What is Learned Helplessness?

Introduction

Learned helplessness is behaviour exhibited by a subject after enduring repeated aversive stimuli beyond their control. It was initially thought to be caused from the subject’s acceptance of their powerlessness: discontinuing attempts to escape or avoid the aversive stimulus, even when such alternatives are unambiguously presented. Upon exhibiting such behaviour, the subject was said to have acquired learned helplessness.

Over the past few decades, neuroscience has provided insight into learned helplessness and shown that the original theory actually had it backwards: the brain’s default state is to assume that control is not present, and the presence of “helpfulness” is what is actually learned.

In humans, learned helplessness is related to the concept of self-efficacy; the individual’s belief in their innate ability to achieve goals. Learned helplessness theory is the view that clinical depression and related mental illnesses may result from such real or perceived absence of control over the outcome of a situation.

Refer to Learned Optimism.

Foundation of Research and Theory

Early Experiments

American psychologist Martin Seligman initiated research on learned helplessness in 1967 at the University of Pennsylvania as an extension of his interest in depression. This research was later expanded through experiments by Seligman and others. One of the first was an experiment by Seligman & Maier:

  • In Part 1 of this study, three groups of dogs were placed in harnesses.
    • Group 1 dogs were simply put in a harness for a period of time and were later released.
    • Groups 2 and 3 consisted of “yoked pairs”.
    • Dogs in Group 2 were given electric shocks at random times, which the dog could end by pressing a lever.
    • Each dog in Group 3 was paired with a Group 2 dog; whenever a Group 2 dog got a shock, its paired dog in Group 3 got a shock of the same intensity and duration, but its lever did not stop the shock.
    • To a dog in Group 3, it seemed that the shock ended at random, because it was their paired dog in Group 2 that was causing it to stop.
    • Thus, for Group 3 dogs, the shock was “inescapable”.
  • In Part 2 of the experiment the same three groups of dogs were tested in a shuttle-box apparatus (a chamber containing two rectangular compartments divided by a barrier a few inches high).
    • All of the dogs could escape shocks on one side of the box by jumping over a low partition to the other side.
    • The dogs in Groups 1 and 2 quickly learned this task and escaped the shock.
    • Most of the Group 3 dogs – which had previously learned that nothing they did had any effect on shocks – simply lay down passively and whined when they were shocked.

In a second experiment later that year with new groups of dogs, Overmier and Seligman ruled out the possibility that, instead of learned helplessness, the Group 3 dogs failed to avert in the second part of the test because they had learned some behaviour that interfered with “escape”. To prevent such interfering behaviour, Group 3 dogs were immobilised with a paralysing drug (curare), and underwent a procedure similar to that in Part 1 of the Seligman and Maier experiment. When tested as before in Part 2, these Group 3 dogs exhibited helplessness as before. This result serves as an indicator for the ruling out of the interference hypothesis.

From these experiments, it was thought that there was to be only one cure for helplessness. In Seligman’s hypothesis, the dogs do not try to escape because they expect that nothing they do will stop the shock. To change this expectation, experimenters physically picked up the dogs and moved their legs, replicating the actions the dogs would need to take in order to escape from the electrified grid. This had to be done at least twice before the dogs would start wilfully jumping over the barrier on their own. In contrast, threats, rewards, and observed demonstrations had no effect on the “helpless” Group 3 dogs.

Later Experiments

Later experiments have served to confirm the depressive effect of feeling a lack of control over an aversive stimulus. For example, in one experiment, humans performed mental tasks in the presence of distracting noise. Those who could use a switch to turn off the noise rarely bothered to do so, yet they performed better than those who could not turn off the noise. Simply being aware of this option was enough to substantially counteract the noise effect. In 2011, an animal study found that animals with control over stressful stimuli exhibited changes in the excitability of certain neurons in the prefrontal cortex. Animals that lacked control failed to exhibit this neural effect and showed signs consistent with learned helplessness and social anxiety.

Expanded Theories

Research has found that a human’s reaction to feeling a lack of control differs both between individuals and between situations, i.e. learned helplessness sometimes remains specific to one situation but at other times generalises across situations. Such variations are not explained by the original theory of learned helplessness, and an influential view is that such variations depend on an individual’s attributional or explanatory style. According to this view, how someone interprets or explains adverse events affects their likelihood of acquiring learned helplessness and subsequent depression. For example, people with pessimistic explanatory style tend to see negative events as permanent (“it will never change”), personal (“it’s my fault”), and pervasive (“I can’t do anything correctly”), and are likely to suffer from learned helplessness and depression.

