What is the Diathesis-Stress Model?

Introduction

The diathesis-stress model, also known as the vulnerability-stress model, is a psychological theory that attempts to explain a disorder, or its trajectory, as the result of an interaction between a predispositional vulnerability, the diathesis, and a stress caused by life experiences. The term diathesis derives from the Greek term (διάθεσις) for a predisposition, or sensibility. A diathesis can take the form of genetic, psychological, biological, or situational factors. A large range of differences exists among individuals’ vulnerabilities to the development of a disorder.

The diathesis, or predisposition, interacts with the individual’s subsequent stress response. Stress is a life event or series of events that disrupts a person’s psychological equilibrium and may catalyse the development of a disorder. Thus the diathesis-stress model serves to explore how biological or genetic traits (diatheses) interact with environmental influences (stressors) to produce disorders such as depression, anxiety, or schizophrenia. The diathesis-stress model asserts that if the combination of the predisposition and the stress exceeds a threshold, the person will develop a disorder. The use of the term diathesis in medicine and in the specialty of psychiatry dates back to the 1800s; however, the diathesis-stress model was not introduced and used to describe the development of psychopathology until it was applied to explaining schizophrenia in the 1960s by Paul Meehl.

The diathesis-stress model is used in many fields of psychology, specifically for studying the development of psychopathology. It is useful for the purposes of understanding the interplay of nature and nurture in the susceptibility to psychological disorders throughout the lifespan. Diathesis-stress models can also assist in determining who will develop a disorder and who will not. For example, in the context of depression, the diathesis-stress model can help explain why Person A may become depressed while Person B does not, even when exposed to the same stressors. More recently, the diathesis-stress model has been used to explain why some individuals are more at risk for developing a disorder than others. For example, children who have a family history of depression are generally more vulnerable to developing a depressive disorder themselves. A child who has a family history of depression and who has been exposed to a particular stressor, such as exclusion or rejection by his or her peers, would be more likely to develop depression than a child with a family history of depression that has an otherwise positive social network of peers. The diathesis-stress model has also served as useful in explaining other poor (but non-clinical) developmental outcomes.

Protective factors, such as positive social networks or high self-esteem, can counteract the effects of stressors and prevent or curb the effects of disorder. Many psychological disorders have a window of vulnerability, during which time an individual is more likely to develop disorder than others. Diathesis-stress models are often conceptualised as multi-causal developmental models, which propose that multiple risk factors over the course of development interact with stressors and protective factors contributing to normal development or psychopathology. The differential susceptibility hypothesis is a recent theory that has stemmed from the diathesis-stress model.

Diathesis

The term diathesis is synonymous with vulnerability, and variants such as “vulnerability-stress” are common within psychology. A vulnerability makes it more or less likely that an individual will succumb to the development of psychopathology if a certain stress is encountered. Diatheses are considered inherent within the individual and are typically conceptualised as being stable, but not unchangeable, over the lifespan. They are also often considered latent (i.e. dormant), because they are harder to recognise unless provoked by stressors.

Diatheses are understood to include genetic, biological, physiological, cognitive, and personality-related factors. Some examples of diatheses include genetic factors, such as abnormalities in some genes or variations in multiple genes that interact to increase vulnerability. Other diatheses include early life experiences such as the loss of a parent, or high neuroticism. Diatheses can also be conceptualised as situational factors, such as low socio-economic status or having a parent with depression.

Stress

Stress can be conceptualised as a life event that disrupts the equilibrium of a person’s life. For instance, a person may be vulnerable to become depressed, but will not develop depression unless they are exposed to a specific stress, which may trigger a depressive disorder. Stressors can take the form of a discrete event, such the divorce of parents or a death in the family, or can be more chronic factors such as having a long-term illness, or ongoing marital problems. Stresses can also be related to more daily hassles such as school assignment deadlines. This also parallels the popular (and engineering) usage of stress, but note that some literature defines stress as the response to stressors, especially where usage in biology influences neuroscience.

It has been long recognised that psychological stress plays a significant role in understanding how psychopathology develops in individuals. However, psychologists have also identified that not all individuals who are stressed, or go through stressful life events, develop a psychological disorder. To understand this, theorists and researchers explored other factors that affect the development of a disorder and proposed that some individuals under stress develop a disorder and others do not. As such, some individuals are more vulnerable than others to develop a disorder once stress has been introduced. This led to the formulation of the diathesis-stress model.

Genetics

Sensory processing sensitivity (SPS) is a temperamental or personality trait involving “an increased sensitivity of the central nervous system and a deeper cognitive processing of physical, social and emotional stimuli”. The trait is characterised by “a tendency to ‘pause to check’ in novel situations, greater sensitivity to subtle stimuli, and the engagement of deeper cognitive processing strategies for employing coping actions, all of which is driven by heightened emotional reactivity, both positive and negative”.

Sensory processing sensitivity captures sensitivity to environment in a heritable, evolutionary-conserved trait, associated with increased information processing in the brain. Moderating sensitivity to environments in a for-better-and-for-worse fashion. Interaction with negative experiences increases risk for psychopathology. Whereas interaction with positive experiences (including interventions), increases positive outcomes. Mast cells are long-lived tissue-resident cells with an important role in many inflammatory settings including host defence to parasitic infection and in allergic reactions. Stress is known to be a mast cell activator.

There is evidence that children exposed to prenatal stress may experience resilience driven by epigenome-wide interactions.” Early life stress interactions with the epigenome show potential mechanisms driving vulnerability towards psychiatric illness. ancestral stress alters lifetime mental health trajectories via epigenetic regulation.

Carriers of congenital adrenal hyperplasia have a predeposition to stress, due to the unique nature of this gene. True rates of prevalence are not known but common genetic variants of the human Steroid 21-Hydroxylase Gene (CYP21A2) are related to differences in circulating hormone levels in the population.

Psychological distress is a known feature of generalised joint hypermobility (gJHM), as well as of its most common syndromic presentation, namely Ehlers-Danlos syndrome, hypermobility type (a.k.a. joint hypermobility syndrome – JHS/EDS-HT), and significantly contributes to the quality of life of affected individuals. Interestingly, in addition to the confirmation of a tight link between anxiety and gJHM, preliminary connections with depression, attention deficit (and hyperactivity) disorder, autism spectrum disorders, and obsessive-compulsive personality disorder were also found.

Protective Factors

Protective factors, while not an inherent component of the diathesis-stress model, are of importance when considering the interaction of diatheses and stress. Protective factors can mitigate or provide a buffer against the effects of major stressors by providing an individual with developmentally adaptive outlets to deal with stress. Examples of protective factors include a positive parent-child attachment relationship, a supportive peer network, and individual social and emotional competence.

Throughout the Lifespan

Many models of psychopathology generally suggest that all people have some level of vulnerability towards certain mental disorders, but posit a large range of individual differences in the point at which a person will develop a certain disorder. For example, an individual with personality traits that tend to promote relationships such as extroversion and agreeableness may engender strong social support, which may later serve as a protective factor when experiencing stressors or losses that may delay or prevent the development of depression. Conversely, an individual who finds it difficult to develop and maintain supportive relationships may be more vulnerable to developing depression following a job loss because they do not have protective social support. An individual’s threshold is determined by the interaction of diatheses and stress.

Windows of vulnerability for developing specific psychopathologies are believed to exist at different points of the lifespan. Moreover, different diatheses and stressors are implicated in different disorders. For example, breakups and other severe or traumatic life stressors are implicated in the development of depression. Stressful events can also trigger the manic phase of bipolar disorder and stressful events can then prevent recovery and trigger relapse. Having a genetic disposition for becoming addicted and later engaging in binge drinking in college are implicated in the development of alcoholism. A family history of schizophrenia combined with the stressor of being raised in a dysfunctional family raises the risk of developing schizophrenia.

