What is considered a major depressive episode?

ICD-10

Unipolar depression is classified somewhat differently in ICD-10 (WHO 1992) than in DSM-IV-TR, depending on whether it is episodic or persistent, as follows:

Depressive disorder:

Depressive episode (mild with or without somatic syndrome, moderate with or without somatic syndrome, severe with or without psychotic symptoms)

Recurrent depressive disorder (with specification to presenting episode as mild, moderate or severe)

Other depressive episodes (including atypical depression and masked depression)

Other recurrent mood disorders (including recurrent brief depressive disorder)

Persistent affective states:

Dysthymia (a chronic syndrome of low mood and associated symptoms never or rarely severe enough to meet criteria for a depressive episode).

Depression is also encountered in other settings, e.g. organic (organic depressive state), other anxiety disorders (mixed anxiety and depressive disorder), or adjustment disorder, which includes brief or prolonged depressive reactions. Post-schizophrenic depression is classified under the psychoses.

Abstract

According to the most recent version of the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (American Psychiatric Association, 2013), major depressive disorder (MDD) is characterized by two primary diagnostic criteria: depressed mood and loss of interest or pleasure in activities (anhedonia), at least one of which must occur for at least two weeks. Secondary symptoms include significant weight loss or gain or decrease in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or energy loss, feelings of worthlessness or excessive or inappropriate guilt, attentional or concentration difficulties, and recurrent thoughts of death and/or suicide. In adults, of these symptoms, depressed mood, anhedonia, and feelings of worthlessness or guilt are most common, while weight loss, weight gain, hypersomnia, and psychomotor changes are less common (Rice et al., 2019). Globally, MDD is consistently among the most prevalent mental disorders (Vos et al., 2016; 2017) and there are 322 million people living with depressive disorders worldwide (World Health Organization, 2017). A functional analytic approach is useful for conceptualizing the disorder and its treatment. There is now considerable evidence for interventions such as behavioral activation, ACT, Problem-solving Therapy and an accumulating evidence base for interventions such as Functional Analytic Psychotherapy, Mindfulness-Based Cognitive Therapy, and Cognitive-Behavioral Analysis System of Psychotherapy.

Signal Transduction Mechanisms Show Neuroadaptative Changes with Substance Dependence

Chronic drug use not only increases transmitter release via presynaptic effects but also produces long-lasting alterations in postsynaptic receptor activation, signal transduction, and gene expression (Robison & Nestler, 2011). For example, whereas chronic opioid use has minimal effects on the binding of opioid receptors by opioid peptides, it dramatically alters signal transduction in the terminal regions of the mesolimbic dopamine system, such as the nucleus accumbens (Nestler, 2001). This occurs at least in part by increasing adenylate cyclase activity and CREB. CREB is a transcription factor that increases or decreases the transcription of genes. These changes can result in the expression of novel proteins and, consequently, changes in neuronal function that could explain clinical phenomena, such as protracted abstinence and vulnerability to relapse, in people formerly addicted to drugs (Fig. 41.12).

The persistence of changes in drug reinforcement mechanisms that characterize drug addiction suggests that the underlying molecular mechanisms are long-lasting, and considerable attention has been given to the drug regulation of gene expression. Current research focuses on several types of transcription factors, including CREB and novel Fos-like proteins termed chronic Fos-related antigens. FosB, a member of the Fos family of transcription factors that dimerizes with a member of the Jun family to form activator protein-1 transcription factor complexes, has been implicated in the adaptation to chronic exposure to drugs of abuse. Activator protein-1 transcription factor complexes bind to sites in the regulatory regions of many genes. Acute administration of several drugs of abuse activates c-fos and Fos-related antigens, but chronic administration of drugs of abuse eliminates these activations and produces a gradual accumulation of FosB. This highly stable protein is hypothesized to function as a sustained molecular switch contributing to vulnerability to relapse after prolonged periods of abstinence (Nestler, 2001). These transcription factors may be possible mediators of chronic drug action. However, it has not yet been possible to relate regulation of a specific transcription factor to specific features of drug reinforcement or addiction.

Genetic and molecular genetic animal models have provided a convergence of data to provide hypotheses regarding vulnerability to addiction in some of the neuropharmacological substrates identified in neurocircuitry studies. High alcohol-preferring rats have been bred that show high voluntary consumption of alcohol, increased anxiety-like responses, and numerous neuropharmacological phenotypes such as decreased dopaminergic activity, increased CRF activity, and decreased neuropeptide Y activity, some of which have support from genetic studies of chromosomal linkage (Carr et al., 1998; McBride, Murphy, Lumeng, & Li, 1990; Murphy et al., 2002).

