William V. Bobo, M.D., M.P.H.
Richard C. Shelton, M.D.
Major depressive disorder (MDD) affects more than 350 million people worldwide (World Health Organization 2012), making it one of the most prevalent illnesses in all of medicine. MDD is characterized by pronounced changes in mood (persisting depressed mood or anhedonia) coupled with distinct psychological (feelings of worthlessness or excessive guilt, difficulties maintaining concentration) and neurovegetative (sleep and/or appetite disturbance, fatigue or loss of energy and drive) changes and, all too often, suicidal thinking and behavior (American Psychiatric Association 2013). For many patients with MDD, the illness course is episodic, whereas others may experience more prolonged episodes that persist for years (Coryell et al. 1994; Eaton et al. 2008; Stegenga et al. 2012).
The adverse effects of MDD on quality of life and functioning are staggering. Pooled estimates of global disease burden ranked MDD as the second leading cause of years of life lived with a disability in 2010, accounting for 8.2% of global years of life lived with a disability (Ferrari et al. 2013). Even milder but more chronic and persisting forms of unipolar depression, such as persistent depressive disorder (dysthymia) (formerly known as dysthymic disorder), are among the leading causes of disability in the United States (Murray et al. 2013). The goal of treatment of all forms of depression is to return patients to an asymptomatic state (remission), restore “normal” psychosocial functioning, prevent relapses of depression once patients are well, and minimize adverse effects of treatment (Davidson 2010). Thus, the treatment of patients with MDD and other depressive disorders requires aggressive and varied therapies that may need to continue for years, if not indefinitely.
MDD is one of the most common medical disorders affecting adults worldwide (Lopez and Murray 1998; World Health Organization 2012). In the United States, the lifetime prevalence of MDD is 9% for men and 17% for women (Hasin et al. 2005), whereas the lifetime prevalence of dysthymia is 4% for men and 8% for women (Kessler et al. 1994). The lifetime prevalence of minor depression, a type of depression with milder symptoms than MDD, is 10% for individuals between the ages of 15 and 54 years (Kessler et al. 1997). For persons 65 years and older, the 1-month point prevalence of minor depression is 13%, which is twice the prevalence of MDD for this age group (Judd and Akiskal 2002; McCusker et al. 2005). The lifetime prevalence of subsyndromal depression is 11.8% for the general population (Goldney et al. 2004; Judd et al. 1994).
Risk factors for MDD and other depressive disorders are numerous and include demographic, biological (genetic), and psychosocial (environmental) factors. Risk factors with the strongest body of evidence include female sex, age, a family history of a mood disorder, a history of psychological trauma or childhood adversity, and comorbid medical and psychiatric conditions.
A significant body of evidence indicates that sex is an important risk factor for the development of MDD. Prior to puberty, the prevalence of depression is equal in boys and girls. However, beginning with puberty, women demonstrate a twofold increase in the prevalence of MDD (Burt and Stein 2002; Hasin et al. 2005; Kessler et al. 1994; Weissman and Klerman 1977). This trend is seen across countries and ethnic groups (Joyce et al. 1990; Lee et al. 1990, 2009; Slone et al. 2006; Weissman et al. 1996). However, sex does not appear to affect rates of illness recurrence among people with MDD (Kessler et al. 1993). The lifetime prevalence rate of persistent depressive disorder (dysthymia) is also higher in women than in men (Alonso et al. 2004; Chiu 2004; Falk et al. 2008; Lee et al. 1990; Weissman et al. 1988).
Age is another risk factor in the development of depressive disorders; the onset of MDD can occur at any age, but onset appears to increase dramatically beginning in adolescence (12–16 years) and continuing through the age of about 44 years (Hasin et al. 2005). Whereas the mean age at onset has been reported to be 30 years, the mean age at the start of treatment is 33.5 years, a 3-year span reflecting the amount of time that depression remains undiagnosed or untreated. Early age at MDD onset (i.e., onset during childhood or adolescence) appears to be associated with more severe and recurrent forms of illness, more lifetime suicide attempts, and a greater illness burden (Zisook et al. 2007). In elderly individuals, risk factors for depression include female sex, low socioeconomic status, recent bereavement, prior depression, medical comorbidity, disability, cognitive deterioration, and vascular disease (Helmer et al. 2004).
A family history of psychiatric illness, particularly MDD, is among the most profound risk factors for the development of a major depressive episode (Reinherz et al. 2003; Sullivan et al. 2000). Compared with the general population, first-degree relatives of patients with MDD have two to four times the risk of developing MDD (Gershon et al. 1982; Weissman et al. 1984). Estimated heritability rates of up to 46% for MDD based on data from twin studies strengthen the notion of a strong genetic basis for MDD risk (Kendler et al. 1993).
Prolonged exposure to severe traumatic events in childhood and adolescence has also been linked to the development of depressive episodes later in life (Alloy et al. 2006; Hammen 2005; Hosang et al. 2010). Trauma such as sexual abuse or the loss of a parent that occurs at a critical developmental period can result in permanent alteration of stress-related neuroendocrine systems (especially the hypothalamic-pituitary-adrenal [HPA] axis) and immune/inflammatory markers (Ehlert 2013). It is recognized that individuals with depression, particularly those exposed to early trauma, have altered stress and pro-inflammatory responses (Danese et al. 2008; Gillespie and Nemeroff 2005; Heim et al. 2000, 2008; Nemeroff and Vale 2005).
