase in creativity. Moreover, mania creates increases in productivity and energy. Those in a manic state are more emotionally sensitive and show less inhibition about attitudes, which could create greater expression. Studies performed at Harvard looked into the amount of original thinking in solving creative tasks. Bipolar individuals, whose disorder was not severe, tended to show greater degrees of creativity.”

The relationship between depression and creativity appears to be especially strong among poets.

What is Depression (Mood)?

Introduction

Depression is a state of low mood and aversion to activity. It can affect a person’s thoughts, behaviour, motivation, feelings, and sense of well-being.

The core symptom of depression is said to be anhedonia, which refers to loss of interest or a loss of feeling of pleasure in certain activities that usually bring joy to people. Depressed mood is a symptom of some mood disorders such as major depressive disorder or dysthymia; it is a normal temporary reaction to life events, such as the loss of a loved one; and it is also a symptom of some physical diseases and a side effect of some drugs and medical treatments.

It may feature sadness, difficulty in thinking and concentration and a significant increase or decrease in appetite and time spent sleeping. People experiencing depression may have feelings of dejection, hopelessness and, sometimes, suicidal thoughts. It can either be short term or long term.

Epidemiology

Depression is the leading cause of disability worldwide, the United Nations (UN) health agency reported, estimating that it affects more than 300 million people worldwide – the majority of them women, young people and the elderly. An estimated 4.4% of the global population suffers from depression, according to a report released by the UN World Health Organisation (WHO), which shows an 18 percent increase in the number of people living with depression between 2005 and 2015.

Global Health

Depression is a major mental-health cause of disease burden. Its consequences further lead to significant burden in public health, including a higher risk of dementia, premature mortality arising from physical disorders, and maternal depression impacts on child growth and development. Approximately 76% to 85% of depressed people in low- and middle-income countries do not receive treatment;[48] barriers to treatment include: inaccurate assessment, lack of trained health-care providers, social stigma and lack of resources.

The WHO has constructed guidelines – known as The Mental Health Gap Action Programme (mhGAP) – aiming to increase services for people with mental, neurological and substance-use disorders. Depression is listed as one of conditions prioritised by the programme. Trials conducted show possibilities for the implementation of the programme in low-resource primary-care settings dependent on primary-care practitioners and lay health-workers. Examples of mhGAP-endorsed therapies targeting depression include Group Interpersonal Therapy as group treatment for depression and “Thinking Health”, which utilises cognitive behavioural therapy to tackle perinatal depression. Furthermore, effective screening in primary care is crucial for the access of treatments. The mhGAP programme adopted its approach of improving detection rates of depression by training general practitioners. However, there is still weak evidence supporting this training.

History of the Concept

The Greco-Roman world used the tradition of the four humours to attempt to systematise sadness as “melancholia”.

The well-established idea of melancholy fell out of scientific favour in the 19th century.

Emil Kraepelin tried to give a scientific account of depression (German: das manisch-depressive Irresein) in 1896.

Factors

Life Events

Adversity in childhood, such as bereavement, neglect, mental abuse, physical abuse, sexual abuse, or unequal parental treatment of siblings can contribute to depression in adulthood. Childhood physical or sexual abuse in particular significantly correlates with the likelihood of experiencing depression over the victim’s lifetime.

Life events and changes that may influence depressed moods include (but are not limited to): childbirth, menopause, financial difficulties, unemployment, stress (such as from work, education, family, living conditions etc.), a medical diagnosis (cancer, HIV, etc.), bullying, loss of a loved one, natural disasters, social isolation, rape, relationship troubles, jealousy, separation, or catastrophic injury. Adolescents may be especially prone to experiencing a depressed mood following social rejection, peer pressure, or bullying.

Personality

Changes in personality or in one’s social environment can affect levels of depression. High scores on the personality domain neuroticism make the development of depressive symptoms as well as all kinds of depression diagnoses more likely, and depression is associated with low extraversion. Other personality indicators could be: temporary but rapid mood changes, short term hopelessness, loss of interest in activities that used to be of a part of one’s life, sleep disruption, withdrawal from previous social life, appetite changes, and difficulty concentrating.

Medical Treatment

Depression may also be the result of healthcare, such as with medication induced depression. Therapies associated with depression include interferon therapy, beta-blockers, isotretinoin, contraceptives, cardiac agents, anticonvulsants, antimigraine drugs, antipsychotics, and hormonal agents such as gonadotropin-releasing hormone agonist.

Substance-Induced

Several drugs of abuse can cause or exacerbate depression, whether in intoxication, withdrawal, and from chronic use. These include alcohol, sedatives (including prescription benzodiazepines), opioids (including prescription pain killers and illicit drugs such as heroin), stimulants (such as cocaine and amphetamines), hallucinogens, and inhalants.

Non-Psychiatric Illnesses

Refer to Differential Diagnoses of Depression.

Depressed mood can be the result of a number of infectious diseases, nutritional deficiencies, neurological conditions, and physiological problems, including hypoandrogenism (in men), Addison’s disease, Cushing’s syndrome, hypothyroidism, hyperparathyroidism, Lyme disease, multiple sclerosis, Parkinson’s disease, chronic pain, stroke, diabetes, and cancer.

Psychiatric Syndromes

Refer to Depressive Mood Disorders.