Box 41.8

Major Depressive Disorders

Feeling sad and blue are common and universal moods experienced in response to transient loss, stress, or disappointment. The clinical diagnosis of major depressive disorder (MDD) involves a persistent symptom complex that includes some combination of depressed mood, diminished interest or pleasure, changes in sleep and appetite, excessive guilt, agitation or retardation, loss of energy, diminished ability to think or concentrate, thoughts of death, and thoughts of suicide. These symptoms are recurrent and persistent and produce impairment.

Major depression is highly prevalent in all cultures and countries studied, and it is the most common psychiatric condition in medical patients. The community lifetime prevalence is approximately 12 to 15%, with the lowest rates in Asian countries and the highest in the Americas, Europe, and Australia. Even in countries with lower rates, it is not rare. The rates are two- to threefold higher in women than men. MDD is uncommon before puberty, with a marked increase in females during adolescence and following childbirth, and a decrease in first onset after menopause. Major depression with a first onset in the 60s or later is often associated with dementia or a medical condition.

Epidemiologic studies from the United States and elsewhere have documented higher lifetime rates of MDD in younger age groups. An analysis by birth cohort showed that rates of depression rose in cohorts born after World War II (the baby-boom generation). Numerous hypotheses noting the social changes that have occurred since that period have been considered, with no confirmed explanation. Follow-up epidemiologic studies carried out a decade or more later, in the 2000s, found the highest prevalence among the middle-age group (30–64 years), suggesting that the cohort born after WWII were carrying forth their high rates as they aged.

Different subtypes of major depression have been identified, including depression with psychotic features and a typical depression. Efforts to understand the heterogeneity of MDD by subtyping symptoms, however, are inherently difficult, as patients’ symptoms may change with different episodes. Major depression in the context of a history of mania (bipolar disorder) has the most severe course and requires treatment that prevents both the depressive and the manic symptoms.

Depression is an extremely disabling disorder. About 75% of patients have recurrent episodes. Ten to 30% recover incompletely, with persistent residual symptoms. MDD also complicates the course of cardiovascular illness, diabetes, hypertension, and other chronic medical conditions. Suicide, accidents, and the risk of death from heart disease are highest among the depressed. Because onset is early, recurrence rates are high, and the years lived with disability are high, MDD is considered, according to the World Health Organization, to be among the most disabling medical conditions in the world, similar to ischemic heart disease.

Rates of MDD are highest in persons who are divorced, separated, or widowed, and lowest in unmarried or never-married persons. These differences vary by country and are confounded by the difficulty in determining the sequence of divorce, separation, and depression. The one clear finding is that the ending of marriage, when it occurs, is associated with an increase in MDD.

The increased risk of MDD in first-degree relatives of a depressed patient is approximately two- to sixfold, depending on the severity of the disorder. This pattern of transmission is found across cultures and countries. Early-onset recurrent MDD has the highest relative risk, with estimates as high as eightfold. The best replicated findings are the high rates of MDD, anxiety disorders, and conduct disorder found in the biological young offspring of depressed as compared to nondepressed parents. These studies have been carried out in three generations and show that grandchildren with two generations affected are at extremely high risk of developing MDD at a young age.

The high familial rate of MDD across generations is supported by twin studies showing higher rates of depression in monozygotic twins, and an estimated heritability of 37 to 43%. These estimates are similar to those described for Type 2 diabetes. Several large-scale molecular genetic studies of MDD have been undertaken; most have focused on early-onset (<30 years) recurrent MDD, since this subtype has the highest familial rate. DNA and deidentified clinical information from these studies are stored in the National Institute of Mental Health (NIMH)'s national repositories for use by qualified scientists. As of 2012, a large Genome-Wide Association (GWA) study with participation by numerous investigators across the globe is underway. Many sequence variations in several genes have been reported, but no consistently replicated findings are yet available.