Diathesis-stress models are often conceptualised as multi-causal developmental models, which propose that multiple risk factors over the course of development interact with stressors and protective factors contributing to normal development or psychopathology. For example, a child with a family history of depression likely has a genetic vulnerability to depressive disorder. This child has also been exposed to environmental factors associated with parental depression that increase their vulnerability to developing depression as well. Protective factors, such as strong peer network, involvement in extracurricular activities, and a positive relationship with the non-depressed parent, interact with the child’s vulnerabilities in determining the progression to psychopathology versus normative development.

Some theories have branched from the diathesis-stress model, such as the differential susceptibility hypothesis, which extends the model to include a vulnerability to positive environments as well as negative environments or stress. A person could have a biological vulnerability that when combined with a stressor could lead to psychopathology (diathesis-stress model); but that same person with a biological vulnerability, if exposed to a particularly positive environment, could have better outcomes than a person without the vulnerability.

What is the Management of Depression?

Introduction

Depression is a symptom of some physical diseases; a side effect of some drugs and medical treatments; and a symptom of some mood disorders such as major depressive disorder or dysthymia. Physical causes are ruled out with a clinical assessment of depression that measures vitamins, minerals, electrolytes, and hormones. Management of depression may involve a number of different therapies: medications, behaviour therapy, psychotherapy, and medical devices.

Though psychiatric medication is the most frequently prescribed therapy for major depression, psychotherapy may be effective, either alone or in combination with medication. Combining psychotherapy and antidepressants may provide a “slight advantage”, but antidepressants alone or psychotherapy alone are not significantly different from other treatments, or “active intervention controls”. Given an accurate diagnosis of major depressive disorder, in general the type of treatment (psychotherapy and/or antidepressants, alternate or other treatments, or active intervention) is “less important than getting depressed patients involved in an active therapeutic program.”

Psychotherapy is the treatment of choice in those under the age of 18, with medication offered only in conjunction with the former and generally not as a first line agent. The possibility of depression, substance misuse or other mental health problems in the parents should be considered and, if present and if it may help the child, the parent should be treated in parallel with the child.

Psychotherapy and Behaviour Therapy

There are a number of different psychotherapies for depression which are provided to individuals or groups by psychotherapists, psychiatrists, psychologists, clinical social workers, counsellors or psychiatric nurses. With more chronic forms of depression, the most effective treatment is often considered to be a combination of medication and psychotherapy. Psychotherapy is the treatment of choice in people under 18. A meta-analysis examined the effectiveness of psychotherapy for depression across ages from younger than 13 years to older than 75 years. It summarizes results from 366 trials included 36,702 patients. It found that the best results were for young adults, with an average effect size of g=.98 (95% CI, 0.79-1.16). The effects were smallest for young children (<13 years), g = .35 (95% CI, 0.15-0.55), and second largest in the oldest group, g = .97 (95% CI, 0.42-1.52). The study was not able to compare the different types of therapy to each other. Most of the studies with children used therapies originally developed with adults, which may have reduced the effectiveness. The greater benefits with young adults might be due to a large number of studies including college students, who might have an easier time learning therapy skills and techniques. Most of the studies in children were done in the USA, whereas in older age groups, more balanced numbers of studies came from Europe and other parts of the world as well.

As the most studied form of psychotherapy for depression, cognitive behavioural therapy (CBT) is thought to work by teaching clients to learn a set of cognitive and behavioural skills, which they can employ on their own. Earlier research suggested that cognitive behavioural therapy was not as effective as antidepressant medication in the treatment of depression; however, more recent research suggests that it can perform as well as antidepressants in treating patients with moderate to severe depression. Beck’s treatment manual, Cognitive therapy of depression, has undergone the most research and accumulated the most evidence for its use. However, a number of other CBT manuals also have evidence to support their effectiveness with depression.

The effect of psychotherapy on patient and clinician rated improvement as well as on revision rates have declined steadily from the 1970s.

A systematic review of data comparing low-intensity CBT (such as guided self-help by means of written materials and limited professional support, and website-based interventions) with usual care found that patients who initially had more severe depression benefited from low-intensity interventions at least as much as less-depressed patients.

For the treatment of adolescent depression, one published study found that CBT without medication performed no better than a placebo, and significantly worse than the antidepressant fluoxetine. However, the same article reported that CBT and fluoxetine outperformed treatment with only fluoxetine. Combining fluoxetine with CBT appeared to bring no additional benefit in two different studies or, at the most, only marginal benefit, in a fourth study.

Behaviour therapy for depression is sometimes referred to as behavioural activation. Studies exist showing behavioural activation to be superior to CBT. In addition, behavioural activation appears to take less time and lead to longer lasting change. Two well-researched treatment manuals include Social skills training for depression and Behavioural activation treatment for depression.

Emotionally focused therapy, founded by Sue Johnson and Les Greenberg in 1985, treats depression by identifying and processing underlying emotions. The treatment manual, Facilitating emotional change, outlines treatment techniques.

Acceptance and commitment therapy (ACT), a mindfulness form of CBT, which has its roots in behaviour analysis, also demonstrates that it is effective in treating depression, and can be more helpful than traditional CBT, especially where depression is accompanied by anxiety and where it is resistant to traditional CBT.

A review of four studies on the effectiveness of mindfulness-based cognitive therapy (MBCT), a recently developed class-based program designed to prevent relapse, suggests that MBCT may have an additive effect when provided with the usual care in patients who have had three or more depressive episodes, although the usual care did not include antidepressant treatment or any psychotherapy, and the improvement observed may have reflected non-specific or placebo effects. Of note, although Mindfulness-based cognitive therapy for depression prevented relapse of future depressive episodes, there is no research on whether it can cause the remission of a current depressive episode.

Interpersonal psychotherapy (IPT) focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment for depression. Here, the therapy takes a fairly structured course (often 12 sessions, as in the original research versions) as in the case with CBT; however, the focus is on relationships with others. Unlike family therapy, IPT is an individual format, so it is possible to work on interpersonal themes even if other family members do not come to the session. Therapy can be used to help a person develop or improve interpersonal skills in order to allow him or her to communicate more effectively and reduce stress. In a meta-analysis of 16 studies and 4,356 patients, the average improvement in depressive symptoms was an effect size of d = 0.63 (95% CI, 0.36 to 0.90). IPT combined with pharmacotherapy was more effective in preventing relapse than pharmacotherapy alone, number needed to treat = 7.63.

Psychoanalysis, a school of thought founded by Sigmund Freud that emphasizes the resolution of unconscious mental conflicts, is used by its practitioners to treat clients presenting with major depression. A more widely practiced technique, called psychodynamic psychotherapy, is loosely based on psychoanalysis and has an additional social and interpersonal focus. In a meta-analysis of three controlled trials, psychodynamic psychotherapy was found to be as effective as medication for mild to moderate depression.

Shared Care

Shared decision making is an approach whereby patients and clinicians freely share important evidence when tasked with decision making and where patients are guided to consider the best available options to make an informed decision. The principles are well documented, but there is a gap in that it’s hard to apply them in routine clinical practice. The steps have been simplified into five steps. The first step is seeking patient participation in that the health practitioner is tasked with communicating existing choices and therefore inviting them to the decision making process. The next step involves assisting the patient to explore and compare the treatment options by a critical analysis of the risks and benefits. The third step involves the assessment of the patient’s values and what they prefer taking to account what is of paramount urgency to the patient. Step 4 involves decision making where the patient and the practitioner make a conclusive decision on the best option and arrange for subsequent follow up meetings. Finally, the fifth step involves the analysis of the patient’s decision’. Five steps for you and your patients to work together to make the best possible health care decisions. The step involves monitoring of the degree of implementation, overcoming of barriers of decision implantation consequently the decisions need to be revisited and optimised thus ensuring the decision has a positive impact on health outcomes its success relies on the ability of the health practitioner to create a good interpersonal relationship with the patient.