A number of psychiatric syndromes feature depressed mood as a main symptom. The mood disorders are a group of disorders considered to be primary disturbances of mood. These include major depressive disorder (MDD; commonly called major depression or clinical depression) where a person has at least two weeks of depressed mood or a loss of interest or pleasure in nearly all activities; and dysthymia, a state of chronic depressed mood, the symptoms of which do not meet the severity of a major depressive episode.

Another mood disorder, bipolar disorder, features one or more episodes of abnormally elevated mood, cognition, and energy levels, but may also involve one or more episodes of depression. When the course of depressive episodes follows a seasonal pattern, the disorder (major depressive disorder, bipolar disorder, etc.) may be described as a seasonal affective disorder.

Outside the mood disorders: borderline personality disorder often features an extremely intense depressive mood; adjustment disorder with depressed mood is a mood disturbance appearing as a psychological response to an identifiable event or stressor, in which the resulting emotional or behavioural symptoms are significant but do not meet the criteria for a major depressive episode; and posttraumatic stress disorder, a mental disorder that sometimes follows trauma, is commonly accompanied by depressed mood.

Historical Legacy

Refer to Dispossession, Oppression and Depression.

Researchers have begun to conceptualise ways in which the historical legacies of racism and colonialism may create depressive conditions.

Measures of Depression

Measures of depression as an emotional disorder include (but are not limited to) the Beck Depression Inventory-11 and the 9-item depression scale in the Patient Health Questionnaire.

Both of these measures are psychological tests that ask personal questions of the participant, and have mostly been used to measure the severity of depression. The Beck Depression Inventory (BDI) is a self-report scale that helps a therapist identify the patterns of depression symptoms and monitor recovery. The responses on this scale can be discussed in therapy to devise interventions for the most distressing symptoms of depression. Several studies, however, have used these measures to also determine healthy individuals who are not suffering from depression as a mental disorder, but as an occasional mood disorder. This is substantiated by the fact that depression as an emotional disorder displays similar symptoms to minimal depression and low levels of mental disorders such as major depressive disorder; therefore, researchers were able to use the same measure interchangeably. In terms of the scale, participants scoring between 0-13 and 0-4 respectively were considered healthy individuals.

Another measure of depressed mood would be the IWP Multi-affect Indicator. It is a psychological test that indicates various emotions, such as enthusiasm and depression, and asks for the degree of the emotions that the participants have felt in the past week. There are studies that have used lesser items from the IWP Multi-affect Indicator which was then scaled down to daily levels to measure the daily levels of depression as an emotional disorder.

Connections

Alcoholism

Alcohol can be a depressant which slows down some regions of the brain, like the prefrontal and temporal cortex, negatively affecting rationality and memory. It also lowers the level of serotonin in the brain, which could potentially lead to higher chances of depressive mood.

The connection between the amount of alcohol intake, level of depressed mood, and how it affects the risks of experiencing consequences from alcoholism, were studied in a research done on college students. The study used 4 latent, distinct profiles of different alcohol intake and level of depression; Mild or Moderate Depression, and Heavy or Severe Drinkers. Other indicators consisting of social factors and individual behaviours were also taken into consideration in the research. Results showed that the level of depression as an emotion negatively affected the amount of risky behaviour and consequence from drinking, while having an inverse relationship with protective behavioural strategies, which are behavioural actions taken by oneself for protection from the relative harm of alcohol intake. Having an elevated level of depressed mood does therefore lead to greater consequences from drinking.

Bullying

Social abuse, such as bullying, are defined as actions of singling out and causing harm on vulnerable individuals. In order to capture a day-to-day observation of the relationship between the damaging effects of social abuse, the victim’s mental health and depressive mood, a study was conducted on whether individuals would have a higher level of depressed mood when exposed to daily acts of negative behaviour. The result concluded that being exposed daily to abusive behaviours such as bullying has a positive relationship to depressed mood on the same day.

The study has also gone beyond to compare the level of depressive mood between the victims and non-victims of the daily bullying. Although victims were predicted to have a higher level of depressive mood, the results have shown otherwise that exposure to negative acts has led to similar levels of depressive mood, regardless of the victim status. The results therefore have concluded that bystanders and non-victims feel as equally depressed as the victim when being exposed to acts such as social abuse.

Creative Thinking

Divergent thinking is defined as a thought process that generates creativity in ideas by exploring many possible solutions. Having a depressed mood will significantly reduce the possibility of divergent thinking, as it reduces the fluency, variety and the extent of originality of the possible ideas generated.

However, some depressive mood disorders might have a positive effect for creativity. Upon identifying several studies and analysing data involving individuals with high levels of creativity, Christa Taylor was able to conclude that there is a clear positive relationship between creativity and depressive mood. A possible reason is that having a low mood could lead to new ways of perceiving and learning from the world, but it is unable to account for certain depressive disorders. The direct relationship between creativity and depression remains unclear, but the research conducted on this correlation has shed light that individuals who are struggling with a depressive disorder may be having even higher levels of creativity than a control group, and would be a close topic to monitor depending on the future trends of how creativity will be perceived and demanded.

Stress Management Techniques

There are empirical evidences of a connection between the type of stress management techniques and the level of daily depressive mood.

Problem-focused coping leads to lower level of depression. Focusing on the problem allows for the subjects to view the situation in an objective way, evaluating the severity of the threat in an unbiased way, thus it lowers the probability of having depressive responses. On the other hand, emotion-focused coping promotes a depressed mood in stressful situations. The person has been contaminated with too much irrelevant information and loses focus on the options for resolving the problem. They fail to consider the potential consequences and choose the option that minimises stress and maximises well-being.