Other clinical and demographic variables have been linked to an increased risk of developing depressive disorders. These include stressful life events such as the death of a loved one, divorce, or job loss (Kendler et al. 1999). Certain personality characteristics may also predispose an individual to developing a mood disorder. Individuals who score higher on measures of neuroticism, interpersonal dependency, or external locus of control may be vulnerable to stressful life events precipitating a major depressive episode (Hirschfeld et al. 1983; Paykel et al. 1996). Investigations suggesting that some cultural groups may be at increased risk of mood disorders (Native Americans) or may have greater inherent resilience (Asian and Hispanic groups) are an area of continued interest (Hasin et al. 2005), as are potential epigenetic mediators of the effect of stressful life events (including childhood trauma) on the risk of MDD across generations (Franklin et al. 2010; Sun et al. 2013).
Many medical illnesses are comorbid with MDD (Table 46–1). Cancer, AIDS, respiratory disease, cardiovascular disease, Parkinson’s disease, and stroke are associated with an increased risk for depression (Katon 2003). MDD is associated with poorer outcomes in medically ill persons. For example, in patients with coronary heart disease and heart failure, depression is associated with a higher risk of rehospitalization and mortality (Rutledge et al. 2006; van Melle et al. 2004). The clinical course and level of functioning are poorer in patients with MDD and co-occurring medical conditions (Katon and Schulberg 1992; Keitner et al. 1991).
Infectious conditions |
Metabolic conditions |
Neurological conditions |
General medical conditions |
Encephalitis Hepatitis HIV/AIDS Influenza Meningitis Mononucleosis Pneumonia Postviral syndrome Syphilis Tuberculosis Urinary tract infection |
Addison’s disease Cushing’s disease Diabetes Hyponatremia Nutritional deficiencies Pituitary dysfunction Renal disease Thyroid disease |
Brain tumor Dementia, cortical Dementia, subcortical Huntington’s disease Migraine headaches Multiple sclerosis Parkinson’s disease Poststroke syndrome Seizure disorders Traumatic brain injury |
Alcohol or sedative withdrawal Arthritis Cancer Cardiovascular disease Chronic pain syndromes Cocaine or stimulant withdrawal Connective tissue diseases Fibromyalgia Heavy metal poisoning Irritable bowel syndrome Liver failure Menopause Myocardial infarction Premenstrual dysphoric disorder Pulmonary disease Selenium toxicity Sleep disturbance |
Note. AIDS=acquired immunodeficiency syndrome; HIV=human immunodeficiency virus. |
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MDD is also highly comorbid with other psychiatric disorders. In primary care settings, more than 75% of patients with diagnosed depression also have an anxiety disorder (Olfson et al. 1997). Patients with depression and anxiety have more chronic and severe illness, greater occupational and psychosocial impairment, and (when the comorbidity is unrecognized) higher rates of psychiatric hospitalization and suicide attempt (Hirschfeld 2001; Sareen et al. 2005). In acknowledgment of the high comorbidity of anxiety disorders with MDD, DSM-5 includes a specifier—“with anxious distress”—that can be added to a major depressive episode diagnosis if at least two of the following symptoms are present during the majority of the episode: feeling keyed up or tense, feeling unusually restless, difficulty concentrating because of worry, fear that something awful may happen, and feeling that one might lose control of oneself (American Psychiatric Association 2013). High anxiety in the context of MDD is associated with lower rates of response to initial treatment with an antidepressant (Fava et al. 2008).
Substance use disorders are also highly comorbid with depressive disorders. The reported prevalence of depressive disorders in patients with alcohol use disorder is 15%–67%; for patients with cocaine use disorder, the prevalence is 33%–53%, and for patients with opioid use disorder, the lifetime rate of mood disorders ranges from 16% to 75% (Davis et al. 2005; Rapaport et al. 1993; Zimmerman et al. 2002). As is the case with comorbid anxiety, co-occurring substance use disorders are associated with worse long-term outcomes and illness course in individuals with MDD (Davis et al. 2005), including higher rates of suicide (Sher et al. 2005). Remission from substance use has been shown to reduce the risk of depression (Agosti and Levin 2006).
In summary, there are several biological and nonbiological factors that can increase the risk of developing a depressive disorder.
MDD is associated with significant disease burden, exceeding that of cerebrovascular disease, cancer, and numerous other chronic medical illnesses (Wells et al. 1989; World Health Organization 2004). It is the leading cause of years lived with disability worldwide for young adults (Lopez et al. 2006) and is predicted to become the second leading cause of disability (behind HIV/AIDS) worldwide by the year 2030 (Mathers and Loncar 2006). It is estimated that the economic burden of adults with MDD in the U.S. is $210.5 billion, 45% of which is attributable to direct costs, 50% to workplace costs, and 5% to suicide-related costs (Greenberg et al. 2015).