Depression still remains a major problem in the US whereby statistics have it that 16 million people were affected in the year 2017. The depression is multifactorial and has been on the increase due to societal pressure, genetic association and increase in use of drugs. incorporation of nursing in management of depression may seem important in that nursing holds a pivotal role in health care delivery where they are the health practitioners that have been trained to be versatile from clinical to psychological care. Their incorporation in shared decision making in treating depression may be important as nurses are known to have the best interpersonal relationship with the patients thus a better collaborative model can be achieved due to this fact. With this in mind, the nurses may serve to administer drugs in management, prepare and maintain the patient’s records, interaction with other care staff to achieve optimum care, and organising therapy sessions. In a study another study concerning shared decision-making interventions for people with mental health conditions there were no overt benefits that were discovered and the called for further research in this area. Another study found that it is important to begin the dissemination and implementation of SDM as they proved that it has benefits in healthcare especially in mental health care and has received social and government support and however transitioning to SDM has proven to be an uphill task. It has been suggested that SDM is of importance in demonstrating patient preferences in decision making when there is no clear approach to treatment. In addition, numerous tools can be used to make the decision making the process easier these include the Controlled Preferences Scale that informs clinicians on how to actively involve patients

Commentators suggest that providers need to embrace shared decision making by making sure that patients participate actively in their management thus enabling the success of the model.

Medication

To find the most effective pharmaceutical drug treatment, the dosages of medications must often be adjusted, different combinations of antidepressants tried, or antidepressants changed. Norepinephrine reuptake inhibitor (NRIs) can be used as antidepressants. Selective serotonin reuptake inhibitors (SSRIs), such as sertraline (Zoloft, Lustral), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac), paroxetine (Seroxat), and citalopram, are the primary medications considered, due to their relatively mild side effects and broad effect on the symptoms of depression and anxiety, as well as reduced risk in overdose, compared to their older tricyclic alternatives. Those who do not respond to the first SSRI tried can be switched to another. If sexual dysfunction is present prior to the onset of depression, SSRIs should be avoided. Another popular option is to switch to the atypical antidepressant bupropion (Wellbutrin) or to add bupropion to the existing therapy; this strategy is possibly more effective. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating noradrenergic and specific serotonergic antidepressant (NaSSA) antidepressant mirtazapine (Zispin, Remeron) can be used in such cases. CBT for Insomnia can also help to alleviate the insomnia without additional medication. Venlafaxine (Effexor) from the SNRI class may be moderately more effective than SSRIs; however, it is not recommended as a first-line treatment because of the higher rate of side effects, and its use is specifically discouraged in children and adolescents. Fluoxetine is the only antidepressant recommended for people under the age of 18, though, if a child or adolescent patient is intolerant to fluoxetine, another SSRI may be considered. Evidence of effectiveness of SSRIs in those with depression complicated by dementia is lacking.

Tricyclic antidepressants (TCAs) have more side effects than SSRIs (but less sexual dysfunctions) and are usually reserved for the treatment of inpatients, for whom the tricyclic antidepressant amitriptyline, in particular, appears to be more effective. A different class of antidepressants, the monoamine oxidase inhibitors, have historically been plagued by questionable efficacy (although early studies used dosages now considered too low) and life-threatening adverse effects. They are still used only rarely, although newer agents of this class (RIMA), with a better side effect profile, have been developed.

In older patients TCAs and SSRIs are of the same efficacy. However, there are differences between TCA related antidepressants and classical TCAs in terms of side effect profiles and withdrawal when compared to SSRIs.

There is evidence a prominent side-effect of antidepressants, emotional blunting, is confused with a symptom of depression itself. The cited study, according to Professor Linda Gask was: ‘funded by a pharmaceutical company (Servier) and two of its authors are employees of that company’, which may bias the results. The study authors’ note: “emotional blunting is reported by nearly half of depressed patients on antidepressants and that it appears to be common to all monoaminergic antidepressants not only SSRIs”. Additionally, they note: “The OQuESA scores are highly correlated with the HAD depression score; emotional blunting cannot be described simply as a side-effect of antidepressant, but also as a symptom of depression…More emotional blunting is associated with a poorer quality of remission…”

Acetyl-l-Carnitine

Acetylcarnitine levels were lower in depressed patients than controls and in rats it causes rapid antidepressant effects through epigenetic mechanisms. A systematic review and meta-analysis of 12 randomised controlled trials found “supplementation significantly decreases depressive symptoms compared with placebo/no intervention, while offering a comparable effect with that of established antidepressant agents with fewer adverse effects.”

Zinc

A 2012 cross-sectional study found an association between zinc deficiency and depressive symptoms among women, but not men, and a 2013 meta-analysis of 17 observational studies found that blood zinc concentrations were lower in depressed subjects than in control subjects. A 2012 meta-analysis found that zinc supplementation as an adjunct to antidepressant drug treatment significantly lowered depressive symptom scores of depressed patients. The potential mechanisms underlying the association between low serum zinc and depression remain unclear, but may involve the regulation of neurotransmitter, endocrine and neurogenesis pathways. Zinc supplementation has been reported to improve symptoms of ADHD and depression. A 2013 review found that zinc supplementation may be an effective treatment in major depression.

Magnesium

Many studies have found an association between magnesium intake and depression. Magnesium was lower in serum of depressed patients than controls. One trial found magnesium chloride to be effective for depression in seniors with type 2 diabetes while another trial found magnesium citrate decreased depression in patients with fibromyalgia. One negative trial used magnesium oxide, which is poorly absorbed. A randomised, open-label study found that consumption of magnesium chloride for 6 weeks resulted in a clinically significant net improvement in depression, and that effects were observed within 2 weeks.

Augmentation

Physicians often add a medication with a different mode of action to bolster the effect of an antidepressant in cases of treatment resistance; a 2002 large community study of 244,859 depressed Veterans Administration patients found that 22% had received a second agent, most commonly a second antidepressant. 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. Addition of atypical antipsychotics when the patient has not responded to an antidepressant is also known to increase the effectiveness of antidepressant drugs, albeit at the cost of more frequent and potentially serious side effects. There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function. Stephen M. Stahl, renowned academician in psychopharmacology, has stated resorting to a dynamic psychostimulant, in particular, d-amphetamine is the “classical augmentation strategy for treatment-refractory depression”. However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.

Efficacy of Medication and Psychotherapy

Antidepressants are statistically superior to placebo but their overall effect is low-to-moderate. In that respect they often did not exceed the National Institute for Health and Clinical Excellence (NICE) criteria for a “clinically significant” effect. In particular, the effect size was very small for moderate depression but increased with severity, reaching “clinical significance” for very severe depression. These results were consistent with the earlier clinical studies in which only patients with severe depression benefited from either psychotherapy or treatment with an antidepressant, imipramine, more than from the placebo treatment. Despite obtaining similar results, the authors argued about their interpretation. One author concluded that there “seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit.” The other author agreed that “antidepressant ‘glass’ is far from full” but disagreed “that it is completely empty”. He pointed out that the first-line alternative to medication is psychotherapy, which does not have superior efficacy.

