Major depressive disorder in adults: Approach to initial management

INTRODUCTION — Major depression is highly prevalent and disabling. Depressive disorders rank 13^th worldwide as a cause of disability and mortality, with a lifetime prevalence of 12 percent [1]. Nationally or regionally representative surveys in 21 countries estimate that the 12-month prevalence of major depression is 5 percent [2]. In the United States, major depression ranks second among all diseases and injuries as a cause of disability, and persistent depressive disorder (dysthymia) ranks 20^th [3,4].

In addition, major depression is often recurrent. More than 40 percent of patients who recover from an initial episode will experience a recurrence within two years. After two episodes, the risk of recurrence within five years is approximately 75 percent [5].

This topic reviews the initial management of major depressive disorder (MDD), including how to choose a treatment regimen, how to optimize treatment, and when to refer for urgent management or to a psychiatrist. It also reviews the management of some other depressive disorders, such as persistent depressive disorder (dysthymia) and depression with mixed features. Other aspects of depression treatment are discussed separately.

Specific components of depression management:

●(See "Major depressive disorder in adults: Initial treatment with antidepressants".)

●(See "Major depressive disorder in adults: Treatment with supplemental interventions".)

●(See "Unipolar major depression: Treatment with mindfulness-based cognitive therapy".)

●(See "Interpersonal Psychotherapy (IPT) for depressed adults: Specific interventions and techniques".)

●(See "Behavioral activation therapy for treating unipolar major depression".)

●(See "Unipolar depression in adults: Family and couples therapy".)

●(Related Pathway(s): Unipolar major depression: Initial pharmacologic therapy in adults.)

Depression management after initial phase treatment:

●(See "Unipolar depression in adults: Continuation and maintenance treatment".)

●(See "Unipolar depression in adults: Choosing treatment for resistant depression".)

●(See "Unipolar depression in adults: Treatment with antidepressant combinations".)

●(See "Unipolar depression in adults: Investigational and nonstandard treatment".)

DEFINITIONS

●Major depressive disorder (MDD) – MDD is diagnosed in patients with a history of at least one major depressive episode and no history of mania or hypomania (table 1) [6]. In this topic, the term "major depression" refers to MDD.

●Major depressive episode – A major depressive episode is a period lasting at least two consecutive weeks, with five or more of the following symptoms: depressed mood, anhedonia, insomnia or hypersomnia, change in appetite or weight, psychomotor retardation or agitation, low energy, poor concentration, thoughts of worthlessness or guilt, and recurrent thoughts about death or suicide. At least one of the symptoms must be depressed mood or anhedonia. A major depressive episode can occur in major depressive or bipolar disorders, as well as other psychiatric disorders.

●Phases of depression – Trials of interventions to treat depression often use specific depression rating scales to rate symptom severity and describe clinical outcomes. The following commonly used terms delineate phases of treatment [7]. Although these definitions are useful for conceptualizing the illness course of depression and evaluating treatment interventions, they are not standardized. In clinical practice, the terms "relapse" and "recurrence" are often used interchangeably, as are "remission" and "recovery."

•Response – Response is the reduction of depression symptoms by a clinically meaningful, specified amount. Response is usually defined as an improvement in symptom score of ≥50 percent that is still above the threshold for remission [8,9].

-Partial response – Partial response is defined as an improvement in symptom score of >30 but <50 percent. However, definitions used in individual studies differ [8,9].

-Nonresponse (no meaningful benefit) – A nonresponse to depression treatment is usually defined as a change in symptom score of ≤30 percent.

•Remission – Remission is the stable reduction of symptoms below the threshold (or specific cut-off) for diagnosis. Studies using the nine-item Patient Health Questionnaire (PHQ-9) often define remission as a score of <5 (table 2). The Montgomery-Asberg Depression Rating Scale (figure 1A-C) often defines remission as a score ≤9.

•Recovery – Recovery occurs when symptom remission has been sustained for 8 to 24 weeks [10-14].

•Relapse – Relapse is the return of depressive symptoms prior to the time of recovery.

•Recurrence – Recurrence is the onset of a new episode of major depression after recovery from a prior episode.

NEED FOR URGENT MANAGEMENT — The first step in managing individuals with MDD includes determining whether they can safely be managed as outpatients. This includes assessing for functional impairment, symptom severity, and the presence of suicidal intent or behavior. Transfer to the emergency department for expedited treatment, including evaluation for inpatient management, is typically necessary for individuals at imminent risk of self-harm (ie, active suicidal behavior and/or plan, inability to care for self), risk of harming others, or need for acute detoxification from drugs or alcohol that complicate depression management. Individuals who need urgent management generally also benefit from referral to a psychiatrist.