Bernard Weiner proposed a detailed account of the attributional approach to learned helplessness. His attribution theory includes the dimensions of globality/specificity, stability/instability, and internality/externality:

  • A global attribution occurs when the individual believes that the cause of negative events is consistent across different contexts.
    • A specific attribution occurs when the individual believes that the cause of a negative event is unique to a particular situation.
  • A stable attribution occurs when the individual believes the cause to be consistent across time.
    • An unstable attribution occurs when the individual thinks that the cause is specific to one point in time.
  • An external attribution assigns causality to situational or external factors,
    • while an internal attribution assigns causality to factors within the person.

Research has shown that those with an internal, stable, and global attributional style for negative events can be more at risk for a depressive reaction to failure experiences.

Neurobiological Perspective

Research has shown that increased 5-HT (serotonin) activity in the dorsal raphe nucleus plays a critical role in learned helplessness. Other key brain regions that are involved with the expression of helpless behaviour include the basolateral amygdala, central nucleus of the amygdala and bed nucleus of the stria terminalis. Activity in medial prefrontal cortex, dorsal hippocampus, septum and hypothalamus has also been observed during states of helplessness.

In the article, “Exercise, Learned Helplessness, and the Stress-Resistant Brain”, Benjamin N. Greenwood and Monika Fleshner discuss how exercise might prevent stress-related disorders such as anxiety and depression. They show evidence that running wheel exercise prevents learned helplessness behaviours in rats. They suggest that the amount of exercise may not be as important as simply exercising at all. The article also discusses the neurocircuitry of learned helplessness, the role of serotonin (or 5-HT), and the exercise-associated neural adaptations that may contribute to the stress-resistant brain. However, the authors finally conclude that:

“The underlying neurobiological mechanisms of this effect, however, remain unknown. Identifying the mechanisms by which exercise prevents learned helplessness could shed light on the complex neurobiology of depression and anxiety and potentially lead to novel strategies for the prevention of stress-related mood disorders”.

Health Implications

People who perceive events as uncontrollable show a variety of symptoms that threaten their mental and physical well-being. They experience stress, they often show disruption of emotions demonstrating passivity or aggressiveness, and they can also have difficulty performing cognitive tasks such as problem-solving. They are less likely to change unhealthy patterns of behaviour, causing them, for example, to neglect diet, exercise, and medical treatment.

Depression

Abnormal and cognitive psychologists have found a strong correlation between depression-like symptoms and learned helplessness in laboratory animals.

Young adults and middle-aged parents with a pessimistic explanatory style often suffer from depression. They tend to be poor at problem-solving and cognitive restructuring, and also tend to demonstrate poor job satisfaction and interpersonal relationships in the workplace. Those with a pessimistic style also tend to have weakened immune systems, having not only increased vulnerability to minor ailments (e.g. cold, fever) and major illness (e.g. heart attack, cancers), but also poorer recovery from health problems.

Social Impact

Learned helplessness can be a factor in a wide range of social situations.

  • In emotionally abusive relationships, the victim often develops learned helplessness.
    • This occurs when the victim confronts or tries to leave the abuser only to have the abuser dismiss or trivialise the victim’s feelings, pretend to care but not change, or impede the victim from leaving.
  • The motivational effect of learned helplessness is often seen in the classroom.
    • Students who repeatedly fail may conclude that they are incapable of improving their performance, and this attribution keeps them from trying to succeed, which results in increased helplessness, continued failure, loss of self-esteem and other social consequences.
  • Child abuse by neglect can be a manifestation of learned helplessness.
    • For example, when parents believe they are incapable of stopping an infant’s crying, they may simply give up trying to do anything for the child.
  • Those who are extremely shy or anxious in social situations may become passive due to feelings of helplessness.
    • Gotlib and Beatty (1985) found that people who cite helplessness in social settings may be viewed poorly by others, which tends to reinforce the passivity.
  • Aging individuals may respond with helplessness to the deaths of friends and family members, the loss of jobs and income, and the development of age-related health problems.
    • This may cause them to neglect their medical care, financial affairs, and other important needs.
  • According to Cox et al., Abramson, Devine, and Hollon (2012), learned helplessness is a key factor in depression that is caused by inescapable prejudice (i.e. “deprejudice”).
    • Thus: “Helplessness born in the face of inescapable prejudice matches the helplessness born in the face of inescapable shocks.”
  • According to Ruby K. Payne’s book A Framework for Understanding Poverty, treatment of the poor can lead to a cycle of poverty, a culture of poverty, and generational poverty.
    • This type of learned helplessness is passed from parents to children.
    • People who embrace this mentality feel there is no way to escape poverty and so one must live in the moment and not plan for the future, trapping families in poverty.