Antidepressants in general are as effective as psychotherapy for major depression, and this conclusion holds true for both severe and mild forms of MDD. In contrast, medication gives better results for dysthymia. The subgroup of SSRIs may be slightly more efficacious than psychotherapy. On the other hand, significantly more patients drop off from the antidepressant treatment than from psychotherapy, likely because of the side effects of antidepressants. Successful psychotherapy appears to prevent the recurrence of depression even after it has been terminated or replaced by occasional “booster” sessions. The same degree of prevention can be achieved by continuing antidepressant treatment.

Two studies suggest that the combination of psychotherapy and medication is the most effective way to treat depression in adolescents. Both TADS (Treatment of Adolescents with Depression Study) and TORDIA (Treatment of Resistant Depression in Adolescents) showed very similar results. TADS resulted in 71% of their teen subjects having “much” or “very much” improvement in mood over the 61% with medication alone and 43% with CBT alone. Similarly, TORDIA showed a 55% improvement with CBT and drugs versus a 41% with drug therapy alone. However, a more recent meta-analysis of 34 trials of 14 drugs used with children and adolescents found that only fluoxetine produced significant benefit compared to placebo, with a medium sized effect (standardize mean difference = .5).

Treatment Resistance

The risk factors for treatment resistant depression are: the duration of the episode of depression, severity of the episode, if bipolar, lack of improvement in symptoms within the first couple of treatment weeks, anxious or avoidant and borderline comorbidity and old age. Treatment resistant depression is best handled with a combination of conventional antidepressant together with atypical antipsychotics. Another approach is to try different antidepressants. It is inconclusive which approach is superior. Treatment resistant depression can be misdiagnosed if subtherapeutic doses of antidepressants is the case, patient nonadherence, intolerable adverse effects or their thyroid disease or other conditions is misdiagnosed as depression.

Experimental Treatments

Chromium

Clinical and experimental studies have reported antidepressant activity of chromium particularly in atypical depression, characterised by increased appetite and carbohydrate craving.

Essential Fatty Acids

A 2015 Cochrane Collaboration review found insufficient evidence with which to determine if omega-3 fatty acid has any effect on depression. A 2016 review found that if trials with formulations containing mostly eicosapentaenoic acid (EPA) are separated from trials using formulations containing docosahexaenoic acid (DHA), it appeared that EPA may have an effect while DHA may not, but there was insufficient evidence to be sure.

Creatine

The amino acid creatine, commonly used as a supplement to improve the performance of bodybuilders, has been studied for its potential antidepressant properties. A double-blinded, placebo-controlled trial focusing on women with major depressive disorder found that daily creatine supplementation adjunctive to escitalopram was more effective than escitalopram alone. Studies on mice have found that the antidepressant effects of creatine can be blocked by drugs that act against dopamine receptors, suggesting that the drug acts on dopamine pathways.

Dopamine Receptor Agonist

Some research suggests dopamine receptor agonist may be effective in treating depression, however studies are few and results are preliminary.

Inositol

Inositol, an alcohol sugar found in fruits, beans grains and nuts may have antidepressant effects in high doses. Inositol may exert its effects by altering intracellular signalling.

Ketamine

Research on the antidepressant effects of ketamine infusions at subanaesthetic doses has consistently shown rapid (4 to 72 hours) responses from single doses, with substantial improvement in mood in the majority of patients and remission in some. However, these effects are often short-lived, and attempts to prolong the antidepressant effect with repeated doses and extended (“maintenance”) treatment have resulted in only modest success.

N-Acetylcysteine

A systematic review and meta-analysis of 5 studies found that N-Acetylcysteine reduces depressive symptoms more than placebo and has good tolerability. N-Acetylecysteine may exert benefits as a precursor to the antioxidant glutathione, thus modulating glutamatergic, neurotropic, and inflammatory pathways.

St John’s Wort

A 2008 Cochrane Collaboration meta-analysis concluded that:

“The available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have fewer side effects than standard antidepressants. The association of country of origin and precision with effects sizes complicates the interpretation.”

The United States National Centre for Complementary and Integrative Health advice is that “St. John’s wort may help some types of depression, similar to treatment with standard prescription antidepressants, but the evidence is not definitive.” and warns that “Combining St. John’s wort with certain antidepressants can lead to a potentially life-threatening increase of serotonin, a brain chemical targeted by antidepressants. St. John’s wort can also limit the effectiveness of many prescription medicines.”

Rhodiola Rosea

A 2011 review reported Rhodiola rosea “is an adaptogen plant that can be especially helpful in treating asthenic or lethargic depression, and may be combined with conventional antidepressants to alleviate some of their common side effects.” A 6 week double-blind, placebo-controlled, randomised study with 89 patients with mild to moderate depression found that R. rosea statistically significantly reduced depression symptoms, and no side effects were reported.

Saffron

A 2013 meta-analysis found that saffron supplementation significantly reduced depression symptoms compared to placebo, and both saffron supplementation and the antidepressant groups were similarly effective in reducing depression symptoms. A 2015 meta-analysis supported the “efficacy of saffron as compared to placebo in improving the following conditions: depressive symptoms (compared to anti-depressants and placebo), premenstrual symptoms, and sexual dysfunction. In addition, saffron use was also effective in reducing excessive snacking behavior.” The antidepressant effect of saffron stigma extracts may be mediated via its components safranal and crocin: “crocin may act via the uptake inhibition of dopamine and norepinephrine, and safranal via serotonin.” Therapeutic doses of saffron exhibits no significant toxicity in both clinical and experimental investigations.

SAMe

S-Adenosyl methionine (SAMe) is available as a prescription antidepressant in Europe and an over-the-counter dietary supplement in the US. Evidence from 16 clinical trials with a small number of subjects, reviewed in 1994 and 1996 suggested it to be more effective than placebo and as effective as standard antidepressant medication for the treatment of major depression.

Tryptophan and 5-HTP

The amino acid tryptophan is converted into 5-hydroxytryptophan (5-HTP) which is subsequently converted into the neurotransmitter serotonin. Since serotonin deficiency has been recognized as a possible cause of depression, it has been suggested that consumption of tryptophan or 5-HTP may therefore improve depression symptoms by increasing the level of serotonin in the brain. 5-HTP and tryptophan are sold over the counter in North America, but requires a prescription in Europe. The use of 5-HTP instead of tryptophan bypasses the conversion of tryptophan into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin, and 5-HTP easily crosses the blood–brain barrier unlike tryptophan, which requires a transporter.

Small studies have been performed using 5-HTP and tryptophan as adjunctive therapy in addition to standard treatment for depression. While some studies had positive results, they were criticised for having methodological flaws, and a more recent study did not find sustained benefit from their use. The safety of these medications has not been well studied. Due to the lack of high quality studies, preliminary nature of studies showing effectiveness, the lack of adequate study on their safety, and reports of Eosinophilia-myalgia syndrome from contaminated tryptophan in 1989 and 1990, the use of tryptophan and 5-HTP is not highly recommended or thought to be clinically useful.

Medical Devices

A variety of medical devices are in use or under consideration for treatment of depression including devices that offer electroconvulsive therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, and cranial electrotherapy stimulation. The use of such devices in the United States requires approval by the US Food and Drug Administration (FDA) after field trials. In 2010 an FDA advisory panel considered the question of how such field trials should be managed. Factors considered were whether drugs had been effective, how many different drugs had been tried, and what tolerance for suicides should be in field trials.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is a standard psychiatric treatment in which seizures are electrically induced in patients to provide relief from psychiatric illnesses. ECT is used with informed consent as a last line of intervention for major depressive disorder. Among the elderly, who often experience depression, the efficacy of ECT is difficult to determine due to the lack of trials comparing ECT to other treatments.