The most severe outcome for persons with depressive disorders is death by suicide. Suicide is the tenth leading cause of death in the United States across all age groups (∼37,000 known suicides were identified in the 2009 census), the second leading cause of death for individuals between the ages of 25 and 34 years, and the third leading cause of death for young people between the ages of 15 and 24 years (Kochanek et al. 2012). Data from the 2013 National Survey on Drug Use and Health showed that among an estimated 15.7 million adults with a major depressive episode in 2013, 4.4 million (28%) had serious thoughts of suicide (Substance Abuse and Mental Health Services Administration 2014). Individuals with unipolar depressive illnesses including MDD have 20 times the risk of dying by suicide compared with the general population (American Association of Suicidology 2009; Harris and Barraclough 1997). Among depressed individuals, suicide risk is highest among males and among persons with past suicide attempts, with more severe depression, with hopelessness, and with comorbid substance use, anxiety, and personality disorders (Hawton et al. 2013).
In summary, depressive disorders in general and MDD in particular are costly and are associated with adverse effects on functioning, including disability that is as severe as—or more severe than—disability associated with most chronic medical illnesses. Depressive disorders are the diagnoses most commonly associated with suicide. Suicidal ideation with intent and a plan is a medical emergency that merits the same type of acute response that a physician would give to a myocardial infarction or stroke.
Current evidence suggests that there is no single, unifying etiopathophysiology for MDD (Kupfer et al. 2012). However, certain neurobiological alterations have been consistently observed in animal models of MDD and in human patients, many of which are modifiable through antidepressant or other biological treatments for MDD. These neurobiological markers of MDD are discussed below.
For several decades, drug development and biological treatment models for MDD were based primarily on the hypothesis that abnormalities in monoamine neurotransmitter signaling caused the psychological and neurovegetative signs and symptoms of the disorder (Owens 2004). Indeed, all known orally administered antidepressant medications interact with monoamine transporters or receptors or with enzymes responsible for their degradation (Li et al. 2012). Although this hypothesis has added profoundly to our understanding of the pathophysiology of MDD and the mechanisms of antidepressive treatment response, it alone cannot explain the wide variation in phenotypic presentation across large numbers of affected patients, nor can it explain the tremendous interindividual variability in clinical response to antidepressants (Hindmarch 2001).
As our understanding of the mechanism of action of antidepressant therapies has grown, more attention has been given to other neurotransmitter systems. Converging evidence from postmortem genetic in vivo neuroimaging studies has implicated glutamate abnormalities in the pathophysiology of mood disorders, including MDD (Duman 2014; Sanacora et al. 2012). Moreover, pharmacotherapies that target glutamatergic N-methyl-D-aspartate (NMDA) receptors have shown considerable promise as putative antidepressants. For example, subanesthetic doses of ketamine, an NMDA receptor antagonist, have been shown to induce rapid (within hours) antidepressant activity that may persist over several days to weeks in patients with pharmacotherapy-resistant MDD and bipolar depression (Newport et al. 2015). However, rates of antidepressant response to ketamine therapy vary widely, and not all glutamatergic compounds—or even all NMDA receptor antagonists—produce antidepressant effects.
Not surprisingly, depression is marked by dysregulation of important biological systems other than those involved in neurotransmitter signaling. Depressed individuals are often characterized as having altered biological responses to stress, likely due to dysregulation and overstimulation of the HPA axis (Gold 2015). Early studies showed that administration of dexamethasone to unmedicated depressed persons failed to suppress the secretion of cortisol (Brown and Shuey 1980; Carroll 1982; Coppen et al. 1983), a condition known as dexamethasone nonsuppression. This impairment of HPA axis regulation has been traced to dysregulated corticotropin-releasing hormone (CRH) secretion from the hypothalamus (Holsboer 2000). Depressed individuals have higher CRH neuronal activity (Raadsheer et al. 1994) and display a blunted adrenocorticotropic hormone and cortisol response to infusion of synthetic CRH (Gispen-de Wied et al. 1993; Gold et al. 1986). Remission of depressive symptoms induces a normalization of responses to dexamethasone or CRH challenge along with normalization of plasma cortisol levels (Amsterdam et al. 1988; Arana et al. 1985; Sachar et al. 1970). As noted earlier, dysregulation of HPA axis activity and higher rates of depression are more common in individuals exposed to childhood trauma or abuse (Ehlert 2013; Heim et al. 2008), suggesting that hyperactivity of the HPA axis during critical periods of brain development leads to higher rates of depression later in life.
This cascade of alterations in the HPA axis, and subsequent increase in glucocorticoids, is thought to be responsible for the structural and functional changes seen in certain limbic structures that are crucial for regulating emotion, motivation, reward, cognitive functioning, and reactivity to stress (Hamon and Blier 2013). Postmortem and neuroimaging studies have reported significant reductions in gray matter volume and glial density in frontolimbic brain regions, including the hippocampus and prefrontal cortex, in depressed patients (Arnone et al. 2012; Kempton et al. 2011; Rajkowska 2003). Successful antidepressant therapy has been shown to increase cellular proliferation in these brain regions (Duman 2004; Warner-Schmidt and Duman 2006), whereas chronically elevated levels of stress and glucocorticoid hormones interfere with normal hippocampal neurogenesis (Anacker et al. 2013). Dysregulation of the HPA axis, however, has not been observed uniformly across samples of depressed individuals and therefore cannot be considered a sole cause of MDD or other depressive states.