Management

Depressed mood may not require professional treatment, and may be a normal temporary reaction to life events, a symptom of some medical condition, or a side effect of some drugs or medical treatments. A prolonged depressed mood, especially in combination with other symptoms, may lead to a diagnosis of a psychiatric or medical condition which may benefit from treatment. The UK National Institute for Health and Care Excellence (NICE) 2009 guidelines indicated that antidepressants should not be routinely used for the initial treatment of mild depression, because the risk-benefit ratio is poor. Physical activity can have a protective effect against the emergence of depression.

Physical activity can also decrease depressive symptoms due to the release of neurotrophic proteins in the brain that can help to rebuild the hippocampus that may be reduced due to depression. Also yoga could be considered an ancillary treatment option for patients with depressive disorders and individuals with elevated levels of depression.

Reminiscence of old and fond memories is another alternative form of treatment, especially for the elderly who have lived longer and have more experiences in life. It is a method that causes a person to recollect memories of their own life, leading to a process of self-recognition and identifying familiar stimuli. By maintaining one’s personal past and identity, it is a technique that stimulates people to view their lives in a more objective and balanced way, causing them to pay attention to positive information in their life stories, which would successfully reduce depressive mood levels.

Self-help books are a growing form of treatment for peoples physiological distress. There may be a possible connection between consumers of unguided self-help books and higher levels of stress and depressive symptoms. Researchers took many factors into consideration to find a difference in consumers and non-consumers of self-help books. The study recruited 32 people between the ages of 18 and 65; 18 consumers and 14 non-consumers, in both groups 75% of them were female. Then they broke the consumers into 11 who preferred problem-focused and 7 preferred growth-oriented. Those groups were tested for many things including cortisol levels, depressive symptomatology, and stress reactivity levels. There were no large differences between consumers of self-help books and non-consumers when it comes to diurnal cortisol level, there was a large difference in depressive symptomatology with consumers having a higher mean score. The growth-oriented group has higher stress reactivity levels than the problem-focused group. However, the problem-focused group shows higher depressive symptomatology.

What is an Antidepressant?

Introduction

Antidepressants are medications used to treat major depressive disorder, some anxiety disorders, some chronic pain conditions, and to help manage some addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, headaches, sexual dysfunction, and emotional blunting. Most types of antidepressants are typically safe to take, but may cause increased thoughts of suicide when taken by children, adolescents, and young adults. A discontinuation syndrome can occur after stopping any antidepressant which resembles recurrent depression.

Some reviews of antidepressants for depression in adults find benefit while others do not. Evidence of benefit in children and adolescents is unclear. There is debate in the medical community about how much of the observed effects of antidepressants can be attributed to the placebo effect. Most research on whether antidepressant drugs work is done on people with very severe symptoms, so the results cannot be extrapolated to the general population.

There are methods for managing depression which do not involve medications or may be used in conjunction with medications.

Refer to Tricyclic Antidepressants (TCAs) and Tetracyclic Antidepressants (TeCAs).

Medical Uses

Antidepressants are used to treat major depressive disorder and of other conditions, including some anxiety disorders, some chronic pain conditions, and to help manage some addictions. Antidepressants are often used in combinations with one another. The proponents of the monoamine hypothesis of depression recommend choosing the antidepressant with the mechanism of action impacting the most prominent symptoms – for example, they advocate that people with major depressive disorder (MDD) who are also anxious or irritable should be treated with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), and the ones with the loss of energy and enjoyment of life – with norepinephrine and dopamine enhancing drugs.

Major Depressive Disorder

The UK National Institute for Health and Care Excellence (NICE) 2009 guidelines indicated that antidepressants should not be routinely used for the initial treatment of mild depression, because the risk-benefit ratio is poor. The guidelines recommended that antidepressant treatment be considered for:

  • People with a history of moderate or severe depression;
  • Those with mild depression that has been present for a long period;
  • As a second-line treatment for mild depression that persists after other interventions; and
  • As a first-line treatment for moderate or severe depression.

The guidelines further note that antidepressant treatment should be used in combination with psychosocial interventions in most cases, should be continued for at least six months to reduce the risk of relapse, and that SSRIs are typically better tolerated than other antidepressants.

American Psychiatric Association treatment guidelines recommend that initial treatment should be individually tailored based on factors that include severity of symptoms, co-existing disorders, prior treatment experience, and the person’s preference. Options may include pharmacotherapy, psychotherapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or light therapy. They recommended antidepressant medication as an initial treatment choice in people with mild, moderate, or severe major depression, that should be given to all people with severe depression unless ECT is planned.

Some reviews of antidepressants in adults with depression find benefits while others do not.

Anxiety Disorders

Generalised Anxiety Disorder

Antidepressants are recommended by NICE for the treatment of generalised anxiety disorder (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder of which the central feature is excessive worry about a number of different events. Key symptoms include excessive anxiety about multiple events and issues, and difficulty controlling worrisome thoughts that persists for at least 6 months.

Antidepressants provide a modest-to-moderate reduction in anxiety in GAD. The efficacy of different antidepressants is similar.