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

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

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

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

Deep Brain Stimulation

The support for the use of deep brain stimulation in treatment-resistant depression comes from a handful of case studies, and this treatment is still in a very early investigational stage. In this technique electrodes are implanted in a specific region of the brain, which is then continuously stimulated. A March 2010 systematic review found that “about half the patients did show dramatic improvement” and that adverse events were “generally trivial” given the younger psychiatric patient population than with movements disorders. Deep brain stimulation is available on an experimental basis only in the United States; no systems are approved by the FDA for this use. It is available in Australia.

Repetitive Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) or deep transcranial magnetic stimulation is a non-invasive method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator, or “coil” is placed near the head of the person receiving the treatment. The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. The coil is connected to a pulse generator, or stimulator, that delivers electric current to the coil.

TMS was approved by the FDA for treatment-resistant major depressive disorder in 2008 and as of 2014 clinical evidence supports this use. The American Psychiatric Association, the Canadian Network for Mood and Anxiety Disorders, and the Royal Australia and New Zealand College of Psychiatrists have endorsed rTMS for trMDD.

Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) uses an implanted electrode and generator to deliver electrical pulses to the vagus nerve, one of the primary nerves emanating from the brain. It is an approved therapy for treatment-resistant depression in the EU and US and is sometimes used as an adjunct to existing antidepressant treatment. The support for this method comes mainly from open-label trials, which indicate that several months may be required to see a benefit. The only large double-blind trial conducted lasted only 10 weeks and yielded inconclusive results; VNS failed to show superiority over a sham treatment on the primary efficacy outcome, but the results were more favourable for one of the secondary outcomes. The authors concluded “This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.”

Cranial Electrotherapy Stimulation

A 2014 Cochrane review found insufficient evidence to determine whether or not Cranial electrotherapy stimulation with alternating current is safe and effective for treating depression.

Transcranial Direct Current Stimulation

A 2016 meta-analysis of transcranial direct current stimulation (tDCS) reported some efficacy of tDCS in the treatment of acute depressive disorder with moderate effect size, and low efficacy in treatment-resistant depression, and that use of 2 mA current strength over 20 minutes per day over a short time span can be considered safe.

Other Treatments

Bright Light Therapy

A meta-analysis of bright light therapy commissioned by the American Psychiatric Association found a significant reduction in depression symptom severity associated with bright light treatment. Benefit was found for both seasonal affective disorder and for non-seasonal depression, with effect sizes similar to those for conventional antidepressants. For non-seasonal depression, adding light therapy to the standard antidepressant treatment was not effective. A meta-analysis of light therapy for non-seasonal depression conducted by Cochrane Collaboration, studied a different set of trials, where light was used mostly in combination with antidepressants or wake therapy. A moderate statistically significant effect of light therapy was found, with response significantly better than control treatment in high-quality studies, in studies that applied morning light treatment, and with patients who respond to total or partial sleep deprivation. Both analyses noted poor quality of most studies and their small size, and urged caution in the interpretation of their results. The short 1-2 weeks duration of most trials makes it unclear whether the effect of light therapy could be sustained in the longer term.

Exercise

The 2013 Cochrane Collaboration review on physical exercise for depression noted that, based upon limited evidence, it is moderately more effective than a control intervention and comparable to psychological or antidepressant drug therapies. Smaller effects were seen in more methodologically rigorous studies. Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that physical exercise is effective as an adjunct treatment with antidepressant medication; the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild-moderate depression and mental illness in general. These studies also found smaller effect sizes in more methodologically rigorous studies. All four systematic reviews called for more research in order to determine the efficacy or optimal exercise intensity, duration, and modality. The evidence for brain-derived neurotrophic factor (BDNF) in mediating some of the neurobiological effects of physical exercise was noted in one review which hypothesized that increased BDNF signalling is responsible for the antidepressant effect.

Meditation

Mindfulness meditation programs may help improve symptoms of depression, but they are no better than active treatments such as medication, exercise, and other behavioural therapies.

Music Therapy

A 2009 review found that 3 to 10 sessions of music therapy resulted in a noticeable improvement in depressive symptoms, with still greater improvement after 16 to 51 sessions.

Sleep

Depression is sometimes associated with insomnia – (difficulty in falling asleep, early waking, or waking in the middle of the night). The combination of these two results, depression and insomnia, will only worsen the situation. Hence, good sleep hygiene is important to help break this vicious circle. It would include measures such as regular sleep routines, avoidance of stimulants such as caffeine and management of sleeping disorders such as sleep apnoea.

Smoking Cessation

Quitting smoking cigarettes is associated with reduced depression and anxiety, with the effect “equal or larger than” those of antidepressant treatments.

Total/Partial Sleep Deprivation

Sleep deprivation (skipping a night’s sleep) has been found to improve symptoms of depression in 40-60% of patients. Partial sleep deprivation in the second half of the night may be as effective as an all night sleep deprivation session. Improvement may last for weeks, though the majority (50-80%) relapse after recovery sleep. Shifting or reduction of sleep time, light therapy, antidepressant drugs, and lithium have been found to potentially stabilise sleep deprivation treatment effects.

Shared Care

Shared care, when primary and specialty physicians have joint management of an individual’s health care, has been shown to alleviate depression outcomes.

What is the Centre for Epidemiologic Studies Depression Scale?

Introduction

The Centre for Epidemiologic Studies Depression Scale (CES-D) is a brief self-report questionnaire developed in 1977 by Laurie Radloff to measure depressive symptoms severity in the general population.

The CES-D consists of 20 questions that asks about various symptoms of depression as they have occurred in the past week, and the majority of the items focus on the affective component of depression. Although initially designed for use in general population surveys, CES-D now serves as a screening instrument in primary care clinics and in research.

A revision, the CESD-R was produced in 2004.

Centre for Epidemiologic Studies Depression Scale for Children

The Centre for Epidemiologic Studies Depression Scale for Children (CES-DC) is a modified version of the Centre for Epidemiologic Studies Depression Scale. This measure assesses both depressive symptoms as well as symptom improvement in a wide range of children and adolescents, ages 6-17. The CES-DC was first developed to measure the incidence and prevalence of depression among children and adolescents in large-scale epidemiological research. Several research studies have found the CES-DC to be a reliable and valid measure of depressive symptoms in children.

Question Breakdown and Scoring

The CES-DC is an inventory of 20 self-report items regarding depressive symptoms, taking about 5 minutes to complete. Each item asks how often a symptom has occurred within the last week. Response choices are assigned point values, which are summed together to determine a total measure score. Response choices for each item and their corresponding point values are as follows:

  • 0 points: “Not at all”.
  • 1 point: “A little”.
  • 2 points: “Some”.
  • 3 points: “A lot”.

Items 4, 8, 12 and 16 are phrased to reflect positive affect and behaviour, and therefore are scored in opposite order as follows:

  • 0 points: “A lot”.
  • 1 point: “Some”.
  • 2 points: “A little”.
  • 3 points: “Not at all”.

Interpretation

Scores on the CES-DC range from 0 to 60, in which higher scores suggest a greater presence of depressive symptoms. A score of 15 or higher is interpreted to indicate a risk for depression. However, screening for depression is a complex process and scoring a 15 or higher on the CES-DC should be followed by further evaluation.

Limitations

A study evaluating the CES-DC found that the scores do not necessarily match up to a DSM diagnosis, and while it is a good psychometric tool for adolescents, reliability and validity is poor when applied to children.

What is Recurrent Brief Depression?

Introduction

Recurrent brief depression (RBD) defines a mental disorder characterised by intermittent depressive episodes, not related to menstrual cycles in women, occurring between approximately 6-12 times per year, over at least one year or more fulfilling the diagnostic criteria for major depressive episodes (DSM-IV and ICD-10) except for duration which in RBD is less than 14 days, typically 5-7 days.