Psychosocial stressors are known to activate not only the HPA axis but also pro-inflammatory responses, which may represent another link between the effects of stress and the onset of MDD (Haroon et al. 2012). Compared with healthy subjects, depressed patients have been found to have higher levels of inflammatory biomarkers, including higher circulating pro-inflammatory cytokines, such as interleukin 6 (IL-6), IL-1, and tumor necrosis factor–alpha (TNF-α) (Dantzer et al. 2008; Hiles et al. 2012). Exposure to interferon-α (INF-α), an inflammatory cytokine used to treat chronic hepatitis C and neoplastic diseases, can induce depressive symptoms that overlap with MDD (Capuron et al. 2009) and that can be reduced or prevented by antidepressants (Baraldi et al. 2012; Udina et al. 2014). Pro-inflammatory cytokines have been shown to activate the HPA axis and to alter the metabolism of monoamine neurotransmitters and gluatamate (Haroon et al. 2012). Antidepressant treatment of depressed patients has been shown to reduce plasma levels of cytokines (IL-1β and possibly IL-6) in some studies but not others (Hannestad et al. 2011; Hiles et al. 2012), and decreases in pro-inflammatory cytokine levels over time have not always correlated with improvement in depressive symptoms (Brunoni et al. 2014b). For this reason, a neuroimmune mechanism cannot account for all cases of clinically significant depression or serve as a unified explanation of antidepressant activity.
Deficiencies in a host of growth factors (neurotrophins) that regulate plasticity in the human brain have also been implicated in the pathophysiology of MDD and of other disease states. More specifically, several types of psychosocial stress have been linked with reduced brain-derived neurotrophic factor (BDNF) signaling in the hippocampus (Duman and Monteggia 2006). Expression of BDNF and BDNF-related genes is reduced or altered in postmortem brain samples and circulating lymphocytes from depressed persons, and serum BDNF levels are decreased in patients with MDD (Krishnan and Nestler 2008). Antidepressant treatment and electroconvulsive therapy (ECT) have both been found to produce upregulation of BDNF expression in clinical and preclinical studies (Brunoni et al. 2014a; Cattaneo et al. 2013; Polyakova et al. 2015). Additionally, preclinical studies have shown that BDNF infused directly into the hippocampus produces antidepressant-like effects that are blocked in animals lacking the BDNF gene (Krishnan and Nestler 2008). However, infusion of BDNF into other brain regions produces increases in depression-like behaviors (Krishnan and Nestler 2008). Enthusiasm for a “neurotrophic hypothesis” for MDD has been further tempered by negative findings from studies that failed to replicate stress- or antidepressant-induced changes in BDNF expression, by the lack of a satisfactory mechanism through which neurotrophic factors might improve mood in depressed patients, and by findings indicating that decreased neurogenesis is not a sole cause of depression (Groves 2007; Krishnan and Nestler 2008).
A variety of susceptibility genes have been investigated in hopes of identifying a genetic profile that will help us to better understand the pathophysiology of MDD and provide novel neurobiological targets for treatment interventions. Candidate gene studies have identified several potential risk genes for MDD, including BDNF, SLC6A4, ACE, P2RX7, TPH2, PDE9A, PDE11A, DISC1, NR3C1, GRIK3, and genes for monoamine oxidase A and glycogen synthase kinase–3β (Fan et al. 2010; Levinson 2006; van Rossum et al. 2006; Yoon and Kim 2010). No single gene has been clearly identified as a cause of MDD (López-León et al. 2008), and it may be concluded that depressive disorders are likely polygenetic in nature (Uher 2009). Interactions between genes and environmental factors (including childhood trauma and other adverse life events) may contribute more strongly than either alone to the development of depression (Caspi et al. 2010; Cohen-Woods et al. 2013; Kendler et al. 1995).
Gene expression is influenced by more than simple variations in DNA sequence. The field of epigenetics investigates changes in gene expression caused by biological processes (such as DNA methylation/demethylation and histone acetylation) that do not change the underlying DNA sequence but instead either activate or deactivate the expression of specific genes. Epigenetic alterations in chromatin structure have been associated with depression-like behaviors in animal models and have been found in postmortem brains of depressed persons (Nestler et al. 2016). Epigenetic changes can occur in response to environmental insults and stress, resulting in long-lasting effects on gene expression (Qureshi and Mehler 2014). Therefore, epigenetic modifications are candidate mechanisms for stress-induced effects on gene expression, neuronal functioning, and the risk of MDD and other depressive states (Nestler et al. 2016). Interestingly, treatment with antidepressants has been shown to result in epigenetic changes in genes associated with the risk of MDD, including BDNF and SLC6A4 (Domschke et al. 2014; Duclot and Kabbaj 2015). Epigenetic (dys)regulation of gene expression may therefore represent not only an important pathophysiological mechanism linking environmental or life stress and the risk of MDD but also an important neurobiological mechanism of antidepressant treatment response.
Pharmacotherapy with antidepressants is an important component of a comprehensive biopsychosocial treatment plan for managing MDD. The pharmacological profiles of individual antidepressants are extensively reviewed in Chapters 8–23 of this volume. Our focus in this chapter is the practical aspects of antidepressant use and the broader range of treatments for MDD and other depressive disorders.