Social Anxiety Disorder

Some antidepressants are used as a treatment for social anxiety disorder (SAD), but their efficacy is not entirely convincing, as only a small proportion of antidepressants showed some efficacy for this condition. Paroxetine was the first drug to be Food and Drug Administration (FDA)-approved for this disorder. Its efficacy is considered beneficial, although not everyone responds favourably to the drug. Sertraline and fluvoxamine extended release were later approved for it as well, while escitalopram is used off-label with acceptable efficacy. However, there is not enough evidence to support citalopram for treating social phobia, and fluoxetine was no better than placebo in clinical trials. SSRIs are used as a first-line treatment for social anxiety, but they do not work for everyone. One alternative would be venlafaxine, which is a SNRI. It showed benefits for social phobia in five clinical trials against placebo, while the other SNRIs are not considered particularly useful for this disorder as many of them didn’t undergo testing for it. As of now, it is unclear if duloxetine and desvenlafaxine can provide benefits for social anxiety sufferers. However, another class of antidepressants called MAOIs (monoamine oxidase inhibitors) are considered effective for social anxiety, but they come with many unwanted side effects and are rarely used. Phenelzine was shown to be a good treatment option, but its use is limited by dietary restrictions. Moclobemide is a RIMA (reversible inhibitors of monoamine oxidase-A) and showed mixed results but still got approval in some European countries for social anxiety disorder. TCA antidepressants (tricyclic antidepressants), such as clomipramine and imipramine, are not considered effective for this anxiety disorder in particular. This leaves out SSRIs such as paroxetine, sertraline and fluvoxamine CR as acceptable and tolerated treatment options for this disorder.

Obsessive Compulsive Disorder

SSRIs are a second-line treatment of adult obsessive compulsive disorder (OCD) with mild functional impairment and as first-line treatment for those with moderate or severe impairment. In children, SSRIs are considered as a second-line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects. SSRIs appear useful for OCD, at least in the short term. Efficacy has been demonstrated both in short-term treatment trials of 6 to 24 weeks and in discontinuation trials of 28 to 52 weeks duration. Clomipramine, a TCA drug, is considered effective and useful for OCD, however it is used as a second line treatment because it is less well tolerated than the SSRIs. Despite this, it has not shown superiority to fluvoxamine in trials. All SSRIs can be used effectively for OCD, and in some cases, SNRIs can also be tried even though none of them is approved specifically for OCD. However, even with all these treatment options, many people remain symptomatic after initiating the medication, and less than half of them do achieve remission.

Post Traumatic Stress Disorder

Antidepressants are one of the treatment options for post traumatic stress disorder (PTSD), however their efficacy is not well established. Two antidepressants are FDA approved for it, paroxetine and sertraline, they belong to the serotonin reuptake inhibitors class. Paroxetine has slightly higher response and remission rates than sertraline for this condition, however both drugs are not considered very helpful for every person that takes them. Fluoxetine and venlafaxine are used off label, with fluoxetine producing unsatisfactory mixed results and venlafaxine, while having a response rates of 78%, which is significantly higher than what paroxetine and sertraline achieved, but it did not address all the symptoms of PTSD like the two drugs did, which is in part due to the fact the venlafaxine is an SNRI, this class of drugs inhibit the reuptake of norepinephrine too, this could cause some anxiety in some people. Fluvoxamine, escitalopram and citalopram were not well tested in this disorder. MAOIs, while some of them may be helpful, are not used much because of their unwanted side effects. This leaves paroxetine and sertraline as acceptable treatment options for some people, although more effective antidepressants are needed.

Panic Disorder

Panic disorder is relatively treated well with medications compared with other disorders, several classes of antidepressants have shown efficacy for this disorder, however SSRIs and SNRIs are used first-line. Paroxetine, sertraline, fluoxetine are FDA approved for panic disorder, although fluvoxamine, escitalopram and citalopram are considered effective for it. The SNRI venlafaxine is also approved for this condition. Unlike with social anxiety and PTSD, some TCAs antidepressants, like clomipramine and imipramine, have shown efficacy for panic disorder. Moreover, the MAOI phenelzine is considered useful too. Panic disorder has many drugs for its treatment, however, the starting dose must be lower than the one used for MDD because people, in the initiation of treatment, have reported an increase in anxiety as a result of starting the medication. In conclusion, while panic disorder’s treatment options seem acceptable and useful for this condition, many people are still symptomatic after treatment with residual symptoms.

Eating Disorders

Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa. SSRIs (fluoxetine in particular) are preferred over other antidepressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterised. Bupropion is not recommended for the treatment of eating disorders due to an increased risk of seizure.

Similar recommendations apply to binge eating disorder. SSRIs provide short-term reductions in binge eating behaviour, but have not been associated with significant weight loss.

Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa. Treatment guidelines from NICE recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association note that SSRIs confer no advantage regarding weight gain, but that they may be used for the treatment of co-existing depressive, anxiety, or OCD.

Pain

Fibromyalgia

A 2012 meta-analysis concluded that antidepressants treatment favourably affects pain, health-related quality of life, depression, and sleep in fibromyalgia syndrome. Tricyclics appear to be the most effective class, with moderate effects on pain and sleep and small effects on fatigue and health-related quality of life. The fraction of people experiencing a 30% pain reduction on tricyclics was 48% versus 28% for placebo. For SSRIs and SNRIs the fraction of people experiencing a 30% pain reduction was 36% (20% in the placebo comparator arms) and 42% (32% in the corresponding placebo comparator arms). Discontinuation of treatment due to side effects was common. Antidepressants including amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole are recommended by the European League Against Rheumatism (EULAR) for the treatment of fibromyalgia based on “limited evidence”.