Despite the short duration of the depressive episodes, such episodes are severe, and suicidal ideation and impaired function is rather common. The majority of patients with RBD also report symptoms of anxiety and increased irritability. Hypersomnia is also rather frequent. About 1/2 of patients fulfilling diagnostic criteria for RBD may have additional short episodes of brief hypomania which is a severity marker of RBD. RBD may be the only mental disorder present, but RBD may also occur as part of a history of recurrent major depressive episodes or bipolar disorders. RBD is also seen among some patients with personality disorders.

Prevalence

The lifetime prevalence of RBD has been estimated at 2.6-10.0%, and the one-year prevalence at 5.0-8.2%. The WHO project on “Psychological problems in general health care”, which was based on primary care samples, reported a one-year prevalence of 3.7-9.9%. However none of these studies differentiate between RBD with and without a history of other mood disorders (e.g. major depression). DSM-IV field trial estimated the lifetime of RBD only to be about 2%.

Brief History

Disorders characterised by periods with depressive episodes lasting hours to days have been described since 1852 and have been labelled “periodic melancholia”, “intermittent depressive disorder” or “very brief depression”. The third version of the Diagnostic and Statistical Manual of Mental Disorders (1980), which relied heavily on findings from studies conducted in psychiatric in- and out-patient settings, required at least 14 days duration for a diagnosis of depression. No diagnostic category was allocated a depressive episode of shorter duration. Thus, intermittent depressive disorder, included in the Research Diagnostic Criteria (1975) was considered to identify minor versions of major depression (“minor depression”) and not included in the DSM-III.

However, based on data from epidemiological studies, the Swiss psychiatrist and researcher, Jules Angst, coined the concept “recurrent brief depression” (RBD) and provided diagnostic criteria for this type of mood disorder in 1985. Several other European studies independently confirmed the occurrence of RBD in the general population and clinical samples. RBD was thus included in the 10th classification of mental and behavioural disorders (ICD-10 F38.1) published by the World Health Organisation in 1992 (WHO, 1992; WHO, 1993). Less frequent episodes of brief depressions were labelled infrequent brief depression and not included in ICD-10. The American classification system of mental disorders, DSM-IV (1994), provided provisional diagnostic criteria for RBD, but decided to await further studies before including RBD in the classification system. The fate of RBD in DSM-5, expected to occur in 2013, is not known.

Causes

The cause (aetiology) of RBD is unknown, but recent findings may suggest a link between RBD and bipolar disorders, pointing to the importance of genetic factors. A small subgroup of patients with RBD has temporal lobe epilepsy.

Diagnosis

From the International Statistical Classification of Mental and Behavioral Disorders:

F33 Recurrent depressive disorder

  • G1. There has been at least one previous episode, mild (F32.0), moderate (F32.1), or severe (F32.2 or F32.3), lasting a maximum of two weeks and separated from the current episode by at least two months free from any significant mood symptoms.
  • G2. At no time in the past has there been an episode meeting the criteria or hypomanic or manic episode (F30.-).
  • G3. Most commonly used exclusion criteria: the episode is not attributable to psychoactive substance use (F1) or any organic mental disorder, in the sense of F0. It is recommended to specify the predominant type of previous episodes (mild, moderate, severe, uncertain).

F33.0 Recurrent depressive disorder, current episode mild

  • A. The general criteria for recurrent depressive disorder (F33) are met.
  • B. The current episode meets the criteria for depressive episode, mild severity (F32.0).
  • A fifth character may be used to specify the presence of the somatic syndrome, as defined in F32, in the current episode:
    • F33.00 without somatic syndrome.
    • F33.01 with somatic syndrome.

F33.1 Recurrent depressive disorder, current episode moderate

  • A. The general criteria for recurrent depressive disorders (F33) are met.
  • B. The current episode meets the criteria for depressive episode, moderate severity (F32.1).
  • A fifth character may be used to specify the presence of the somatic syndrome, as defined in F32, in the current episode:
    • F33.10 without somatic syndrome
    • F33.11 with somatic syndrome.

F33.2 Recurrent depressive disorder, current episode severe without psychotic symptoms

  • A. The general criteria for recurrent depressive disorders (F33) are met.
  • B. The current episode meets the criteria for severe depressive episode without psychotic symptoms (F32.2).

F33.3 Recurrent depressive disorder, current episode severe with psychotic symptoms

  • A. The general criteria for recurrent depressive disorders (F33) are met.
  • B. The current episode meets the criteria for severe depressive episode with psychotic symptoms (F32.3). A fifth character may be used to specify whether the psychotic symptoms are congruent or incongruent with the mood:
    • F33.30 with mood congruent psychotic symptoms.
    • F33.31 with mood incongruent psychotic symptoms.

F33.4 Recurrent depressive disorder, currently in remission

  • A. The general criteria for recurrent depressive disorder (F33) have been met in the past.
  • B. The current state does not meet the criteria for a depressive episode (F32.-) of any severity, or for any other disorder in F3 (the patient may receive treatment to reduce the risk of further episodes).

F33.8 Other recurrent depressive disorders.

F33.9 Recurrent depressive disorder, unspecified.

Treatment

Both psychotherapy as well as different drugs (e.g. serotonin reuptake inhibitors – SSRIs or mood stabilisers, e.g. lithium, antiepileptics) have been suggested as treatments. However, no randomised controlled treatment trial of RBD has been conducted.

Can We Improve Diagnosis of Depression with XGBOOST Machine Learning Model & a Large Biomarkers Dutch Dataset?

Research Paper Title

Improving Diagnosis of Depression With XGBOOST Machine Learning Model and a Large Biomarkers Dutch Dataset ( n = 11,081).

Abstract

Machine Learning has been on the rise and healthcare is no exception to that. In healthcare, mental health is gaining more and more space. The diagnosis of mental disorders is based upon standardised patient interviews with defined set of questions and scales which is a time consuming and costly process.

The objective of the researchers was to apply the machine learning model and to evaluate to see if there is predictive power of biomarkers data to enhance the diagnosis of depression cases.

In this research paper, they aimed to explore the detection of depression cases among the sample of 11,081 Dutch citizen dataset. Most of the earlier studies have balanced datasets wherein the proportion of healthy cases and unhealthy cases are equal but in their study, the dataset contains only 570 cases of self-reported depression out of 11,081 cases hence it is a class imbalance classification problem. The machine learning model built on imbalance dataset gives predictions biased toward majority class hence the model will always predict the case as no depression case even if it is a case of depression.

The researchers used different resampling strategies to address the class imbalance problem. They created multiple samples by under sampling, over sampling, over-under sampling and ROSE sampling techniques to balance the dataset and then, they applied machine learning algorithm “Extreme Gradient Boosting” (XGBoost) on each sample to classify the mental illness cases from healthy cases.

The balanced accuracy, precision, recall and F1 score obtained from over-sampling and over-under sampling were more than 0.90.

Reference

Sharma, A. & Verbeke, W.J.M.I. (2021) Improving Diagnosis of Depression With XGBOOST Machine Learning Model and a Large Biomarkers Dutch Dataset ( n = 11,081). Frontiers in Big Data. doi: 10.3389/fdata.2020.00015. eCollection 2020.

Long-Term Depression & Latent Inhibition

Research Paper Title

Disruption of long-term depression potentiates latent inhibition: Key role for central nucleus of the amygdala.

Background

Latent inhibition (LI) reflects an adaptive form of learning, which is impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified.