Active suicidal ideation or behavior — We send patients at imminent risk of suicide to the emergency department for evaluation and possible hospitalization. Identifying individuals at imminent risk of danger from self-harm can be challenging. Although over half of outpatients with depression experience suicidal ideation, most do not act on these thoughts [15]. Patients who endorse thoughts of suicide have a wide range of symptom severity, from those who have occasional thoughts that "I would be better off dead" to those whose thoughts of suicide are intrusive and occur multiple times a day. Patients who have a specific plan for self-harm, the means available to carry out the plan, and an intention to do so are at high risk, and we refer these individuals for emergency evaluation and management. Additional features that indicate an increased risk for suicide include the following [16-22]:

●Prior suicide attempt (strongest risk factor)

●Psychotic symptoms

●Severe anxiety or agitation

●Increased alcohol and/or drug use

●Access to firearms

●Recent increase in rage or anger

●Expressions of hopelessness or a lack of reason for living

●History of impulsivity or reckless behavior

Assessment of suicide risk is discussed separately. (See "Suicidal ideation and behavior in adults", section on 'Patient evaluation'.)

Intent to harm others — Although the absolute risk of violence in patients with depression is low, those whose symptoms place others at risk of imminent harm need urgent referral to the emergency department. This includes patients with demonstrated aggressive or violent behavior or who communicate an imminent plan to harm specific others. It may also include those whose inability to care for dependent others, such as children, places them at imminent risk of harm. (See "Assessment and emergency management of the acutely agitated or violent adult".)

Inability to care for self — Individuals with depression who demonstrate severe functional impairment and are at imminent danger from lack of self-care need inpatient management. As an example, this could include patients who are unable to take in adequate nutrition and have signs of dehydration or volume depletion. Less severe degrees of functional impairment include inability to get dressed, get out of bed, or perform typical work or home responsibilities. Although patients with this level of impairment need expedited management and close monitoring, they usually do not require referral to the emergency department, particularly if the patient has adequate support from family and/or friends.

Psychotic features or mania — Individuals with symptoms or signs of psychosis or mania require expedited evaluation and treatment, generally in an inpatient psychiatric setting. Psychotic features often manifest with delusions (false, fixed beliefs) or hallucinations; we suspect psychosis in individuals who appear distracted by internal stimuli or exhibit severe agitation or psychomotor retardation. Delusions and hallucinations are associated with a higher risk of self-harm and suicide attempts. (See "Psychosis in adults: Initial management" and "Bipolar mania and hypomania in adults: Choosing pharmacotherapy".)

Need to detoxify from alcohol or drugs — Patients with depression and a concomitant substance use disorder, who require close observation for safe detoxification from alcohol or drugs, will also benefit from inpatient management [23].

CHOOSING A TREATMENT REGIMEN FOR PATIENTS WITH MAJOR DEPRESSION

Goals of treatment — The goals of initial treatment are symptom remission and restoration of baseline function [22,24,25]. Although treatment response without remission is still clinically meaningful and associated with functional improvement, remission is the ideal goal, because it is associated with a better prognosis and more significant improvements in daily function than response without remission [26]. As an example, in a large trial of 3671 outpatients with MDD who received pharmacotherapy and/or psychotherapy, relapse rates at 12 months were higher in participants with a treatment response but no remission compared with those with a remission [27].

Shared decision making — Given clinical equipoise between treatment options for most patients and that treatment effectiveness depends on adherence, we elicit and integrate patients' preferences and priorities into discussions about treatment selection and engage in shared decision making to develop a treatment plan [7,26]. We consider costs of treatment and whether the patient has access to evidence-based, high-quality psychotherapy. Additional factors that influence treatment selection for individuals with MDD include the patient's prior experiences with depression treatments and number and severity of prior depressive episodes.

Severity-based approach to treatment — We generally target treatment strategies based on the severity of the patient's depression (algorithm 1).