With regard to initial antidepressant choice, there is little evidence that one antidepressant is clearly superior to other agents under most routine treatment conditions, although there may be some evidence of modest efficacy advantages for venlafaxine or other serotonin–norepinephrine reuptake inhibitors (SNRIs) over selective serotonin reuptake inhibitors (SSRIs) (Nemeroff et al. 2008; Papakostas et al. 2007b; Schueler et al. 2011) and for sertraline, escitalopram, or mirtazapine over selected other antidepressants (Cipriani et al. 2008, 2009; Gartlehner et al. 2011; Kennedy et al. 2009; Montgomery et al. 2007). However, there is limited research supporting differential benefit. Therefore, in most cases, initial antidepressant choice is made on the basis of differential side-effect and tolerability profiles. For example, SSRIs are generally preferred for initial antidepressant treatment in patients with MDD because they are associated with fewer side effects than SNRIs, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) (Anderson 2000; Nemeroff et al. 2008; Schueler et al. 2011) and are regarded as being relatively safe in overdose (Barbey and Roose 1998). However, sexual side effects can be treatment limiting with the SSRIs (and with SNRIs, TCAs, MAOIs, vilazodone, and vortioxetine), whereas bupropion and mirtazapine have lower rates of treatment-emergent sexual dysfunction and therefore may be preferred by some patients (Montejo et al. 2015).
Additional factors that may be considered when choosing among antidepressants for treating patients with depressive disorders are summarized in Table 46–2. Drug–drug interactions may increase blood levels of concomitantly administered medications, and at times those interactions can be unpleasant or even life-threatening (Spina et al. 2012). When comorbid psychiatric or medical conditions are present, it may be particularly advantageous to select an antidepressant that effectively addresses both the depression and the comorbid disorder and to avoid antidepressants that may aggravate the comorbid condition. Persons with MDD with atypical features—a DSM-5 (American Psychiatric Association 2013) specifier defined as depression with intact mood reactivity and at least two associated symptoms (significant weight gain/increase in appetite, hypersomnia, “lead-like” heaviness in the limbs, sensitivity to perceived rejection)—may respond preferentially to an oral MAOI or to SSRIs (Henkel et al. 2006). For most patients with MDD with psychotic features (defined as the presence of hallucinations or delusions), the use of an antidepressant in combination with an antipsychotic drug is more efficacious than antidepressant monotherapy, although the side-effect burden may be greater with combination therapy than with monotherapy (Farahani and Correll 2012).
Efficacy profile (no evidence of large differences between agents for routine use) |
Side-effect (tolerability) profile |
Safety in overdose |
Concomitant medications and the potential for drug–drug interactions |
Comorbid psychiatric illness(es) |
Comorbid general medical illness(es) |
Prior treatment response to the medication (efficacy, tolerability) |
Family history of treatment response to the medication (efficacy, tolerability) |
Patient preference |
Medication cost/insurance coverage |
Source. Cleare et al. 2015; Lam et al. 2009; Malhi et al. 2013; Mann 2005. |
Compared with the extensive literature on antidepressants in MDD, far fewer studies have focused on antidepressant efficacy in patients with persistent depressive disorder (dysthymia); however, SSRIs and TCAs appear to be effective in this disorder (Kriston et al. 2014).
The initial goals of treatment are to achieve symptom remission (absence of clinically significant depressive symptoms) and to restore normal functioning. Once a patient is well, the primary goals are to prevent relapses and minimize adverse effects.
In general, 2–6 weeks of treatment are required for most antidepressants to show positive clinical benefit, and some patients require an even longer period of time. However, lack of significant clinical benefit by 4 weeks predicts lower odds of an eventual positive treatment response, and a change in treatment may be needed (Szegedi et al. 2003). Lack of discernible positive treatment response to an antidepressant may reflect inefficacy of the medication for that patient; however, this conclusion can be reached only after practical reasons for poor response to antidepressant pharmacotherapy have been ruled out (Table 46–3).
Poor adherence to medication (consider therapeutic drug monitoring, where appropriate) |
Inadequate dosage (or serum value in the case of certain TCAs) |
Inadequate duration of treatment |
Inaccurate diagnosis (e.g., secondary depression, bipolar I or II depression) |
Undiagnosed psychiatric symptoms (e.g., psychotic or atypical features) or comorbidity (e.g., substance use disorder, personality disorder, anxiety disorder) |
New or worsening medical comorbidities |
Drug–drug interactions (particularly concomitant medications that may worsen depressive symptoms, aggravate antidepressant side effects, or lead to excessively rapid metabolism of the antidepressant) |
Undiagnosed psychosocial factors that are prolonging depressive symptoms |
Note. TCAs=tricyclic antidepressants. Source. Cleare et al. 2015; Culpepper et al. 2015. |
Positive antidepressant responses that fall short of remission are clinically meaningful but are also associated with higher rates of relapse and residual functional impairment (Culpepper et al. 2015). Strategies for managing partial response to antidepressants include incrementally increasing the dosage of antidepressant (assuming good tolerability), adding another medication and/or psychotherapy to the antidepressant (if the dosage of the antidepressant cannot be increased and switching to a new drug carries the risk of a full symptom relapse), or switching to a new antidepressant (if combination pharmacotherapy is infeasible or if side effects are intolerable).