Social problems resulting from learned helplessness may seem unavoidable to those entrenched. However, there are various ways to reduce or prevent it. When induced in experimental settings, learned helplessness has been shown to resolve itself with the passage of time. People can be immunized against the perception that events are uncontrollable by increasing their awareness of previous experiences, when they were able to effect a desired outcome. Cognitive therapy can be used to show people that their actions do make a difference and bolster their self-esteem.

Extensions

Cognitive scientist and usability engineer Donald Norman used learned helplessness to explain why people blame themselves when they have a difficult time using simple objects in their environment.

The UK educationalist Phil Bagge describes it as a learning avoidance strategy caused by prior failure and the positive reinforcement of avoidance such as asking teachers or peers to explain and consequently do the work. It shows itself as sweet helplessness or aggressive helplessness often seen in challenging problem solving contexts, such as learning to use a new computer programming language.

The US sociologist Harrison White has suggested in his book Identity and Control that the notion of learned helplessness can be extended beyond psychology into the realm of social action. When a culture or political identity fails to achieve desired goals, perceptions of collective ability suffer.

Emergence under Torture

Studies on learned helplessness served as the basis for developing enhanced interrogation techniques. In CIA interrogation manuals, learned helplessness is characterised as “apathy” which may result from prolonged use of coercive techniques which result in a “debility-dependency-dread” state in the subject, “If the debility-dependency-dread state is unduly prolonged, however, the arrestee may sink into a defensive apathy from which it is hard to arouse him.”

Is the Mental Wellbeing of Doctors Becoming an Increasing Concern?

Research Paper Title

Depressive symptoms in residents of a tertiary training hospital in Malaysia: The prevalence and associated factors.

Background

The mental wellbeing of doctors is becoming an increasing concern in the world today.

In Malaysia, residency is a challenging period in a doctor’s life, with many changes professionally and possibly in their personal lives as well.

This study aims to determine the prevalence of depressive symptoms and the socio-demographic correlates among residents in a tertiary training hospital in Malaysia.

It is a cross sectional study and all residents were approached to participate in the study.

Methods

The instruments used were a socio-demographic questionnaire and the Patient Health Questionnaire 9 (PHQ-9).

Chi-square test was used to explore the association between the socio-demographic correlates, and those that were found to have significant associations were further tested using multivariate logistic regression.

Results

The prevalence of depression among residents was 25.1 %. Longer working hours, missing meals, and working in Department of Surgery and Department of Anaesthesia was significantly positively associated while having protected study time, CME/lectures, leisure/hobbies and exercise were negatively associated with depression.

The Department of Rehabilitation Medicine had a significantly negative association with depression. After logistic regression, longer working hours and a lack of protected study time was significantly associated with depression in the respective departments.

Conclusions

In summary, the prevalence of depression among residents is high and is associated with longer working hours, missing meals and a lack of protected study time are significantly associated with depression.

Remedial steps should be taken to improve the mental health among residents.

Reference

Nair, N., Ng, C.G. & Sulaiman, A.H. (2021) Depressive symptoms in residents of a tertiary training hospital in Malaysia: The prevalence and associated factors. Asian Journal of Psychiatry. doi: 10.1016/j.ajp.2021.102548. Online ahead of print.

What is Dispossession, Oppression, and Depression?

Introduction

Supplementing the medical model of depression, many researchers have begun to conceptualise ways in which the historical legacies of racism and colonialism create depressive conditions. Given the lived experiences of marginalised peoples, ranging from conditions of migration, class stratification, cultural genocide, labour exploitation, and social immobility, depression can be seen as a “rational response to global conditions”, according to Ann Cvetkovich.

Background

Psychogeographical depression overlaps somewhat with the theory of “deprejudice”, a portmanteau of depression and prejudice proposed by Cox, Abramson, Devine, and Hollon in 2012, who argue for an integrative approach to studying the often comorbid experiences. Cox, Abramson, Devine, and Hollon are concerned with the ways in which social stereotypes are often internalised, creating negative self-stereotypes that then produce depressive symptoms.

Unlike the theory of “deprejudice”, a psychogeographical theory of depression attempts to broaden study of the subject beyond an individual experience to one produced on a societal scale, seeing particular manifestations of depression as rooted in dispossession; historical legacies of genocide, slavery, and colonialism are productive of segregation, both material and psychic material deprivation, and concomitant circumstances of violence, systemic exclusion, and lack of access to legal protections. The demands of navigating these circumstances compromise the resources available to a population to seek comfort, health, stability, and sense of security. The historical memory of this trauma conditions the psychological health of future generations, making psychogeographical depression an intergenerational experience as well.