Determination of severity — The severity of depression is determined by the combination of the degree of functional impairment and the number, frequency, intensity, and duration of the individual's symptoms. We use the self-report nine-item Patient Health Questionnaire (PHQ-9) to assess symptom number and frequency (table 2). The PHQ-9 classifies symptoms as follows:

Mild – 5 to 9

Moderate – 10 to 14

Moderately severe – 15 to 19

Severe – 20 or higher

However, treatment selection for individuals with MDD requires a nuanced approach that goes beyond a one-time symptom score measurement. Given a specific PHQ-9 score, we may consider the depression to be more severe if the patient has more severe functional impairment, longer symptom duration, a worsening trajectory of symptoms, severe suicidal thoughts and/or behaviors, or the presence of psychotic features or catatonia.

Mild major depression — Individuals with mild major depression have at least five depression symptoms (table 1) and a PHQ-9 symptom score of 5 to 9 (table 2). They have minor to no functional impairment and do not have severe suicidal ideation (eg, a specific plan and intent to act on it) or suicidal behavior [6]. Our approach to the treatment of patients with mild major depression takes into account patient preferences, duration of symptoms, and prior psychiatric history.

●No prior depressive episodes and short duration of symptoms – For individuals with mild major depression whose symptoms are of relatively short duration (eg, one to three months) and who have minimal functional impairment and no prior episodes of major depression, we suggest active surveillance (watchful waiting) and exercise (see "Major depressive disorder in adults: Treatment with supplemental interventions", section on 'Role and selection of supplemental treatments'). Individuals who opt for active surveillance, exercise, and/or other supplemental treatment require close follow-up (eg, two to four weeks) to monitor for symptom progression.

In-person psychotherapy is a reasonable alternative for these individuals (see 'Psychotherapy' below) [7]. Internet-based psychotherapy and other supplemental treatments may also be options for these patients, although limited data exist to support their efficacy (see "Major depressive disorder in adults: Treatment with supplemental interventions", section on 'Role and selection of supplemental treatments'). To minimize overtreatment, we typically do not use antidepressants in this group of patients unless the patient has a strong preference for pharmacotherapy or is developing familiar depressive symptoms that have responded to medication in the past.

●Prior depressive episodes or longer symptom duration – For individuals with mild MDD who have a prior history of major depression, greater functional impairment, and/or longer duration of symptoms (more than three months), we suggest either psychotherapy or antidepressants [20]. We base the selection of psychotherapy or antidepressants on patient preference, cost, and availability of evidence-based psychotherapy. We also consider prior treatment with antidepressants and whether the patient experienced remission with antidepressant or psychotherapeutic treatment. The selection of a specific antidepressant or psychotherapy is discussed separately (see 'Specific treatment components' below). We encourage exercise as an adjunctive treatment, and other adjunctive modalities may also improve symptoms. However, in this group of patients, we generally do not offer supplemental interventions as "stand-alone" treatments. (See "Major depressive disorder in adults: Treatment with supplemental interventions".)

This approach is consistent with guidelines from the US American College of Physicians, the United Kingdom's National Institute for Health and Clinical Excellence (NICE), the Canadian Network for Mood and Anxiety Treatments (CANMAT), and the American Psychiatric Association [7,20,22,28].

For patients with mild major depression, data regarding definitive treatment are limited [29]. Support for using psychotherapy and/or antidepressants to treat mild major depression comes primarily from trials of individuals with moderate to severe symptoms [7] (see 'Moderate major depression' below and 'Severe major depression' below). One small meta-analysis that evaluated effects of symptom severity on response to treatment found that in those with milder depression, psychotherapy alone was equivalent to combination interventions (psychotherapy plus antidepressant treatment) [30].

Moderate major depression — Individuals with moderate major depression have at least five depression symptoms (table 1) and a PHQ-9 symptom score of 10 to 19 (table 2). This includes those with "moderate" and "moderately severe" major depression (see 'Determination of severity' above). These patients generally have mild to moderate functional impairment and may have suicidal ideation.

●Selecting a treatment regimen – For the initial treatment of most individuals with moderate major depression, we suggest treatment with either an antidepressant or in-person psychotherapy. Exercise and other supplemental interventions can be used as adjunctive treatments. (See "Major depressive disorder in adults: Treatment with supplemental interventions", section on 'Role and selection of supplemental treatments'.)

For individuals with moderate major depression who have a prior history of MDD, longer duration of symptoms (eg, >6 months), or active suicidal ideation or marked functional impairment, combination treatment (ie, pharmacotherapy plus psychotherapy) is a reasonable alternative [31], although initiating two modalities simultaneously may be challenging for patients and affect adherence. Combination treatment is discussed separately. (See 'Severe major depression' below.)