Methods

Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus (CS) to signal a pending footshock. The researchers employed two mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), or the selective glutamate n-methyl-d-aspartate receptor (NMDAR) 2B antagonist, Ro25-6981, administered prior to the acquisition of two-way conditioned avoidance with or without tone pre-exposure.

Results

Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in CS-pre-exposed rats compared to normal conditioning in non-pre-exposed controls. Systemic Ro25-6981 had no significant effects. Brain-region specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, central or basolateral amygdala demonstrated that disruption of AMPAR endocytosis in the central amygdala also potentiated the LI effect.

Conclusions

These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.

Reference

Ashby, D.M., Dias, C., Aleksandrova, L.R., Lapish, C.C., Wang, Y.T. & Phillips, A.G. (2021) Disruption of long-term depression potentiates latent inhibition: Key role for central nucleus of the amygdala. The International Journal of Neuropsychopharmacology. doi: 10.1093/ijnp/pyab011. Online ahead of print.

What is Treatment-Resistant Depression?

Introduction

Treatment-resistant depression (TRD) is a term used in clinical psychiatry to describe a condition that affects people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time.

Typical definitions of TRD vary, and they do not include a resistance to psychological therapies. Inadequate response has traditionally been defined as no clinical response whatsoever (e.g. no improvement in depressive symptoms). However, many clinicians consider a response inadequate if the person does not achieve full remission of symptoms. People with treatment-resistant depression who do not adequately respond to antidepressant treatment are sometimes referred to as pseudoresistant. Some factors that contribute to inadequate treatment are: early discontinuation of treatment, insufficient dosage of medication, patient noncompliance, misdiagnosis, and concurrent psychiatric disorders. Cases of treatment-resistant depression may also be referred to by which medications people with TRD are resistant to (e.g.: SSRI-resistant). In TRD adding further treatments such as psychotherapy, lithium, or aripiprazole is weakly supported as of 2019.

Refer to Atypical Depression and Masked Depression.

Risk Factors

Comorbid Psychiatric Disorders

Comorbid psychiatric disorders commonly go undetected in the treatment of depression. If left untreated, the symptoms of these disorders can interfere with both evaluation and treatment. Anxiety disorders are one of the most common disorder types associated with treatment-resistant depression. The two disorders commonly co-exist, and have some similar symptoms. Some studies have shown that patients with both MDD and panic disorder are the most likely to be nonresponsive to treatment. Substance abuse may also be a predictor of treatment-resistant depression. It may cause depressed patients to be noncompliant in their treatment, and the effects of certain substances can worsen the effects of depression. Other psychiatric disorders that may predict treatment-resistant depression include attention deficit hyperactivity disorder, personality disorders, obsessive compulsive disorder, and eating disorders.

Comorbid Medical Disorders

Some people who are diagnosed with treatment-resistant depression may have an underlying undiagnosed health condition that is causing or contributing to their depression. Endocrine disorders like hypothyroidism, Cushing’s disease, and Addison’s disease are among the most commonly identified as contributing to depression. Others include diabetes, coronary artery disease, cancer, HIV, and Parkinson’s disease. Another factor is that medications used to treat comorbid medical disorders may lessen the effectiveness of antidepressants or cause depression symptoms.

Features of Depression

People with depression who also display psychotic symptoms such as delusions or hallucinations are more likely to be treatment resistant. Another depressive feature that has been associated with poor response to treatment is longer duration of depressive episodes. Finally, people with more severe depression and those who are suicidal are more likely to be nonresponsive to antidepressant treatment.

Treatment

There are three basic categories of drug treatment that can be used when a medication course is found to be ineffective. One option is to switch the patient to a different medication. Another option is to add a medication to the patient’s current treatment. This can include combination therapy: the combination of two different types of antidepressants, or augmentation therapy: the addition of a non-antidepressant medication that may increase the effectiveness of the antidepressant.

Medication

Antidepressants

Dose Increase

Increasing the dosage of an antidepressant is a common strategy to treat depression that does not respond after adequate treatment duration. Practitioners who use this strategy will usually increase the dose until the person reports intolerable side effects, symptoms are eliminated, or the dose is increased to the limit of what is considered safe.

Switching Antidepressants

Studies have shown a wide variability in the effectiveness of switching antidepressants, with anywhere from 25-70% of people responding to a different antidepressant. There is support for the effectiveness of switching people to a different SSRI; 50% of people that were non-responsive after taking one SSRI were responsive after taking a second type. Switching people with TRD to a different class of antidepressants may also be effective. People who are non-responsive after taking an SSRI may respond to moclobemide or tricyclic antidepressant, bupropion or an MAOI.

However, the more antidepressants an individual had already tried, the less likely they were to benefit from a new antidepressant trial.

Some off label antidepressants are low dose ketamine and highly serotonergic catecholamines (including very controlled use of MDMA in the treatment of PTSD and crippling depression/anxiety). For lethargic syndromes, dysthymia, or caffeine-resistant amotivation, a dopaminergic stimulant such as methlyphenidate, or even 2.5 mg dextroamphetamine can be helpful.

Primarily dopaminergic or norepinephrine releasing stimulants, in low doses, have been used especially in the past, or in conjunction with a multidisciplinary therapy approach, although more targeted and “mild” agents, including modafinil and atomoxetine are considered first line for both childhood and adult lethargy and inattention disorders, due to their virtually non-existent abuse potential (limited to one or two cases per 10,000), and higher selectivity, safety, and thus slightly broader therapeutic index. When depression is related or co-morbid to an inattention disorder, often ADHD, then both can be carefully managed with the same first line stimulant medication, typically both methylphenidate and lisdexamphetamine.

Other Medications

Medications that have been shown to be effective in people with treatment-resistant depression include lithium, triiodothyronine, benzodiazepines, atypical antipsychotics, and stimulants. Adding lithium may be effective for people taking some types of antidepressants; it does not appear to be effective in patients taking SSRIs. Triiodothyroxine (T3) is a type of thyroid hormone and has been associated with improvement in mood and depression symptoms. Benzodiazepines may improve treatment-resistant depression by decreasing the adverse side effects caused by some antidepressants and therefore increasing patient compliance. Since the entry of olanzapine into psychopharmacology, anecdotal evidence suggests that many psychiatrists have been adding low dose olanzapine to antidepressants and other atypical antipsychotics such as aripiprazole and quetiapine. Eli Lilly, the company that sells both olanzapine and fluoxetine individually, has also released a combination formulation which contains olanzapine and fluoxetine in a single capsule. Some low to moderate quality evidence points to success in the short term (8-12 weeks) using mianserin (or antipsychotics cariprazine, olanzapine, quetiapine or ziprasidone) to augment antidepressant medications.

These have shown promise in treating refractory depression but come with serious side effects. Stimulants such as amphetamines and methylphenidate have also been tested with positive results but have potential for abuse. However, stimulants have been shown to be effective for the unyielding depressed combined lacking addictive personality traits or heart problems.

Ketamine has been tested as a rapid-acting antidepressant for treatment-resistant depression in bipolar disorder, and major depressive disorder.

Research

A 2016 placebo randomised controlled trial (RCT) evaluated the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression with positive outcome.