Neuropathic Pain

A 2014 meta-analysis from the Cochrane Collaboration found the antidepressant duloxetine to be effective for the treatment of pain resulting from diabetic neuropathy. The same group reviewed data for amitriptyline in the treatment of neuropathic pain and found limited useful randomised clinical trial data. They concluded that the long history of successful use in the community for the treatment of fibromyalgia and neuropathic pain justified its continued use. The group was concerned about the potential for overestimating the amount of pain relief provided by amitriptyline, and highlighted that only a small number of people will experience significant pain relief by taking this medication.

Other

Antidepressants may be modestly helpful for treating people who both have depression and alcohol dependence, however the evidence supporting this association is of low quality. Buproprion is used to help people stop smoking. Antidepressants are also used to control some symptoms of narcolepsy. Antidepressants may be used to relieve pain in people with active rheumatoid arthritis however, further research is required. Antidepressants have been shown to be superior to placebo in treating depression in individuals with physical illness, although reporting bias may have exaggerated this finding.

Limitations and Strategies

Between 30% and 50% of individuals treated with a given antidepressant do not show a response. Approximately one-third of people achieve a full remission, one-third experience a response and one-third are non-responders. Partial remission is characterised by the presence of poorly defined residual symptoms. These symptoms typically include depressed mood, anxiety, sleep disturbance, fatigue and diminished interest or pleasure. It is currently unclear which factors predict partial remission. However, it is clear that residual symptoms are powerful predictors of relapse, with relapse rates 3-6 times higher in people with residual symptoms than in those who experience full remission. In addition, antidepressant drugs tend to lose efficacy over the course of treatment. According to data from the Centres for Disease Control and Prevention, less than one-third of Americans taking one antidepressant medication have seen a mental health professional in the previous year. A number of strategies are used in clinical practice to try to overcome these limits and variations. They include switching medication, augmentation, and combination.

Switching Antidepressants

The American Psychiatric Association 2000 Practice Guideline advises that where no response is achieved following six to eight weeks of treatment with an antidepressant, to switch to an antidepressant in the same class, then to a different class of antidepressant. A 2006 meta-analysis review found wide variation in the findings of prior studies; for people who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug. However, the more antidepressants an individual had already tried, the less likely they were to benefit from a new antidepressant trial. However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication; although 34% of treatment resistant people responded when switched to the new drug, 40% responded without being switched.

Augmentation and Combination

For a partial response, the American Psychiatric Association guidelines suggest augmentation, or adding a drug from a different class. These include lithium and thyroid augmentation, dopamine agonists, sex steroids, NRIs, glucocorticoid-specific agents, or the newer anticonvulsants.

A combination strategy involves adding another antidepressant, usually from a different class so as to have effect on other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy. Other tests conducted include the use of psychostimulants as an augmentation therapy. Several studies have shown the efficacy of combining modafinil for treatment-resistant people. It has been used to help combat SSRI-associated fatigue.

Long-Term Use

The effects of antidepressants typically do not continue once the course of medication ends. This results in a high rate of relapse. A 2003 meta-analysis found that 18% of people who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a placebo.

A gradual loss of therapeutic benefit occurs in a minority of people during the course of treatment. A strategy involving the use of pharmacotherapy in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies.

Adverse Effects

Difficulty tolerating adverse effects is the most common reason for antidepressant discontinuation.

Almost any medication involved with serotonin regulation has the potential to cause serotonin toxicity (also known as serotonin syndrome) – an excess of serotonin that can induce mania, restlessness, agitation, emotional lability, insomnia and confusion as its primary symptoms. Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24 hours) it is rarely fatal. Antidepressants appear to increase the risk of diabetes by about 1.3 fold.

MAOIs tend to have pronounced (sometimes fatal) interactions with a wide variety of medications and over-the-counter drugs. If taken with foods that contain very high levels of tyramine (e.g. mature cheese, cured meats, or yeast extracts), they may cause a potentially lethal hypertensive crisis. At lower doses, the person may only experience a headache due to an increase in blood pressure.

In response to these adverse effects, a different type of MAOI has been developed: the reversible inhibitor of monoamine oxidase A (RIMA) class of drugs. Their primary advantage is that they do not require the person to follow a special diet, while being purportedly effective as SSRIs and tricyclics in treating depressive disorders.

Tricyclics and SSRI can cause the so-called drug-induced QT prolongation, especially in older adults; this condition can degenerate into a specific type of abnormal heart rhythm called torsades de points which can potentially lead to sudden cardiac arrest.

Pregnancy

SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflects a causative relationship has been difficult in some cases. In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.

SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold, and is associated with preterm birth and low birth weight.

A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies. A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that just missed statistical significance. Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants. Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies. The FDA advises for the risk of birth defects with the use of paroxetine and the MAOI should be avoided.

A 2013 systematic review and meta-analysis found that antidepressant use during pregnancy was statistically significantly associated with some pregnancy outcomes, such as gestational age and preterm birth, but not with other outcomes. The same review cautioned that because differences between the exposed and unexposed groups were small, it was doubtful whether they were clinically significant.

A neonate (infant less than 28 days old) may experience a withdrawal syndrome from abrupt discontinuation of the antidepressant at birth. Antidepressants have been shown to be present in varying amounts in breast milk, but their effects on infants are currently unknown.