This work is supported by recent studies in genetic science which has demonstrated an epigenetic link between the trauma suffered by Holocaust survivors and the genetic reverberations for subsequent generations. Likewise, research by scientists at Emory University suggests that memories of trauma can be inherited, rendering offspring vulnerable to psychological predispositions for stress disorders, schizophrenia, and PTSD.

Vacant Lot Greening and Mood

A 2018 study asked low income residents of Philadelphia “how often they felt nervous, hopeless, restless, depressed and worthless.” As an experimental mental health intervention, trash was removed from vacant lots. Some of the vacant lots were “greened”, with plantings of trees, grass, and small fences. Residents near the “greened” lots who had incomes below the poverty line reported a decrease in feelings of depression of 68%, while residents with incomes above the poverty line reported a decrease of 41%. Removing trash from vacant lots without installing landscaping did not have an observable mental health impact.

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 are the Differential Diagnoses of Depression?

Introduction

Depression, one of the most commonly diagnosed psychiatric disorders, is being diagnosed in increasing numbers in various segments of the population worldwide. For example, depression in the United States (US) alone affects 17.6 million Americans each year or 1 in 6 people. Depressed patients are at increased risk of type 2 diabetes, cardiovascular disease and suicide. Within the next twenty years depression is expected to become the second leading cause of disability worldwide and the leading cause in high-income nations, including the US. In approximately 75% of completed suicides, the individuals had seen a physician within the prior year before their death, 45-66% within the prior month. About a third of those who completed suicide had contact with mental health services in the prior year, a fifth within the preceding month.

There are many psychiatric and medical conditions that may mimic some or all of the symptoms of depression or may occur comorbid to it. A disorder either psychiatric or medical that shares symptoms and characteristics of another disorder, and may be the true cause of the presenting symptoms is known as a differential diagnosis.

Many psychiatric disorders such as depression are diagnosed by allied health professionals with little or no medical training, and are made on the basis of presenting symptoms without proper consideration of the underlying cause, adequate screening of differential diagnoses is often not conducted. According to one study, non-medical mental health care providers may be at increased risk of not recognising masked medical illnesses in their patients.

Misdiagnosis or missed diagnoses may lead to lack of treatment or ineffective and potentially harmful treatment which may worsen the underlying causative disorder. A conservative estimate is that 10% of all psychological symptoms may be due to medical reasons, with the results of one study suggesting that about half of individuals with a serious mental illness have general medical conditions that are largely undiagnosed and untreated and may cause or exacerbate psychiatric symptoms.

In a case of misdiagnosed depression recounted in Newsweek, a writer received treatment for depression for years; during the last 10 years of her depression the symptoms worsened, resulting in multiple suicide attempts and psychiatric hospitalisations. When an MRI finally was performed, it showed the presence of a tumour. However, she was told by a neurologist that it was benign. After a worsening of symptoms, and upon the second opinion of another neurologist, the tumour was removed. After the surgery, she no longer suffered from depressive symptoms.

Autoimmune Disorders

  • Celiac disease:
    • This is an autoimmune disorder in which the body is unable to digest gluten which is found in various food grains, most notably wheat, and also rye and barley.
    • Current research has shown its neuropsychiatric symptoms may manifest without the gastrointestinal symptoms.
    • However, more recent studies have emphasized that a wider spectrum of neurologic syndromes may be the presenting extraintestinal manifestation of gluten sensitivity with or without intestinal pathology.
  • Lupus:
    • Systemic lupus erythematosus (SLE), is a chronic autoimmune connective tissue disease that can affect any part of the body.
    • Lupus can cause or worsen depression.