Availability of families at high risk for MDD (by virtue of having a FDR with the disorder) and the numerous positive clinical trials of drugs for MDD have led to a search for biomarkers or “endophenotypes” for MDD. By identifying subjects at risk for depression but not yet ill, this approach allows the disentangling of processes that present prior to the illness and are therefore more likely to be true risk factors. One study using magnetic resonance imaging (MRI) found 30% cortical thinning in the second and third generations of high-risk, as compared to low-risk, families that was independent of presence of MDD in the subject. Cortical thinning in areas that regulate emotion and cognitive stress response may thus be a familial trait marker for vulnerability to MDD. The first large-scale study to develop a platform for biomarkers using MRI, electroencephalography, behavioral tasks, and genetics to predict treatment response to MDD using selective serotonin reuptake inhibitors was initiated in 2011. Other promising areas for depression research include studies of circulatory levels of peripheral/serum growth factors and cytokines, which are altered in patients with MDD and which may be normalized or reversed with antidepressant treatment. There is agreement that a single biomarker approach may not be useful. The development of biomarker panels that profile a diverse array of peripheral/serum growth factors, cytokines, hormones, and metabolic markers may provide better coverage of the biologic abnormalities in MDD.

There are numerous studies on the efficacy of both medications and psychotherapy for depression. Treatment can hasten remission, may reduce suicide risk, and, if continued, can prevent relapse. Many of the pharmacologic agents with effective antidepressant action amplify serotonin or norepinephrine signaling by inhibiting reuptake. There are also several evidence-based psychotherapies developed for MDD. They target the distorted thinking of depression (cognitive therapy) or stressful life events (grief, disputes, transitions) that trigger an episode (interpersonal psychotherapy). Drugs and psychotherapy in combination have been shown usually to have the best outcome, but many patients do not have access to, cannot afford, or do not want both. Both classes of treatment need to deal with the delayed response rate (3 to 4 weeks) and the high recurrence rate. Continuation or maintenance therapy (drugs or psychotherapy) is usually indicated.

Myrna M. Weissman and Ardesheer Talati

Advances in molecular biology have led to the ability to systematically inactivate the genes that control the expression of proteins that make up receptors or neurotransmitter/neuromodulators in the central nervous system using the gene knockout approach. Notable positive results with gene knockout studies in mice have focused on knockout of the μ opioid receptor, which eliminates opioid, nicotine, alcohol, and cannabinoid reward in mice (Contet, Kieffer, & Befort, 2004). Selective deletion of the genes for expression of the dopamine D1 and D2 receptor subtypes and the dopamine transporter has revealed significant decreases in activation and reward produced by psychomotor stimulants. Although developmental factors must be taken into account for the compensatory effect of deleting any one or a combination of genes, it is clear that D1 and D2 receptors and the dopamine transporter play important roles in the actions of psychomotor stimulants (Caine, Gabriel, Berkowitz, Zhang, & Xu, 2002).

Diagnosis

MDD is diagnosed using criteria from the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) (Table 1), and symptoms must include either depressed mood or loss of interest or pleasure from activities. Perinatal MDD includes MDD during pregnancy and the postpartum period but is not a distinct diagnostic entity. Symptoms of MDD must interfere with function in daily life and cannot be due to substance use or a general medical condition.

Table 1. Criteria for diagnosis of major depressive disorder (MDD)

The DSM-IV-TR does not classify perinatal major depression as a separate disorder from MDD. There is a ‘postpartum onset’ subtype of MDD (i.e., MDD with postpartum onset), which classifies onset of depressive symptoms within the first 4 weeks postdelivery. However, many experts argue that onset of symptoms can occur up to 12 months postpartum and still be considered postpartum major depression (PMD).

MDD and CG: Overlapping but Distinct Disorders

MDD and CG frequently co-occur. Irrespective of the time of onset, approximately half of individuals with CG meet criteria for current comorbid MDD and approximately two thirds report a lifetime history of MDD [34, 35]. Most individuals with CG and comorbid MDD report an age of onset for MDD prior to bereavement [34], which suggests that preexisting MDD could be a risk factor for CG. In addition, CG in early life predicts increased risk for subsequent MDD and a shorter time to the incidence of MDD [24]. Taken together, these data indicate that MDD and CG may share common risk factors or serve as risk factors for one another.

Despite the high rates of comorbidity between MDD and CG, research suggests they are distinct disorders. For example, symptoms of MDD and CG load on separate statistical factors [36, 37] and respond to different treatments (e.g., [38–40]). Thus, MDD and CG appear similar to other mood, anxiety, and trauma-related disorders, which frequently co-occur. CG can be differentiated from MDD in that loss and loneliness, rather than persistent and pervasive dysphoria, are the predominant preoccupations [5, 20, 41]. Hallmark symptoms of CG include yearning and longing for the deceased as well as painful waves of affect, such as pangs of grief [5, 20, 41]. CG can be further differentiated from MDD in that guilt is typically centered on deeds done or not done in relation to the deceased, and all-consuming feelings of worthlessness are not common [5, 20]. Suicidal ideation among those with CG may be motivated by a desire to join the deceased, rather than feeling undeserving of living [5].