Moreover, SSRIs inhibit nitric oxide synthesis, which plays an important role in setting vascular tone. Several studies have pointed to an increased risk of prematurity associated with SSRI use, and this association may be due to an increase risk of pre-eclampsia of pregnancy.

Antidepressant-Induced Mania

Another possible problem with antidepressants is the chance of antidepressant-induced mania or hypomania in people with or without a diagnosis of bipolar disorder. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the person can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20-40% of people with bipolar disorder. For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.

Suicide

Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behaviour and thinking (suicidality) in those aged under 25. This problem has been serious enough to warrant government intervention by the FDA to warn of the increased risk of suicidality during antidepressant treatment. According to the FDA, the heightened risk of suicidality occurs within the first one to two months of treatment. NICE places the excess risk in the “early stages of treatment”. A meta-analysis suggests that the relationship between antidepressant use and suicidal behaviour or thoughts is age-dependent. Compared with placebo, the use of antidepressants is associated with an increase in suicidal behaviour or thoughts among those 25 or younger (OR=1.62). There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).

Sexual

Sexual side effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm, and erectile dysfunction. Although usually reversible, these sexual side-effects can, in rare cases, continue after the drug has been completely withdrawn.

In a study of 1,022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1% with SSRI values between 57% and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7% and moclobemide 4%. Moclobemide, a selective reversible MAO-A inhibitor, does not cause sexual dysfunction, and can actually lead to an improvement in all aspects of sexual function.

Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5-HT2 and 5-HT3 receptors; decreased dopamine; decreased norepinephrine; blockade of cholinergic and α1adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels. Mirtazapine is reported to have fewer sexual side effects, most likely because it antagonizes 5-HT2 and 5-HT3 receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.

Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of SSRI treatment.

Changes in Weight

Changes in appetite or weight are common among antidepressants, but are largely drug-dependent and related to which neurotransmitters they affect. Mirtazapine and paroxetine, for example, may be associated with weight gain and/or increased appetite, while others (such as bupropion and venlafaxine) achieve the opposite effect.

The antihistaminic properties of certain TCA- and TeCA-class antidepressants have been shown to contribute to the common side effects of increased appetite and weight gain associated with these classes of medication.

Discontinuation Syndrome

Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or discontinuation of antidepressant medication. The symptoms may include flu-like symptoms, trouble sleeping, nausea, poor balance, sensory changes, and anxiety. The problem usually begins within three days and may last for several months. Rarely psychosis may occur.

A discontinuation syndrome can occur after stopping any antidepressant including SSRIs, SNRIs, and TCAs. The risk is greater among those who have taken the medication for longer and when the medication in question has a short half-life. The underlying reason for its occurrence is unclear. The diagnosis is based on the symptoms.

Methods of prevention include gradually decreasing the dose among those who wish to stop, though it is possible for symptoms to occur with tapering. Treatment may include restarting the medication and slowly decreasing the dose. People may also be switched to the long acting antidepressant fluoxetine which can then be gradually decreased.

Approximately 20-50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome. The condition is generally not serious. Though about half of people with symptoms describe them as severe. Some restart antidepressants due to the severity of the symptoms.

Emotional Blunting

SSRIs appear to cause emotional blunting, or numbness in some people who take them. This is a reduction in extremes of emotion, both positive and negative. While the person may feel less depressed, they may also feel less happiness or empathy. This may be cause for a dose reduction or medication change. The mechanism is unknown.

Pharmacology

The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine).

It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway.

Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants. A number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses.

Types of Antidepressant

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are believed to increase the extracellular level of the neurotransmitter serotonin by limiting its reabsorption into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the norepinephrine and dopamine transporters.

SSRIs are the most widely prescribed antidepressants in many countries. The efficacy of SSRIs in mild or moderate cases of depression has been disputed.

Serotonin-Norepinephrine Reuptake Inhibitors

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are potent inhibitors of the reuptake of serotonin and norepinephrine. These neurotransmitters are known to play an important role in mood. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act mostly upon serotonin alone.

The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane proteins that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of monoamine reuptake can possibly offer advantages over other antidepressants drugs by treating a wider range of symptoms.

SNRIs are sometimes also used to treat anxiety disorders, obsessive–compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, and fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.

Serotonin Modulators and Stimulators

Serotonin modulator and stimulators (SMSs), sometimes referred to more simply as “serotonin modulators”, are a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was coined in reference to the mechanism of action of the serotonergic antidepressant vortioxetine, which acts as a serotonin reuptake inhibitor (SRI), partial agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors. However, it can also technically be applied to vilazodone, which is an antidepressant as well and acts as an SRI and 5-HT1A receptor partial agonist.

An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to vilazodone.

Serotonin Antagonists and Reuptake Inhibitors

Serotonin antagonist and reuptake inhibitors (SARIs) while mainly used as antidepressants, are also anxiolytics and hypnotics. They act by antagonising serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also act as α1-adrenergic receptor antagonists. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds. They include trazodone and nefazodone.

Norepinephrine Reuptake Inhibitors

Norepinephrine reuptake inhibitors (NRIs or NERIs) are a type of drug that acts as a reuptake inhibitor for the neurotransmitter norepinephrine (noradrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine.