Bacterial-Viral-Parasitic Infection

  • Lyme disease:
    • This is a bacterial infection caused by Borrelia burgdorferi, a spirochete bacterium transmitted by the Deer tick (Ixodes scapularis).
    • Lyme disease is one of a group of diseases which have earned the name the “great imitator” for their propensity to mimic the symptoms of a wide variety of medical and neuropsychiatric disorders.
    • Lyme disease is an underdiagnosed illness, partially as a result of the complexity and unreliability of serologic testing.
    • Because of the rapid rise of Lyme borreliosis nationwide and the need for antibiotic treatment to prevent severe neurologic damage, mental health professionals need to be aware of its possible psychiatric presentations.
  • Syphilis:
    • The prevalence of which is on the rise, is another of the “great imitators”, which if left untreated can progress to neurosyphilis and affect the brain, can present with solely neuropsychiatric symptoms.
    • This case emphasises that neurosyphilis still has to be considered in the differential diagnosis within the context of psychiatric conditions and diseases.
    • Owing to current epidemiological data and difficulties in diagnosing syphilis, routine screening tests in the psychiatric field are necessary.
  • Neurocysticercosis (NCC):
    • This is an infection of the brain or spinal cord caused by the larval stage of the pork tapeworm, Taenia solium.
    • NCC is the most common helminthic (parasitic worm) infestation of the central nervous system worldwide. Humans develop cysticercosis when they ingest eggs of the pork tapeworm via contact with contaminated fecal matter or eating infected vegetables or undercooked pork.
    • While cysticercosis is endemic in Latin America, it is an emerging disease with increased prevalence in the United States.
    • The rate of depression in those with neurocysticercosis is higher than in the general population.
  • Toxoplasmosis:
    • This is an infection caused by Toxoplasma gondii an intracellular protozoan parasite. Humans can be infected in 3 different ways:
      • Ingestion of tissue cysts;
      • Ingestion of oocysts; or
      • In utero infection with tachyzoites.
    • One of the prime methods for transmission to humans is contact with the faeces of the host species, the domesticated cat.
    • Toxoplasma gondii infects approximately 30% of the world’s human population, but causes overt clinical symptoms in only a small segment of those infected.
    • Exposure to Toxoplasma gondii (seropositivity) without developing Toxoplasmosis has been proven to alter various characteristics of human behaviour as well as being a causative factor in some cases of depression, in addition, studies have linked seropositivity with an increased rate of suicide
  • West Nile virus (WNV):
    • This can cause encephalitis has been reported to be a causal factor in developing depression in 31% of those infected in a study conducted in Houston, Texas and reported to the Centre for Disease Control (CDC).
    • The primary vectors for disease transmission to humans are various species of mosquito.
    • WNV which is endemic to Southern Europe, Africa the Middle East and Asia was first identified in the United States in 1999.
    • Between 1999 and 2006, 20,000 cases of confirmed symptomatic WNV were reported in the US, with estimates of up to 1 million being infected.
    • WNV is now the most common cause of epidemic viral encephalitis in the United States, and it will likely remain an important cause of neurological disease for the foreseeable future.

Blood Disorders

  • Anaemia:
    • This is a decrease in normal number of red blood cells (RBCs) or less than the normal quantity of haemoglobin in the blood.
    • Depressive symptoms are associated with anaemia in a general population of older persons living in the community.

Chronic Fatigue Syndrome

Between 1 and 4 million Americans are believed to have chronic fatigue syndrome (CFS), yet only 50% have consulted a physician for symptoms of CFS. In addition individuals with CFS symptoms often have an undiagnosed medical or psychiatric disorder such as diabetes, thyroid disease or substance abuse. CFS, at one time considered to be psychosomatic in nature, is now considered to be a valid medical condition in which early diagnosis and treatment can aid in alleviating or completely resolving symptoms. While frequently misdiagnosed as depression, differences have been noted in rate of cerebral blood flow.

CFS is underdiagnosed in more than 80% of the people who have it; at the same time, it is often misdiagnosed as depression.

Dietary Disorders

  • Fructose malabsorption and lactose intolerance; deficient fructose transport by the duodenum, or by the deficiency of the enzyme, lactase in the mucosal lining, respectively.
  • As a result of this malabsorption the saccharides reach the colon and are digested by bacteria which convert them to short chain fatty acids, CO2, and H2.
  • Approximately 50% of those afflicted exhibit the physical signs of irritable bowel syndrome.
  • Fructose malabsorption may play a role in the development of depressed mood. Fructose malabsorption should be considered in patients with symptoms of major depression.
  • Fructose and sorbitol reduced diet in subjects with fructose malabsorption does not only reduce gastrointestinal symptoms but also improves mood and early signs of depression.

Endocrine System Disorders

Dysregulation of the endocrine system may present with various neuropsychiatric symptoms; irregularities in the hypothalamic-pituitary- adrenal (HPA) axis and the hypothalamic-pituitary-thyroid (HPT) axis have been shown in patients with primary depression.