With regard to combination pharmacotherapy to improve efficacy, there is evidence supporting the adjunctive use of lithium with TCAs or possibly SSRIs (Crossley and Bauer 2007; Zhou et al. 2015); the adjunctive use of selected atypical antipsychotic drugs primarily with SSRIs (Papakostas et al. 2007a, 2015); and the adjunctive use of thyroid hormone (T3, liothyronine) with SSRIs and TCAs (Zhou et al. 2015). There is also evidence supporting the use of mirtazapine or TCAs in combination with SSRIs in improving remission rates, as compared with SSRIs alone (Rocha et al. 2012). Other commonly used strategies in clinical practice include augmentation of antidepressants with a second antidepressant (e.g., bupropion, mirtazapine), with buspirone, with modafinil or armodafinil, or with a traditional psychostimulant such as methylphenidate; however, there is less evidence supporting most of these strategies (Lam et al. 2009; Zhou et al. 2015).
There is some evidence supporting combination pharmacotherapy to manage adverse effects of antidepressants, including bupropion or selected phosphodiesterase inhibitors (sildenafil, tadalafil) for reducing antidepressant-associated sexual side effects (Taylor et al. 2013), with the best evidence supporting sildenafil for both men and women (Fava et al. 2006; Nurnberg et al. 2008). Use of adjunctive pharmacotherapy to manage antidepressant-associated side effects may be appropriate if lowering the antidepressant dosage or switching to a new antidepressant is not feasible, provided that adding the second agent does not introduce unacceptable medical risk or drug interactions.
There is controlled evidence supporting the benefit of switching from one SSRI to another after insufficient response to an initial SSRI trial, especially if the first SSRI was poorly tolerated (Ruhé et al. 2006). Clinical guidelines and controlled evidence also support the benefit of switching to a non-SSRI antidepressant if there is either a lack of clinical benefit from the initial SSRI trial or a lack of response to two SSRI trials (Cleare et al. 2015; Lam et al. 2009; Malhi et al. 2013; Ruhé et al. 2006). Treatment-resistant depression—defined as depression that has not responded to at least two therapeutic trials of antidepressants from different pharmacological classes (e.g., an SSRI followed by an SNRI, an SSRI followed by bupropion)—is discussed in the following subsection, “Managing Treatment-Resistant Major Depressive Disorder.”
In general, patients who respond well to an antidepressant at a given dosage should continue at that same dosage for at least 6–9 months. However, there is no broad consensus as to how long antidepressants should be continued in patients whose depressive symptoms remit before a medication-free trial is undertaken. A longer duration of antidepressant treatment may be beneficial for patients who are at higher risk of relapse, including those with a history of multiple depressive episodes. Adjunctive psychotherapy may be useful as an added relapse-preventive measure (see section “Psychotherapies” later in this chapter).
Unfortunately, up to one-third of patients with MDD do not respond to at least two therapeutic trials of antidepressants from different pharmacological classes and are considered to have treatment-resistant depression (TRD). Compared with treatment-responsive depression, TRD is associated with more severe and chronic depressive symptoms, greater psychiatric and medical comorbidity, higher health care costs, and higher risks of death from medical illness and suicide (Greden 2001).
For patients whose depression has not responded to serial therapeutic trials of antidepressants and whose nonresponse cannot be better explained by practical factors (see Table 46–3), management options include switching antidepressants, using combination pharmacotherapy, augmenting antidepressants with psychotherapy, or initiating a course of ECT. There is support in the literature for switching to a different antidepressant after nonresponse to the current antidepressant at virtually any stage of treatment. For patients with TRD, there is also support for initiating a therapeutic trial of mirtazapine or TCAs (in the case of poor response to other antidepressants), for initiating combination pharmacotherapy with an augmenting agent (e.g., adding an atypical antipsychotic, lithium, or thyroid hormone to the antidepressant), and for switching to an alternative TCA or to an oral MAOI (in the case of poor response to an initial TCA trial) (Carvalho et al. 2014; Culpepper et al. 2015; McIntyre et al. 2014; Zhou et al. 2015). Psychotherapy and somatic therapies such as ECT are also treatment options and are reviewed in the following subsections.
There has been recent excitement about the therapeutic potential of ketamine and related glutamatergic NMDA receptor–targeting agents in treatment-resistant unipolar and bipolar depression. When provided at subanesthetic doses, ketamine has shown a rapid onset (within hours) of transient (1–4 weeks) antidepressive effects with very large effect sizes in patients with severely refractive depression (Newport et al. 2015). However, ketamine therapy for depression is still considered investigational at this time.