Physical Psychiatric Treatments

Electroconvulsive Therapy

Electroconvulsive therapy is generally only considered as a treatment option in severe cases of treatment-resistant depression. It is used when medication has repeatedly failed to improve symptoms, and usually when the patient’s symptoms are so severe that they have been hospitalised. Electroconvulsive therapy has been found to reduce thoughts of suicide and relieve depressive symptoms. It is associated with an increase in glial cell line derived neurotrophic factor.

rTMS

rTMS (repetitive transcranial magnetic stimulation) is gradually becoming recognised as a valuable therapeutic option in treatment-resistant depression. A number of randomised placebo-controlled trials have compared real versus sham rTMS. These trials have consistently demonstrated the efficacy of this treatment against major depression. There have also been a number of meta-analyses of RCTs confirming the efficacy of rTMS in treatment-resistant major depression, as well as naturalistic studies showing its effectiveness in “real world” clinical settings.

dTMS

dTMS (deep transcranial magnetic stimulation) is a continuation of the same idea as rTMS, but with the hope that deeper stimulation of subcortical areas of the brain leads to increased effect. A 2015 systematic review and health technology assessment found lacking evidence in order to recommend the method over either ECT or rTMS because so few studies had been published.

Psychotherapy

There is sparse evidence on the effectiveness of psychotherapy in cases of treatment-resistant depression. However, a review of the literature suggests that it may be an effective treatment option. Psychotherapy may be effective in people with TRD because it can help relieve stress that may contribute to depressive symptoms.

A Cochrane systematic review has shown that psychological therapies (including cognitive behavioural therapy, dialectal behavioural therapy, interpersonal therapy and intensive short-term dynamic psychotherapy) added to usual care (with antidepressants) can be beneficial for depressive symptoms and for response and remission rates over the short term (up to six months) for patients with TRD. Medium‐ (7-12 months) and long‐term (longer than 12 months) effects seem similarly beneficial. Psychological therapies added to usual care (antidepressants) seem as acceptable as usual care alone.

Outcomes

Treatment-resistant depression is associated with more instances of relapse than depression that is responsive to treatment. One study showed that as many as 80% of people with TRD who needed more than one course of treatment relapsed within a year. Treatment-resistant depression has also been associated with lower long-term quality of life.

Another study saw just 8 of 124 patients in remission after two years of regular treatment with therapy and medicines.

Epidemiology

Treatment-resistance is relatively common in people with MDD. Rates of total remission following antidepressant treatment are only 50.4%. In cases of depression treated by a primary care physician, 32% of people partially responded to treatment and 45% did not respond at all.

What is Masked Depression?

Introduction

Masked depression (MD) was a proposed form of atypical depression in which somatic symptoms or behavioural disturbances dominate the clinical picture and disguise the underlying affective disorder.

The concept (as of March 2021) is not currently supported by the mental health profession.

Refer to Atypical Depression and Treatment-Resistant Depression.

Clinical Manifestations

Somatic manifestations of MD are distinguished by an extreme diversity and include headaches, back pain, abdominal pain etc. Pathological behaviour masking depression may take the form of compulsive gambling, compulsive work, changes in arousal or orgasmic function, decreased libido or, on the contrary, impulsive sexual behaviour, alcoholism, or drug addiction.

Dispute about the Concept

MD has been variously described as “depression sine (without) depression” (K. Schneider, 1925), “latent” depression (Lange J., 1928), “vegetative depression” (R. Lemke, 1949) “hidden” or “masked” depression (Lopez Ibor J.J. [es], 1972; Kielholz J.J., 1983; Pichot P.; Hasson J., 1973), “larvate” or “somatisation depression” (Gayral L., 1972), “depressive equivalents” etc. Most investigators, especially those in the German-speaking countries, assumed masked depression (German: die larvierte Depression) to be endogenous depression. The term was largely used in the 1970s and 1980s, but at the end of the 20th century there was a decline in interest in the study of masked depression. Today this diagnosis does not play a significant clinical or scientific role.

Epidemiology

MD is supposed to be a common clinical phenomenon. According to some authors, masked depression is as frequent as overt depression. Although masked depression can be found at any age, it has been observed more commonly after mid-life.

Making the diagnosis and the management of MD in clinical practice are complicated by the fact that the individual who has MD is unaware of their mental illness. Patients with MD are reluctant to associate their physical symptoms with an affective disorder and refuse mental health care. As a rule, these patients attribute their disturbances to physical illness, seek medical care for them, and report only somatic complaints to their medical professional, with the consequence that many of such depressions are not recognised or are misdiagnosed and mistreated Estimates of depressed patients who are correctly identified and treated range from 5% to 60%. Recent data show that about 10% of people who consult a medical professional for any reason originally suffer from affective disorders disguised by physical symptoms.

Official Diagnostic Status

Current classifications: ICD-10 and DSM-5 do not contain the term “masked depression”.

Some Ukrainian psychiatrists claim that MD is to be qualified as “depression with somatic symptoms” (F 3x.01), according to ICD-10. This means that those who struggle with masked depression often have more physical symptoms such as back pain, abdominal pain, headaches, and even pain during sexual activity or painful periods.

For those with more clinical depression, while they still may have physical symptoms, their symptoms are usually more mental or emotional. This includes feelings of helplessness, extreme and/or persisting sadness, numbness, tiredness, drowsiness, exhaustion, and even suicidal thoughts or feelings.

Diagnostic Criteria

Affective disorders in patients with MD can only be detected by means of a clinician-administered diagnostic interview. Organic exclusion rules and other criteria are used in making the diagnosis of MD. Some physical symptoms of masked depression include general aches, pains including headache, backache, musculoskeletal aches, and other nonpainful symptoms such as changes in appetite and libido, lack of energy, sleep disturbance, dizziness, palpitations, dyspnoea, and gastrointestinal tract disturbances.

Book: Physical Health and Schizophrenia

Book Title:

Physical Health and Schizophrenia (Oxford Psychiatry Library Series).

Author(s): David J. Castle, Peter F. Buckley, and Fiona P. Gaughran.

Year: 2017.

Edition: First (1st), Illustrated Edition.

Publisher: Oxford University Press.

Type(s): Paperback and Kindle.

Synopsis:

In comparison to the general population, people with schizophrenia and related disorders have poorer physical health and increased mortality. Whilst it is recognized that serious mental illnesses such as schizophrenia carry a reduced life expectancy, it is often assumed that suicide is the main cause of this disparity. In actuality, suicide accounts for no more than a third of the early mortality associated with schizophrenia: the vast majority is due to cardiovascular factors

Physical Health and Schizophreniaoffers a user-friendly guide to the physical health problems associated with schizophrenia and a clear overview of strategies and interventions to tackle these issues. Spanning eight chapters this resource covers the essential topics in a practical and easy-to-read format to suit the needs of busy clinicians. It also includes an appendix designed specifically for patients and carers, with practical tips on how to be actively involved in monitoring and managing physical health problems.

Part of the Oxford Psychiatry Library series, Physical Health and Schizophrenia offers readers a fully up-to-date and valuable insight into this complex issue. With helpful key points at the start of each chapter and a clear layout, this is an essential resource for busy clinicians and researchers in any mental health field as well as those working in primary care.

Book: Schizophrenia and Psychiatric Comorbidities – Recognition Management

Book Title:

Schizophrenia and Psychiatric Comorbidities – Recognition Management (Oxford Psychiatry Library Series).

Author(s): David J. Castle, Peter F. Buckley, and Rachel Upthegrove.

Year: 2021.

Edition: First (1st).

Publisher: Oxford University Press.

Type(s): Paperback and Kindle.

Synopsis:

Psychiatric comorbidities such as depression, anxiety and substance use are extremely common amongst people with schizophrenia. They add to poor clinical outcomes and disability, yet are often not at the forefront of the minds of clinicians, who tend to concentrate on assessing and treating the core symptoms of schizophrenia, notably delusions and hallucinations. There is an imperative to assess every patient with schizophrenia for psychiatric comorbidities, as they might masquerade as core psychotic symptoms and also because they warrant treatment in their own right. This volume addresses these issues using a clinical lens informed by the current literature. Published as part of the Oxford Psychiatry Library series, the book serves as a concise and practical reference for busy clinicians.