HPT and HPA axes abnormalities observed in patients with depression:

  • HPT axes irregularities:
    • Alterations in thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH).
    • An abnormally high rate of antithyroid antibodies.
    • Elevated cerebrospinal fluid (CSF) TRH concentrations.
  • HPA axes irregularities:
    • Adrenocorticoid hypersecretion.
    • Enlarged pituitary and adrenal gland size (organomegaly).
    • Elevated corticotropin-releasing factor (CSF) concentrations.

Adrenal Gland

  • Addison’s disease:
    • Also known as chronic adrenal insufficiency, hypocortisolism, and hypocorticism) is a rare endocrine disorder wherein the adrenal glands, located above the kidneys, produce insufficient steroid hormones (glucocorticoids and often mineralocorticoids).
    • Addison’s disease presenting with psychiatric features in the early stage has the tendency to be overlooked and misdiagnosed.
  • Cushing’s Syndrome:
    • Also known as hypercortisolism, is an endocrine disorder characterised by an excess of cortisol.
    • In the absence of prescribed steroid medications, it is caused by a tumour on the pituitary or adrenal glands, or more rarely, an ectopic hormone-secreting tumour.
    • Depression is a common feature in diagnosed patients and it often improves with treatment.

Thyroid and Parathyroid Glands

  • Graves’ disease:
    • An autoimmune disease where the thyroid is overactive, resulting in hyperthyroidism and thyrotoxicosis.
  • Hashimoto’s thyroiditis:
    • Also known chronic lymphocytic thyroiditis is an autoimmune disease in which the thyroid gland is gradually destroyed by a variety of cell and antibody mediated immune processes.
    • Hashimoto’s thyroiditis is associated with thyroid peroxidase and thyroglobulin autoantibodies
  • Hashitoxicosis.
  • Hypothyroidism.
  • Hyperthyroidism.
  • Hypoparathyroidism:
    • Can affect calcium homeostasis, supplementation of which has completely resolved cases of depression in which hypoparathyroidism is the sole causative factor.

Pituitary Tumours

Tumours of the pituitary gland are fairly common in the general population with estimates ranging as high as 25%. Most tumours are considered to be benign and are often an incidental finding discovered during autopsy or as of neuroimaging in which case they are dubbed “incidentalomas”. Even in benign cases, pituitary tumours can affect cognitive, behavioural and emotional changes. Pituitary microadenomas are smaller than 10 mm in diameter and are generally considered benign, yet the presence of a microadenoma has been positively identified as a risk factor for suicide.

Patients with pituitary disease are diagnosed and treated for depression and show little response to the treatment for depression.

Pancreas

  • Hypoglycemia:
    • An overproduction of insulin causes reduced blood levels of glucose.
    • In one study of patients recovering from acute lung injury in intensive care, those patients who developed hypoglycaemia while hospitalised showed an increased rate of depression.

Neurological

Central Nervous System Tumours

In addition to pituitary tumours, tumours in various locations in the central nervous system (CNS) may cause depressive symptoms and be misdiagnosed as depression.

Post Concussion Syndrome

Post-concussion syndrome (PCS), is a set of symptoms that a person may experience for weeks, months, or occasionally years after a concussion with a prevalence rate of 38-80% in mild traumatic brain injuries, it may also occur in moderate and severe cases of traumatic brain injury. A diagnosis may be made when symptoms resulting from concussion, depending on criteria, last for more than three to six months after the injury, in which case it is termed persistent post-concussive syndrome (PPCS). In a study of the prevalence of post concussion syndrome symptoms in patients with depression utilising the British Columbia Post-concussion Symptom Inventory: “Approximately 9 out of 10 patients with depression met liberal self-report criteria for a post-concussion syndrome and more than 5 out of 10 met conservative criteria for the diagnosis.” These self reported rates were significantly higher than those obtained in a scheduled clinical interview. Normal controls have exhibited symptoms of PCS as well as those seeking psychological services. There is considerable debate over the diagnosis of PCS in part because of the medico-legal and thus monetary ramifications of receiving the diagnosis.

Pseudobulbar Affect

Pseudobulbar affect (PBA) is an affective disinhibition syndrome that is largely unrecognised in clinical settings and thus often untreated due to ignorance of the clinical manifestations of the disorder; it may be misdiagnosed as depression. It often occurs secondary to various neurodegenerative diseases such as amyotrophic lateral sclerosis, and also can result from head trauma. PBA is characterised by involuntary and inappropriate outbursts of laughter and/or crying. PBA has a high prevalence rate with estimates of 1.5-2 million cases in the United States alone.

Multiple Sclerosis

Multiple sclerosis is a chronic demyelinating disease in which the myelin sheaths of cells in the brain and spinal cord are irreparably damaged. Symptoms of depression are very common in patients at all stages of the disease and may be exacerbated by medical treatments, notably interferon beta-1a.