ECT is the best studied of the somatic interventions. It is a clearly one of the treatments of choice for individuals with TRD, and it is effective for MDD with psychotic or catatonic features and for other situations in which a rapid antidepressive effect is needed and lag times to therapeutic benefit with conventional antidepressants are unacceptable (e.g., persons with MDD who are at high suicide risk or those who are nutritionally compromised because of food refusal). Although the mechanism of action of ECT is still not well understood, it is a safe and effective treatment. In repeated studies, ECT has been found to be more effective than placebo (sham ECT) and pharmacotherapy in patients with TRD (UK ECT Review Group 2003). Adverse cognitive effects and relapses following a successful course (even with ongoing pharmacotherapy) are the main limitations of ECT (Jelovac et al. 2013; UK ECT Review Group 2003). Relapse rates can be reduced with maintenance ECT. Cognitive side effects may be limited by the use of alternative electrode placements (unilateral instead of bitemporal) and by the use of ultrabrief-pulse (instead of brief-pulse) ECT (Tor et al. 2015). For a review of recent advances in ECT and other somatic therapies, see Chapter 45 in this volume, “Electroconvulsive Therapy and Other Neuromodulation Therapies,” by McDonald et al.
Vagus nerve stimulation (VNS) was initially developed for the treatment of epilepsy. In 2005 it was approved by the U.S. Food and Drug Administration (FDA) for use in TRD. One of the key findings to emerge from studies of VNS is that its effects may be cumulative, with the full benefits usually not evident until 9–12 months after treatment initiation (Sackeim et al. 2007; Schlaepfer et al. 2008). VNS is generally available only in specialized settings with adequate surgical capabilities.
Transcranial magnetic stimulation (TMS) was first identified as a treatment for depression in 1995 by a group of National Institute of Mental Health researchers (George et al. 1995). Since that time, several smaller studies have supported the efficacy of TMS for the treatment of MDD (Allan et al. 2011). At present, TMS is FDA approved for the treatment of MDD in individuals whose depressive episode has been unresponsive to one adequate medication trial. A number of related neurostimulation treatments are in development, including magnetic seizure therapy, transcranial direct current stimulation, low-field magnetic stimulation, and cranial electrical stimulation (Rosa and Lisanby 2012).
Deep brain stimulation (DBS) is an FDA-approved treatment for severe, intractable Parkinson’s disease, essential tremor, dystonia, and obsessive-compulsive disorder (under a humanitarian device exemption). In a large multisite study of DBS therapy in 20 individuals with TRD, the initial 6-month response and remission rates were 60% and 30%, respectively (Lozano et al. 2008). Significant reductions in depressive symptoms and high remission rates have subsequently been demonstrated in small open studies of DBS therapy for severely treatment-resistant depression (Anderson et al. 2012). Despite these encouraging results, there is still an inadequate understanding of the precise mechanisms underlying the therapeutic effects of DBS for TRD, and its use in the treatment of MDD is still considered to be investigational. Furthermore, larger trials of DBS in TRD have not confirmed its efficacy (Dougherty et al. 2015). As with VNS, longer periods of exposure to DBS may yield better effects (Holtzheimer et al. 2012).
Bright light therapy appears to be an effective augmentation therapy for certain types of depressive disorders (Oldham and Ciraulo 2014). Light has been best studied in patients with seasonal affective disorder (i.e., DSM-5 major depressive episode with seasonal pattern), although it also appears to be effective for some patients with nonseasonal depression (Even et al. 2008). Light therapy for up to 90 minutes per day has been shown to effectively treat—and also to prevent the development of—depressive disorders (Even et al. 2008; Westrin and Lam 2007), especially those with a seasonal pattern. Light therapy has also been shown to improve depressive symptoms in pregnant and postpartum women (Corral et al. 2007; Wirz-Justice et al. 2011).
In summary, ECT is clearly effective for TRD and severe forms of depression, including MDD with psychotic features. VNS and TMS are also approved for the treatment of MDD that has not responded to at least one antidepressant trial. Additional neuromodulatory treatments such as DBS are under clinical development and show considerable promise but are likely to be available only in highly specialized treatment settings. It is clear that more work needs to be done in investigating somatic options for patients with TRD.
Cognitive-behavioral therapy (CBT) is a time-limited psychotherapy that aims to help patients systematically assess and modify distorted (depression promoting) automatic thoughts and assumptions about themselves, their current situation, and their future. These cognitive techniques are coupled with behavioral interventions designed to combat passive disengagement from life activities, including social withdrawal. CBT has been shown to be effective in reducing active symptoms of depression and preventing depressive relapses (Lynch et al. 2010). Although practice guidelines have preferentially recommended antidepressant pharmacotherapy over psychotherapy for severe episodes of MDD, recent evidence has suggested that for patients with nonpsychotic MDD, baseline depression severity may not moderate differences in antidepressive efficacy between CBT and antidepressant pharmacotherapy (Weitz et al. 2015). The combination of CBT with antidepressant pharmacotherapy may be more effective than medication alone in reducing depressive symptoms and improving recovery rates and adherence to treatment (Hollon et al. 2014). CBT also appears to be just as effective as continuation medication in preventing relapse after recovery from a depressive episode (Hollon et al. 2005).
Interpersonal psychotherapy (IPT) is a time-limited individual psychotherapy that focuses on four problem areas—grief, role transitions, role disputes, and interpersonal deficits—during acute treatment of depression. IPT has been demonstrated to be an efficacious acute treatment for patients with MDD, both alone and in combination with antidepressant pharmacotherapy (Cuijpers et al. 2011).