Because in-person psychotherapy and antidepressants have similar efficacy, the choice between them depends primarily on patient preference, access to treatment, quality of available psychotherapy, and cost. Antidepressants are generally more available, more convenient, and less expensive than psychotherapy [22,32]. Some patients also prefer pharmacotherapy [33]. By contrast, some individuals prefer psychotherapy over taking an antidepressant, in part because they may wish to avoid medication side effects and/or minimize the risk of drug-drug interactions. Psychotherapy may also be more optimal for individuals with significant life stressors or relationship issues.

Clinical trials have not established the superiority of any specific medication/psychotherapy combination [22]. Consequently, we use the same approach to select each modality for combination treatment as used when choosing a monotherapy. (See 'Selecting a specific antidepressant' below and 'Selecting a specific psychotherapy' below.)

This approach is consistent with multiple practice guidelines, including recommendations from the American Psychiatric Association, American College of Physicians, and NICE [7,20,22,28].

The comparative efficacy of antidepressants, psychotherapy, and combination therapy is summarized below.

●Efficacy of monotherapy with antidepressants versus psychotherapy – Both antidepressant treatment and psychotherapy are more effective than placebo, and they have comparable efficacy for the initial treatment of MDD [34-40]. As an example, a meta-analysis of four trials with 775 participants found that monotherapy with cognitive behavioral therapy (CBT) was comparable with monotherapy with an second-generation antidepressant (SGA; eg, selective serotonin reuptake inhibitor [SSRI]) for achieving response (54.2 and 55.4 percent; relative risk [RR] 0.98; 95% CI 0.78-1.22) and remission (40.8 and 43.8 percent; RR 0.93; 95% CI 0.79-1.10) [7,41]. Data on the efficacy of each are discussed below. (See 'Specific treatment components' below.)

Psychotherapy may confer a more lasting effect than pharmacotherapy. Benefits may continue after a course of psychotherapy, whereas the benefits of antidepressants often wane after medications are discontinued [22,42]. As an example, in a meta-analysis of 11 trials (602 participants), those randomized to psychotherapy were more likely to experience persistent symptom improvement at a mean follow-up of 15 months than were those who received pharmacotherapy [43]. The lasting benefit of psychotherapy may result from patients learning skills to resolve maladaptive thought patterns, respond more resiliently to stressful life events, and reduce their problematic behaviors.

Although machine learning, pharmacogenetic, and other predictive models are under investigation, these currently lack sufficient discrimination to guide the choice between psychotherapy and pharmacotherapy or the selection of among specific antidepressants or psychotherapies [44-56].

Severe major depression — Severe major depression is characterized by seven to nine depressive symptoms (table 1) that occur nearly every day, as indicated by a score ≥20 points on the PHQ-9 (table 2). Individuals with severe major depression often report suicidal ideation and behavior and demonstrate marked functional impairment. Features of catatonia or psychosis also denote a severe level of depression.

●Timing and site of treatment – Because individuals with severe MDD are more likely to require inpatient management, clinicians should assess if they can safely be managed in an outpatient or partial hospital setting (see 'Need for urgent management' above). Individuals treated as outpatients should nevertheless receive prompt treatment initiation, and clinicians should inform them that delaying treatment may delay recovery. Management of individuals with severe MDD should ideally include referral to a psychiatrist [22].

Outpatients with severe major depression require close follow-up, particularly if they have suicidal ideation and/or severe functional impairment. We initially see these patients every one to two weeks. Monitoring of initial treatment with antidepressants is discussed separately. (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Monitoring initial treatment'.)

Delaying treatment may prolong recovery in individuals with severe major depression [57]. As an example, a meta-analysis of three studies (two observational studies and one randomized trial, total n = 486 patients with major depression) found that remission was more likely in patients with a shorter duration of untreated illness, compared with patients with a longer duration (RR 1.7, 95% CI 1.3-2.1) [58].

●Selecting a treatment regimen – We suggest combined treatment with antidepressants and psychotherapy for most patients with severe MDD. Monotherapy with antidepressants is an acceptable alternative for individuals who are not able or willing to participate in psychotherapy.

For the subset of individuals with severe MDD who require a rapid onset of treatment (eg, those with suicidal behavior, catatonia, or dehydration or malnutrition due to food refusal), electroconvulsive therapy (ECT) is an acceptable alternative [28]. For these patients, psychotherapy and/or antidepressant treatment can be used in conjunction with ECT. (See 'Antidepressant medications' below and "Major depressive disorder in adults: Initial treatment with antidepressants".)