Neurotoxicity

Various compounds have been shown to have neurotoxic effects many of which have been implicated as having a causal relationship in the development of depression.

Cigarette Smoking

There has been research which suggests a correlation between cigarette smoking and depression. The results of one recent study suggest that smoking cigarettes may have a direct causal effect on the development of depression. There have been various studies done showing a positive link between smoking, suicidal ideation and suicide attempts.

In a study conducted among nurses, those smoking between 1-24 cigarettes per day had twice the suicide risk; 25 cigarettes or more, 4 times the suicide risk, than those who had never smoked. In a study of 300,000 male US Army soldiers, a definitive link between suicide and smoking was observed with those smoking over a pack a day having twice the suicide rate of non-smokers.

Medication

Various medications have been suspected of having a causal relation in the development of depression; this has been classified as “organic mood syndrome”. Some classes of medication such as those used to treat hypertension, have been recognised for decades as having a definitive relationship with the development of depression.

Monitoring of those taking medications which have shown a relationship with depression is often indicated, as well as the necessity of factoring in the use of such medications in the diagnostic process.

  • Topical Tretinoin (Retin-A):
    • Derived from Vitamin A and used for various medical conditions such as in topical solutions used to treat acne vulgaris.
    • Although applied externally to the skin, it may enter the bloodstream and cross the blood brain barrier where it may have neurotoxic effects.
  • Interferons:
    • Proteins produced by the human body, three types have been identified alpha, beta and gamma.
    • Synthetic versions are utilised in various medications used to treat different medical conditions such as the use of interferon-alpha in cancer treatment and hepatitis C treatment.
    • All three classes of interferons may cause depression and suicidal ideation.

Chronic Exposure to Organophosphates

The neuropsychiatric effects of chronic organophosphate exposure include mood disorders, suicidal thinking and behaviour, cognitive impairment and chronic fatigue.

Neuropsychiatric

Bipolar Disorder

Bipolar disorder is frequently misdiagnosed as major depression, and is thus treated with antidepressants alone which is not only not efficacious it is often contraindicated as it may exacerbate hypomania, mania, or cycling between moods. There is ongoing debate about whether this should be classified as a separate disorder because individuals diagnosed with major depression often experience some hypomanic symptoms, indicating a continuum between the two.

Nutritional Deficiencies

Nutrition plays a key role in every facet of maintaining proper physical and psychological wellbeing. Insufficient or inadequate nutrition can have a profound effect on mental health. The emerging field of nutritional neuroscience explores the various connections between diet, neurological functioning and mental health.

  • Vitamin B6:
    • Pyridoxal phosphate (PLP), the active form of B6, is a cofactor in the dopamine serotonin pathway, a deficiency in vitamin B6 may cause depressive symptoms.
  • Folate (vitamin B9) – Vitamin B12 cobalamin:
    • Low blood plasma and particularly red cell folate and diminished levels of vitamin B12 have been found in patients with depressive disorders.
    • Research suggests that oral doses of both folic acid (800 μg/(mcg) daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.
  • Long chain fatty acids:
    • Higher levels of omega-6 and lower levels of omega-3 fatty acids has been associated with depression and behavioural change.
  • Vitamin D deficiency is associated with depression

Sleep Disorders

  • Insomnia:
    • While the inability to fall asleep is often a symptom of depression, it can also in some instances serve as the trigger for developing a depressive disorder.
    • It can be transient, acute or chronic.
    • It can be a primary disorder or a co-morbid one.
  • Restless legs syndrome (RLS):
    • Also known as Wittmaack-Ekbom’s syndrome, is characterised by an irresistible urge to move one’s body to stop uncomfortable or odd sensations.
    • It most commonly affects the legs, but can also affect the arms or torso, and even phantom limbs.
    • Restless Leg syndrome has been associated with Major depressive disorder.
    • Adjusted odds ratio for diagnosis of major depressive disorder suggest a strong association between restless legs syndrome and major depressive disorder and/or panic disorder.
  • Sleep apnea:
    • This is a sleep disorder characterised by pauses in breathing during sleep.
    • Each episode, called an apnoea, lasts long enough for one or more breaths to be missed; such episodes occur repeatedly throughout the sleep cycle.
    • Undiagnosed sleep apnoea may cause or contribute to the severity of depression.
  • Circadian rhythm sleep disorders:
    • Few clinicians are aware, and often goes untreated or are treated inappropriately, as when misdiagnosed as either primary insomnia or as a psychiatric condition.