Both IPT and CBT are recommended as first-line psychotherapies for treating patients with MDD, and there is no clear evidence that one is more efficacious than the other (Jakobsen et al. 2012). However, IPT appears to be effective in reducing relapse only while it is continued (Frank et al. 2007).
Mindfulness-based cognitive therapy (MBCT) is a next-generation psychotherapy based in part on cognitive therapy principles, supplemented by techniques that teach depressed patients to adopt a nonjudgmental awareness of the present moment in an effort to disengage from negative thought patterns that maintain depressive episodes and lead to depressive relapses (van der Velden et al. 2015). MBCT has been shown to be effective in preventing relapse in patients with recurrent MDD, particularly those with three or more lifetime mood episodes (Piet and Hougaard 2011). The effectiveness of MBCT in treating acute depressive episodes, including acute episodes in patients with severe MDD, has not been established.
Other forms of psychotherapy that have been studied in patients with MDD and other forms of depressive illness include behavioral activation, short-term psychodynamic psychotherapy, acceptance and commitment therapy, motivational interviewing, cognitive-behavioral analysis system of psychotherapy, and self-guided treatments such as bibliotherapy and computer-based delivery platforms for psychotherapy (Lampe et al. 2013; Parikh et al. 2009). In general, there is much less empirical support for these approaches than for either CBT or IPT; therefore, more high-quality studies are needed.
In conclusion, both CBT and IPT are efficacious in the treatment of MDD. Evidence to date suggests that CBT is also effective in the maintenance treatment of depressive disorders. However, there is still uncertainty about how best to select the most appropriate form of psychotherapy for an individual patient. To a significant degree, the success of IPT and CBT appears to depend on therapist training and competence in delivering the specific form of psychotherapy (Hollon and Ponniah 2010).
There are a host of complementary and alternative medicine approaches that have been studied for treating patients with MDD and other types of unipolar depression. There is evidence from controlled studies to support the use of Hypericum perforatum (St. John’s wort) for mild to moderate depression (Linde et al. 2008), although this agent should not be combined with serotonin-potentiating antidepressants (such as SSRIs, SNRIs, TCAs, or MAOIs) to avoid risk of serotonin syndrome.
There is also some controlled evidence supporting the use of S-adenosylmethionine (SAM-e) alone and omega-3 fatty acid supplementation alone or in combination with antidepressants for mainly mild to moderate depression (Grosso et al. 2014; Papakostas et al. 2010). Other approaches that have also shown promise include partial wake therapy (sleep deprivation) and supplementation with L-methylfolate, dehydroepiandrosterone (DHEA), tryptophan, or other neutraceuticals. Further controlled research is warranted.
A variety of lifestyle interventions have been systematically evaluated, mainly as adjuncts to core depression treatments. Beneficial effects have been observed for increasing physical activity and exercise; making dietary modifications; maintaining adequate relaxation and sleep practices; practicing mindfulness-based meditation; and reducing or eliminating recreational substance use, including nicotine, drugs, and alcohol (Sarris et al. 2014). In general, nearly all of these interventions can be recommended for improving general health and well-being in most patients with little risk of harm.
Over the past decade, there have been remarkable advances in our knowledge about the neurobiology, course and prognosis, and treatment of MDD and other unipolar depressive illnesses. Some patients with MDD have an episodic course with relatively normal functioning between discrete mood episodes. The majority of patients, however, have a more chronic and persisting course.
Fortunately, there are a large number of first-line treatments for MDD, including a wide variety of antidepressants. Although many patients benefit from treatment with antidepressants, a significant percentage of patients do not respond to a degree that leads to symptomatic remission and full functional recovery. Furthermore, a substantial number of patients do not benefit even after multiple therapeutic trials of antidepressants. For those who respond but do not achieve remission, options for management include implementing dosage increases as tolerated, initiating pharmacological augmentation regimens (combination pharmacotherapy), integrating pharmacotherapy with psychosocial treatments (including CBT or IPT), and switching treatments. For patients with TRD, the same general approaches can be used, although older antidepressants (such as TCAs and MAOIs) and ECT are higher-priority treatment options. Most patients with MDD with psychotic features will require combination pharmacotherapy with an antidepressant and an antipsychotic drug. Seasonal forms of depression may respond well to light therapy. Adoption of healthy lifestyle habits can be recommended for nearly all patients.
Although the field has made significant progress with regard to depression treatment, many challenges remain, particularly for patients with TRD, for which treatment options are the most limited. However, advances in basic biological investigations of depression are greatly expanding our knowledge, and new psychotherapies and biological treatments continue to be developed. Future research will be focused on integrating findings across multiple neuroscientific disciplines to better elucidate the roles of and interactions between the variety of neurotransmitter-, neuroendocrine-, immune-, neurohormonal-, neurotrophic-, and circuitry-based systems implicated in the pathogenesis of depression. Advances in translational research will identify novel biological targets for depression treatment and will allow us to develop better and more personalized approaches for our patients.
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This chapter is an update and revision of Shaywitz J, Rapaport MH: “Treatment of Depression,” in Essentials of Clinical Psychopharmacology, Third Edition. Edited by Schatzberg AF, Nemeroff CB. Arlington, VA, American Psychiatric Publishing, 2013, pp 577–589.