Individuals with symptoms of psychosis or catatonia should receive management targeted to those symptoms. (See "Unipolar major depression with psychotic features: Acute treatment" and "Catatonia: Treatment and prognosis".)

We encourage exercise or increased physical activity to augment response to standard treatment in patients with severe MDD. Other supplemental interventions may also improve symptoms. (See "Major depressive disorder in adults: Treatment with supplemental interventions", section on 'Efficacy in special populations'.)

The use of pharmacotherapy plus psychotherapy, pharmacotherapy alone, or ECT for the initial treatment of severe unipolar major depression is consistent with multiple practice guidelines, including those from the American Psychiatric Association and NICE [20,22,24,28,59].

●Sequencing treatments to improve adherence – When considering combination treatment or adding supplemental interventions, it is important to tailor treatment to the individual patient's capacity and willingness to use multiple treatment modalities. Even in individuals who may benefit from combination treatment, we assess the feasibility of starting two interventions simultaneously and may add interventions sequentially (ie, start antidepressants and then add psychotherapy later) [60].

This approach may support treatment adherence and enable clinicians to gauge the effectiveness of a given intervention more accurately. Patients with depression often have difficulty engaging in treatment, even with a single intervention. Consequently, we generally prioritize choosing a single treatment and evaluating its effectiveness rather than starting multiple interventions simultaneously.

●Efficacy of combination treatment versus monotherapy – We typically prefer combination treatment in individuals with severe major depression because limited data suggest its superiority to monotherapy with antidepressants or psychotherapy. As an example, a meta-analysis found that adding short-term psychodynamic psychotherapy to antidepressant treatment was more efficacious for those with high, compared with low, baseline depression severity data [31]. Additionally, a trial of patients hospitalized with severe MDD (n = 124) found higher rates of response (70 versus 51 percent) and functional improvement in those randomized to interpersonal psychotherapy (IPT) plus an antidepressant compared with usual care (psychoeducation and support) plus an antidepressant [61]. The benefits of IPT persisted up to 12 months.

Clinical trials typically have not defined specific patient subgroups who are most likely to benefit from combination treatment, and most data regarding the efficacy of combination treatment include individuals with moderate to severe MDD. In such individuals, combination treatment appears comparable to monotherapy (with psychotherapy or antidepressants). Although some meta-analyses suggest the superiority of combination therapy over monotherapy, others have found minimal differences. These apparently discrepant findings likely stem from differences in study populations and study inclusion criteria for different meta-analyses. As examples:

•In a 2023 network meta-analysis, the combination of CBT plus an SGA demonstrated similar rates of treatment response (79 versus 78 percent; RR 1.02; 95% CI 0.65-1.62), remission (55 versus 57 percent; RR 0.96; 95% CI 0.74-1.25), and treatment discontinuation compared with SGA monotherapy [7,41]. In contrast to some early meta-analyses, this investigation only included pharmacotherapy trials of SGAs and was more selective about trial inclusion.

•In a meta-analysis of 58 trials (9301 participants), response rates trended higher with combination treatment compared with psychotherapy alone (RR 1.35; 95% CI 1.00-1.91) and antidepressants alone (RR 1.30; 95% CI 0.98-1.73) [62], but the differences were not statistically significant. Combination treatment was not superior to monotherapy for outcomes of remission or treatment acceptability.

•By contrast, earlier meta-analyses found that combination therapy was superior to monotherapy [30,63-67]. As an example, a meta-analysis of 25 trials demonstrated a small effect in favor of combination treatment compared with pharmacotherapy alone (mean effect size = 0.31; 95% CI 0.20-0.43) and a lower drop-out rate with combination treatment (odds ratio [OR] = 0.65; 95% CI 0.50-0.83) [63]. Separate analyses of the three subgroups that received CBT (seven trials), IPT (eight trials), or other psychotherapies (10 trials) found that in each case, combined therapy was superior to antidepressants alone.

Despite the lack of robust evidence supporting combination treatment in individuals with severe MDD, we typically prefer this option given the significant impact of severe MDD on patients' function, morbidity, and mortality.

How to select a specific antidepressant or type of psychotherapy for individuals with severe major depression is discussed separately. (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Patients with severe major depression' and 'Selecting a specific psychotherapy' below and "Unipolar major depression with psychotic features: Acute treatment", section on 'Treatment'.)