Abstract

Major depressive disorder (MDD) is associated with significant psychosocial impairment at individual, family, and societal levels. Despite the importance of functional recovery for patients and clinicians, treatment studies in MDD have only recently begun to focus on functional outcomes rather than symptom outcomes. Among the varied symptoms of MDD, fatigue and cognitive dysfunction are key mediators of functional impairment. Both are also common residual symptoms that impede full functional recovery, even when other symptoms of MDD are remitted. Hence, it is important to carefully consider these symptom complexes to optimize functional recovery in patients with MDD. In this chapter, we review the importance of functional recovery in MDD and summarize some of the neurobiological findings and the effects of antidepressants on fatigue and cognitive dysfunction as key mediators of functional recovery.

Pathophysiological Model of Depression

Major depression has genetics and early life adversity causal factors. The intermediate biological phenotypes of MDD must be distinguished from those of the diathesis for suicidal behavior. Causal factors may lead to the development of MDD, and biological correlates of MDD include alterations of the hypothalamic–pituitary–adrenal (HPA) axis, the noradrenergic stress response system, and altered neural circuitry at rest and under conditions of performance of a variety of tasks, such as recognition of emotion on faces, reappraisal, and the Stroop test. Specific neurotransmitter systems abnormalities are described in MDD, mostly in the serotonergic and γ-aminobutyric acidergic (GABAergic) systems (Fig. 43.1).

Abstract

Major depressive disorder (MDD) is a leading cause of disability worldwide and is associated with poor psychological, medical, and socioeconomic outcomes. Although much has been learned about the etiology and treatment options of MDD over the past decade, there remain unanswered questions that pose challenges to improving acute and chronic outcomes for those with MDD. MDD is a clinically heterogeneous disorder. Genetic studies to date have indicated a number of genes, including transporters, neurotransmitters, neurotrophins, and their associated signaling networks that may predispose individuals to MDD and may also predict treatment outcomes. However, twin studies indicate that genes account for only a small degree of the variation in MDD. Thus, other mechanisms, through epigenetic marks, may act to form a molecular memory of previous gene-to-environment interactions and to establish vulnerabilities (or, conversely, resistance) to MDD. Current evidence supports a role for pre-, peri-, and early postnatal adversities and stressful life events into adulthood affecting epigenetic patterns, providing a mechanistic foundation to develop epigenetic marks as biomarkers for MDD. This review presents the evidence supporting a role for epigenetic effects in MDD and in treatment response. We also discuss the controversy behind modulating epigenetic mechanisms in long-term antidepressant pharmacotherapy.

Abstract

Major depressive disorder (MDD) is frequently comorbid with other psychiatric disorders. Compared to patients with only MDD, these patients with co-occurring disorders are more likely to have greater symptom burden, poorer course, and outcome, adding to the overall public healthcare burden. What should clinicians do, then, to optimize outcome? This chapter is a synthesized overview of the epidemiology, diagnostic and treatment strategies for MDD's most frequently comorbid psychiatric disorders. Clinicians should be diligent in assessing for comorbidity when managing patients with MDD and should strive to treat both MDD and the co-occurring psychiatric disorders to full remission.

A Impact of Depression

Major and minor depressions are the two most prevalent forms of acute depressive illness. Major depression has an estimated lifetime prevalence of 17% and affects approximately twice as many women as men (6,7). The exact prevalence of minor depression is unclear due to differences in the diagnostic criteria used across studies; however, its prevalence is thought to approximate that of major depression (8,9). Recently, major depression was identified as a leading source of disease-related disability in developed countries, and it is predicted to be a leading cause of disability worldwide by the year 2020 (second only to heart disease) (10). Minor depressions, by definition, have fewer and less severe symptoms than major depressions (11,12). Nonetheless, they are associated with disability comparable to that of major depression (13–15). In fact, major depressions of moderate severity are not distinguished from minor depressions by family history (16,17), course (i.e., both major and minor depressions occur in subjects over their lifetime) (11,16), or biologic characteristics (18,19). In addition to the functional disability directly attributed to major and minor depressions, adverse medical sequelae of major depression have been identified, including increased risks for osteoporosis, the metabolic syndrome, and cardiovascular disease (20–24). Finally, if depression exists as a comorbid condition, it may increase both the morbidity and mortality of several medical illnesses, particularly heart disease (25–28).