NRIs are commonly used in the treatment of conditions like ADHD and narcolepsy due to their psychostimulant effects and in obesity due to their appetite suppressant effects. They are also frequently used as antidepressants for the treatment of major depressive disorder, anxiety and panic disorder. Additionally, many drugs of abuse such as cocaine and methylphenidate possess NRI activity, though it is important to mention that NRIs without combined dopamine reuptake inhibitor (DRI) properties are not significantly rewarding and hence are considered to have a negligible abuse potential. However, norepinephrine has been implicated as acting synergistically with dopamine when actions on the two neurotransmitters are combined (e.g. in the case of NDRIs) to produce rewarding effects in psychostimulant drugs of abuse.

Norepinephrine-Dopamine Reuptake Inhibitors

The only drug used of this class for depression is bupropion.

Tricyclic Antidepressants

The majority of the tricyclic antidepressants (TCAs) act primarily as SNRIs by blocking the SERT and the NET, respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission. Notably, with the sole exception of amineptine, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).

Although TCAs are sometimes prescribed for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as SSRIs, SNRIs and NRIs. Adverse effects have been found to be of a similar level between TCAs and SSRIs.

Tetracyclic Antidepressants

Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their chemical structure, which contains four rings of atoms, and are closely related to the TCAs, which contain three rings of atoms.

Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) are chemicals which inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression. They are also used in the treatment of Parkinson’s disease and several other disorders.

Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example SSRIs and TCAs) have failed.

MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia, and PTSD, as well as borderline personality disorder. MAOIs appear to be particularly effective in the management of bipolar depression according to a retrospective-analysis. There are reports of MAOI efficacy in OCD, trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports.

MAOIs can also be used in the treatment of Parkinson’s disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons), as well as providing an alternative for migraine prophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety disorders.

NMDA Receptor Antagonists

NMDA receptor antagonists like ketamine and esketamine are rapid-acting antidepressants and seem to work via blockade of the ionotropic glutamate NMDA receptor.

Others

See the list of antidepressants and management of depression for other drugs that are not specifically characterised.

Adjuncts

Adjunct medications are an umbrella category of substances that increase the potency or “enhance” antidepressants. They work by affecting variables very close to the antidepressant, sometimes affecting a completely different mechanism of action. This may be attempted when depression treatments have not been successful in the past.

Common types of adjunct medication techniques generally fall into the following categories:

  • Two or more antidepressants taken together.
  • From the same class (affecting the same area of the brain, often at a much higher level).
  • From different classes (affecting multiple parts of the brain not covered simultaneously by either drug alone).
  • An antipsychotic combined with an antidepressant, particularly atypical antipsychotics such as aripiprazole (Abilify), quetiapine (Seroquel), olanzapine (Zyprexa), and risperidone (Risperdal).

It is unknown if undergoing psychological therapy at the same time as taking anti-depressants enhances the anti-depressive effect of the medication.

Less Common Adjuncts

Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone. Furthermore, lithium dramatically decreases the suicide risk in recurrent depression. There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function.

Psychopharmacologists have also tried adding a stimulant, in particular, d-amphetamine. However, the use of stimulants in cases of treatment-resistant depression is relatively controversial. A review article published in 2007 found psychostimulants may be effective in treatment-resistant depression with concomitant antidepressant therapy, but a more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the somewhat contradictory nature of their results.

Brief History

Before the 1950s, opioids and amphetamines were commonly used as antidepressants. Their use was later restricted due to their addictive nature and side effects. Extracts from the herb St John’s wort have been used as a “nerve tonic” to alleviate depression.

Isoniazid, Iproniazid, and Imipramine

In 1951, Irving Selikoff and Edward H. Robitzek, working out of Sea View Hospital on Staten Island, began clinical trials on two new anti-tuberculosis agents developed by Hoffman-LaRoche, isoniazid and iproniazid. Only patients with a poor prognosis were initially treated; nevertheless, their condition improved dramatically. Selikoff and Robitzek noted “a subtle general stimulation … the patients exhibited renewed vigour and indeed this occasionally served to introduce disciplinary problems.” The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.

In 1952, learning of the stimulating side effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two-thirds of their patients and coined the term antidepressant to refer to its action. A similar incident took place in Paris, where Jean Delay, head of psychiatry at Sainte-Anne Hospital, heard of this effect from his pulmonology colleagues at Cochin Hospital. In 1952 (before Lurie and Salzer), Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients. The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of diamine oxidase, coupled with a weak inhibition of monoamine oxidase A.

Selikoff and Robitzek also experimented with another anti-tuberculosis drug, iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity. Later, Jackson Smith, Gordon Kamman, George E. Crane, and Frank Ayd, described the psychiatric applications of iproniazid. Ernst Zeller found iproniazid to be a potent monoamine oxidase inhibitor. Nevertheless, iproniazid remained relatively obscure until Nathan S. Kline, the influential head of research at Rockland State Hospital, began to popularize it in the medical and popular press as a “psychic energiser”. Roche put a significant marketing effort behind iproniazid. Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.

The antidepressant effect of a tricyclic, a three ringed compound, was first discovered in 1957 by Roland Kuhn in a Swiss psychiatric hospital. Antihistamine derivatives were used to treat surgical shock and later as neuroleptics. Although in 1955 reserpine was shown to be more effective than placebo in alleviating anxious depression, neuroleptics were being developed as sedatives and antipsychotics.

Attempting to improve the effectiveness of chlorpromazine, Kuhn – in conjunction with the Geigy Pharmaceutical Company – discovered the compound “G 22355”, later renamed imipramine. Imipramine had a beneficial effect in patients with depression who showed mental and motor retardation. Kuhn described his new compound as a “thymoleptic” “taking hold of the emotions,” in contrast with neuroleptics, “taking hold of the nerves” in 1955-1956. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.