●Electroconvulsive therapy (ECT) – ECT is an efficacious treatment for severe major depression, but relapse rates following remission are high [68-72]. It also has safety risks, adverse effects, logistical constraints, and high rates of patient refusal. The indications for ECT and its efficacy and administration are discussed separately. (See "Overview of electroconvulsive therapy (ECT) for adults" and "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)" and "Medical evaluation for electroconvulsive therapy" and "Technique for performing electroconvulsive therapy (ECT) in adults".)

SPECIFIC TREATMENT COMPONENTS

Antidepressant medications — Antidepressants are typically used for moderate to severe depressive disorders given their efficacy, availability, and acceptability to patients. Selected individuals with mild major depression may also benefit from antidepressant treatment. Antidepressants can be used as monotherapy, combined with psychotherapy, or combined with supplemental interventions. (See 'Moderate major depression' above and 'Severe major depression' above and 'Mild major depression' above.)

Selecting a specific antidepressant — For patients with MDD whose initial treatment includes antidepressants, we suggest second-generation antidepressants (SGAs), such as selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs), based upon their efficacy and tolerability in randomized trials. Specific agents and guidance for selecting an antidepressant, dose initiation, monitoring, and subsequent management are discussed separately. (See "Major depressive disorder in adults: Initial treatment with antidepressants".)

Efficacy of antidepressants

●Overall outcomes – Multiple meta-analyses of randomized trials in both psychiatric and primary care populations have demonstrated that antidepressants improve rates of treatment response (eg, reduction of baseline symptoms ≥50 percent) and remission [73-86]. These effects are generally consistent in meta-analyses of single agents and antidepressant classes, regardless of baseline symptom severity [86,87]. Antidepressant therapy may also improve quality of life in individuals with major depression [88]. Representative meta-analyses include the following:

•A 2018 network meta-analysis of 432 trials included 102,443 participants; most studies were short-term (median duration eight weeks) and evaluated outpatients (77 percent), and most participants had moderate to severe major depression. All 21 first- and second-generation antidepressants were more effective than placebo in achieving both response (ORs ranging from 1.37 to 2.13) and remission (ORs ranging from 1.23-1.98) [89]. The magnitude of symptom improvement for antidepressants compared with placebo was small to moderate (summary standardized mean difference [SMD] 0.30; 95% CI 0.26-0.34). The odds of discontinuing treatment were also higher with antidepressants, compared with placebo (ORs ranging from 1.64 to 4.44).

•A 2012 meta-analysis of 37 trials of over 8400 participants with major depression found higher rates of remission at six weeks in those who received fluoxetine or venlafaxine compared with placebo (43 versus 29 percent; OR 1.82, 95% CI 1.66–2.00) [86]. Antidepressant treatment was effective in those with both mild (50 versus 37 percent remission) and severe symptoms (38 versus 25 percent remission).

The comparative efficacy of antidepressants versus psychotherapy or combination treatment is discussed above. (See 'Moderate major depression' above and 'Severe major depression' above.)

●Individuals in primary care settings – Antidepressants have demonstrated efficacy in treating individuals with major depression who are seen in primary care settings [84,90,91]. As examples:

•A 2009 meta-analysis of 14 trials in younger (age ≤65 years) primary care patients with depression found that response occurred more often in patients who received SSRIs (RR 1.28; 95% CI 1.15-1.43) and tricyclic antidepressants (TCAs; RR 1.24; 95% CI 1.11-1.38) than placebo [84]. Median numbers needed to treat for TCAs and SSRIs were 9 and 7, respectively; numbers needed to harm for withdrawal due to side effects ranged from 4 to 30 (TCAs) and 20 to 90 (SSRIs). (See "Glossary of common biostatistical and epidemiological terms", section on 'Statistics describing effect sizes'.)

•In a network meta-analyses of 66 trials (n = 15,161 participants), SSRIs, SNRIs, TCAs, and trazodone were all superior to placebo in attaining depression response and remission [90].

●Individuals with chronic medical illness – Antidepressants have shown efficacy in individuals with depression and comorbid medical illnesses. As an example, in a 2023 meta-analysis of individuals with depression and a wide range of chronic medical conditions, antidepressants more effectively reduced depressive symptoms than placebo (SMD 0.42; 95% CI 0.30-0.54; moderate effect size) [92]. Antidepressants more frequently induced depression response (RR 1.54; 95% CI 1.14-1.94) and remission (RR 1.43; 95% CI 1.251.61). Other meta-analyses have shown similar effects [93-96]. Although SSRIs have been more widely studied in this subset of patients than other classes of antidepressants, SNRIs and TCAs also have demonstrated efficacy [97,98].