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.

Linking Eating Habits & Sleep Patterns in Adolescents with Symptoms of Depression

Research Paper Title

Eating habits and sleep patterns of adolescents with depression symptoms in Mumbai, India.

Background

Adolescents with depression engage in unhealthy eating habits and irregular sleep patterns and are often at an increased risk for weight-related problems.

Improvement in these lifestyle behaviours may help to prevent depression, but knowledge about the associations between depression, sleep, eating habits and body weight among adolescents in India is limited.

Methods

This cross-sectional study investigated the prevalence of depression and its association with sleep patterns, eating habits and body weight status among a convenience sample of 527 adolescents, ages 10-17 years in Mumbai, India.

Participants completed a survey on sleep patterns such as sleep duration, daytime sleepiness and sleep problems and eating habits such as frequency of breakfast consumption, eating family meals and eating out.

Depression was assessed using the Patient Health Questionnaire modified for Adolescents (PHQ-A).

Anthropometric measurements were also taken.

Results

Within this sample, 25% had moderate to severe depression (PHQ-A ≥ 10) and 46% reported sleeping less than 6 h > thrice a week.

Adolescents with moderate to severe depression had significantly higher body mass index than those with minimal depression (26.2 ± 6.6 vs. 20.2 ± 4.8 kg/m2 ).

The odds of having clinically significant depression (PHQ-A ≥ 10) was 4.5 times higher in adolescents who had family meals ≤ once a week, 1.6 times higher among those who were sleeping <6 h and 2.3 times higher among participants having trouble falling to sleep more than thrice a week.

Conclusions

The findings indicated that a significant proportion of adolescents had depression symptoms; improving sleep and eating habits may present potential targets for interventions.

Reference

Moitra, P., Madan, J. & Shaikh, N.I. (2020) Eating habits and sleep patterns of adolescents with depression symptoms in Mumbai, India. Maternal & Child Nutrition. 16 Suppl 3(Suppl 3):e12998. doi: 10.1111/mcn.12998.

What is the Impact of Military Service Exposures & Psychological Resilience on the Mental Health Trajectories of Older Male Veterans?

Research Paper Title

The Impact of Military Service Exposures and Psychological Resilience on the Mental Health Trajectories of Older Male Veterans.

Background

The researchers examine the impact of exposure to the dead, dying, and wounded (DDW) during military service on the later-life depressive symptom trajectories of male United States veterans, using psychological resilience as an internal resource that potentially moderates negative consequences.

Methods

The Health and Retirement Study (2006-2014) and linked Veteran Mail Survey were used to estimate latent growth curve models of depressive symptom trajectories, beginning at respondents’ first report of resilience.

Results

Veterans with higher levels of resilience do not have increased depressive symptoms in later life, despite previous exposure to DDW. Those with lower levels of resilience and previous exposure to DDW experience poorer mental health in later life.

Conclusions

Psychological resilience is important for later-life mental health, particularly for veterans who endured potentially traumatic experiences. The researches discuss the importance acknowledging the role individual resources play in shaping adaptation to adverse life events and implications for mental health service needs.

Reference

Urena, S., Taylor, M.G. & Carr, D.C. (2020) The Impact of Military Service Exposures and Psychological Resilience on the Mental Health Trajectories of Older Male Veterans. Journal of Aging and Health. doi: 10.1177/0898264320975231. Online ahead of print.

Book: The Good News About Depression

Book Title:

The Good News About Depression: Cures And Treatments In The New Age Of Psychiatry.

Author(s): Mark S. Gold.

Year: 1995.

Edition: First (1st).

Publisher: Infobase Publishing.

Type(s): Paperback and Kindle.

Synopsis:

Ten years ago pioneering biopsychiatrist Mark S. Gold, M.D. wrote a visionary guide to the effective new medical therapies emerging for the treatment of depression. Now, in this newly revised edition of his classic book, Dr. Gold does it again. The new Good News reveals how, in just a decade, sophisticated new research and drug therapies have revolutionised the care of all types of depression.

This essential resource includes:

  • New treatments for depression and manic depression for 1995 and on the horizon for approval.
  • New diagnostic guidelines for different types of depression, including crucial tests many physicians omit.
  • The most common illnesses that mimic depression.
  • New tools to treat depression, such as light therapy and hormone therapy.
  • An all-new chapter on Prozac and other state-of-the-art medications.
  • New information on depression in women, children, and seniors.
  • Vital new approaches to relapse prevention.

Plus a complete guide to self-help, and in depth advice on getting and evaluating the proper treatment.