Second Generation Antidepressants

Antidepressants became prescription drugs in the 1950s. It was estimated that no more than 50 to 100 individuals per million suffered from the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic in marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers, which were being marketed for different uses. Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of “reversible” forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.

By the 1960s, it was thought that the mode of action of tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later tricyclics were thought to affect serotonin as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug.

Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was zimelidine in 1971, while the first released clinically was indalpine. Fluoxetine was approved for commercial use by the FDA in 1988, becoming the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly and Company in the early 1970s by Bryan Molloy, Klaus Schmiegel, David T. Wong and others. SSRIs became known as “novel antidepressants” along with other newer drugs such as SNRIs and NRIs with various selective effects.

St John’s wort fell out of favour in most countries through the 19th and 20th centuries, except in Germany, where Hypericum extracts were eventually licensed, packaged and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis. It remains an over-the-counter drug (OTC) supplement in most countries. Of concern are lead contaminant; on average, lead levels in women in the United States taking St. John’s wort are elevated about 20%. Research continues to investigate its active component hyperforin, and to further understand its mode of action.

Rapid-Acting Antidepressants

Esketamine (brand name Spravato), the first rapid-acting antidepressant to be approved for clinical treatment of depression, was introduced for this indication in March 2019 in the United States.

Research

A 2016 placebo randomised controlled trial evaluated the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression with positive outcome. In 2018 the FDA granted Breakthrough Therapy Designation for psilocybin-assisted therapy for treatment-resistant depression and in 2019, the FDA granted Breakthrough Therapy Designation for psilocybin therapy treating major depressive disorder.

Society and Culture

Prescription Trends

In the United States, antidepressants were the most commonly prescribed medication in 2013. Of the estimated 16 million “long term” (over 24 months) users, roughly 70% are female. As of 2017, about 16.5% of white people in the United States took antidepressants compared with 5.6% of black people in the United States.

In the UK, figures reported in 2010 indicated that the number of antidepressants prescribed by the National Health Service (NHS) almost doubled over a decade. Further analysis published in 2014 showed that number of antidepressants dispensed annually in the community went up by 25 million in the 14 years between 1998 and 2012, rising from 15 million to 40 million. Nearly 50% of this rise occurred in the four years after the 2008 banking crash, during which time the annual increase in prescriptions rose from 6.7% to 8.5%. These sources also suggest that aside from the recession, other factors that may influence changes in prescribing rates may include: improvements in diagnosis, a reduction of the stigma surrounding mental health, broader prescribing trends, GP characteristics, geographical location and housing status. Another factor that may contribute to increasing consumption of antidepressants is the fact that these medications now are used for other conditions including social anxiety and PTSD.

Adherence

As of 2003, worldwide, 30 to 60% of people did not follow their practitioner’s instructions about taking their antidepressants, and as of 2013 in the US, it appeared that around 50% of people did not take their antidepressants as directed by their practitioner.

When people fail to take their antidepressants, there is a greater risk that the drug will not help, that symptoms get worse, that they miss work or are less productive at work, and that the person may be hospitalised. This also increases costs for caring for them.

Social Science Perspective

Some academics have highlighted the need to examine the use of antidepressants and other medical treatments in cross-cultural terms, due to the fact that various cultures prescribe and observe different manifestations, symptoms, meanings and associations of depression and other medical conditions within their populations. These cross-cultural discrepancies, it has been argued, then have implications on the perceived efficacy and use of antidepressants and other strategies in the treatment of depression in these different cultures. In India, antidepressants are largely seen as tools to combat marginality, promising the individual the ability to reintegrate into society through their use – a view and association not observed in the West.

Environmental Impacts

Because most antidepressants function by inhibiting the reuptake of neurotransmitters serotonin, dopamine, and norepinepherine these drugs can interfere with natural neurotransmitter levels in other organisms impacted by indirect exposure. Antidepressants fluoxetine and sertraline have been detected in aquatic organisms residing in effluent dominated streams. The presence of antidepressants in surface waters and aquatic organisms has caused concern because ecotoxicological effects to aquatic organisms due to fluoxetine exposure have been demonstrated.

Coral reef fish have been demonstrated to modulate aggressive behaviour through serotonin. Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males.

Exposure to fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behaviour. Perinatal exposure to fluoxetine at relevant environmental concentrations has been shown to lead to significant modifications of memory processing in 1-month-old cuttlefish. This impairment may disadvantage cuttlefish and decrease their survival. Somewhat less than 10% of orally administered fluoxetine is excreted from humans unchanged or as glucuronide.

Highlighting the Hidden Links between Mental Disorders

Research Paper Title

The hidden links between mental disorders.

Background

Psychiatrists have a dizzying array of diagnoses and not enough treatments. Hunting for the hidden biology underlying mental disorders could help.

In 2018, psychiatrist Oleguer Plana-Ripoll was wrestling with a puzzling fact about mental disorders. He knew that many individuals have multiple conditions – anxiety and depression, say, or schizophrenia and bipolar disorder. He wanted to know how common it was to have more than one diagnosis, so he got his hands on a database containing the medical details of around 5.9 million Danish citizens.

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Reference

Marshall, M. (2020) The hidden links between mental disorders. Nature. 581(7806), pp.19-21. doi: 10.1038/d41586-020-00922-8.