●Limitations of the evidence – Meta-analyses may overestimate the clinical benefit of antidepressants in treating depression [99-102]. Methodologic challenges that may contribute to this effect include the inclusion of low-quality studies and publication bias. As an example of publication bias, a systematic review of studies of 12 antidepressants (12,564 patients) that were submitted to the US Food and Drug Administration (FDA) for review found that the subset of published trials (n = 51) were more likely to report positive results (94 percent positive) than the FDA-registered trials (n = 74; 51 percent positive) [103]. Moreover, the FDA determined that 23 percent of the trials published as positive were negative.

Other factors that limit the strength of evidence in studies of antidepressants include study heterogeneity, methodologic variability, and high rates of placebo response [86,104,105].

Safety of antidepressants — The decision to start pharmacotherapy should include consideration of antidepressant side effects. Antidepressant classes and individual agents have varying side effect profiles, which are discussed separately (table 3). (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Avoiding specific side effects'.)

There is no clear evidence that antidepressant treatment of individuals with depression increases the average risk of suicidality (ie, suicidal ideation, action to prepare for an attempt, attempt or nonfatal self-harm, or death). However, there may be an age-specific effect; antidepressants may increase the risk of suicide attempts (nonfatal self-harm) or preparatory acts in patients age 18 to 24 years during the first several weeks of treatment and lower the risk in patients 31 years and older. The effects of antidepressants on suicide risk are discussed separately. (See "Effect of antidepressants on suicide risk in adults".)

Some observational studies suggest that antidepressants as a class may be associated with small increased risks of mortality, diabetes, and stroke [106-112] (see "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Side effects' and "Unipolar depression in adults: Course of illness", section on 'All-cause'). It is difficult to discriminate in observational studies whether the increase in risk derives from antidepressant use per se or depression itself. Given the lack of robust evidence that supports a causal relationship between antidepressant use and these conditions and the substantial harms of untreated depression, these data should not deter clinicians from using antidepressants when indicated.

Additional information about side effects of antidepressants is discussed separately in the drug information topic for each drug, as well topics that review antidepressant classes.

Psychotherapy — We suggest psychotherapy as an option for most individuals with MDD given that it has demonstrated efficacy for improving remission rates compared with placebo and has minimal harms. Psychotherapy can be combined with pharmacotherapy or adjunctive treatments or used as monotherapy. (See 'Choosing a treatment regimen for patients with major depression' above.)

Selecting a specific psychotherapy — We typically select among psychotherapy approaches that have demonstrated efficacy in randomized trials. These include cognitive behavioral therapy (CBT), interpersonal psychotherapy (IPT), problem-solving therapy (PST), behavioral activation therapy, and short-term dynamic psychotherapy [20,22,66,113,114]. Although the major psychotherapies appear equally efficacious for treating major depression [115-118], the skill of the psychotherapist may be the most important feature for treatment effectiveness. From a practical standpoint, the choice of psychotherapy usually depends upon availability and patient preference.

Types of psychotherapy that have proven efficacy for the treatment of MDD include [22,28,42,119-122]:

●CBT (see "Overview of psychotherapies", section on 'Cognitive and behavioral therapies')

●IPT (see "Interpersonal Psychotherapy (IPT) for depressed adults: Indications, theoretical foundation, general concepts, and efficacy" and "Interpersonal Psychotherapy (IPT) for depressed adults: Specific interventions and techniques")

●Behavioral activation (see "Behavioral activation therapy for treating unipolar major depression")

●PST (see "Overview of psychotherapies", section on 'Integrated primary and specialty care')

●Family and couples therapy (see "Unipolar depression in adults: Family and couples therapy")

●Psychodynamic psychotherapy (see "Unipolar depression in adults: Psychodynamic psychotherapy")

●Supportive psychotherapy (see "Unipolar depression in adults: Supportive psychotherapy")

Differences in the efficacy and acceptability of different established psychotherapies are at most minor [116,123]. As an example, a network meta-analysis of 331 trials including 34,285 participants with depression found similar efficacy for seven types of psychotherapy (CBT, behavioral activation, PST, "third wave" therapies, IPT, psychodynamic therapy, and life review therapy) [124]. An earlier network meta-analysis found similar results [125].

Ensuring referral success — Because many individuals with depression have difficulty following through with a referral to psychotherapy, we closely monitor patients during this period to ensure the referral's success. We typically follow-up with patients in one to four weeks (depending on depression severity) to ensure engagement with a therapist and monitor depressive symptoms. Given that early dropout from therapy is common, patients should continue follow-up with their primary clinician to ensure ongoing engagement in therapy. Many factors make the referral process challenging, including limited therapist availability, limited insurance coverage of psychotherapy, and depressive symptoms, such as limited energy, concentration, motivation, and self-esteem. Care coordination and support by the clinician and/or clinic staff may help overcome these barriers and facilitate patients' starting and engaging in psychotherapy.

Efficacy of psychotherapy

●Overall outcomes – Psychotherapy is efficacious for the initial treatment of MDD [126-128]. Multiple meta-analyses suggest that it is superior to usual care, wait list, or other control interventions. As an example, in a meta-analysis of 92 trials of 6937 individuals with MDD, remission occurred in more participants randomized to psychotherapy (primarily CBT) than control conditions (eg, waiting list or usual care; 41 versus 21 percent, p≤0.01) [115]. Subsequent network meta-analyses of different psychotherapies found similar results [124,125].

●Individuals in primary care settings – Psychotherapy that is delivered in primary care settings also has demonstrated efficacy for the treatment of depression [129-132]. The most evaluated types of psychotherapy in primary care settings include CBT and IPT. As an example, a network meta-analysis of 58 trials in 9301 primary care patients with depression found that response was more likely with psychotherapy (eg, CBT) compared with either usual care (RR 1.6; 95% CI 1.50-1.83) or waitlist controls (RR 2.35; 95% CI 1.57-3.51) [62].

●Individuals with chronic medical illness – Psychotherapy also has demonstrated efficacy for primary care patients with depression who also have chronic medical illnesses. As an example, in a meta-analysis of four trials of participants with depression and diabetes mellitus, those who received psychotherapy (primarily CBT) were three times more likely to experience remission from depression than those randomized to control interventions (OR 3.0; 95% CI 2-25) [94]. Similarly, a trial of 158 outpatients with major depression and chronic heart failure demonstrated higher rates of remission among those randomized to CBT, compared with usual care (51 versus 20 percent) [133].

●Limitations of the evidence – Factors that limit the strength of evidence in studies of psychotherapy include study heterogeneity, methodologic variability, and high rates of placebo response [86,104,105]. Additionally, studies comparing different psychotherapies are complicated by the fact that psychotherapies often overlap with each other. As examples, techniques from supportive psychotherapy have been adopted by other psychotherapies, and behavioral activation therapy derives from CBT [134-136].

The comparative efficacy of antidepressants versus psychotherapy or combination treatment is discussed above. (See 'Moderate major depression' above and 'Severe major depression' above.)

Supplemental treatments — Supplemental treatments for individuals with MDD include exercise, mind-body interventions (eg, yoga, tai chi, and relaxation), and internet-based psychotherapy. The role, efficacy, and safety of supplemental treatments for depression are discussed in detail separately. (See "Major depressive disorder in adults: Treatment with supplemental interventions".)

Investigational and other nonstandard treatments for MDD are discussed separately. (See "Unipolar depression in adults: Investigational and nonstandard treatment".)

OPTIMIZING TREATMENT

Education and engagement — Patients with major depression are often reluctant to engage in treatment [26]. In a prospective study of patients who presented for initial treatment of depression (n>4000), more than 10 percent did not return for treatment after the initial evaluation [26,137]. Another 30 percent did not complete the first eight weeks of treatment, indicating a failure to retain patients who were initially engaged.

To enhance treatment engagement, we use the following strategies:

●Assessing patient perception of depression – We start by eliciting the patient's perspectives about depression. In many communities, depression is still stigmatized. Common misconceptions include the belief that depression is a character defect or sign of personal weakness, or that individuals with depression are "crazy," will not get better, or should be able to resolve their depression "on their own." Patients are also frequently misinformed about psychotherapy and antidepressant agents. Eliciting the patient's beliefs, expectations of, and fears about treatment can help to tailor the treatment approach and potentially optimize engagement in it.

●Education – Individuals who understand and accept the diagnosis of depression may be more likely to engage in treatment [22]. We tailor education about depression to the patient's specific perspectives, information gaps, and priorities. General parameters to address when educating patients about depression appear in the table (table 4).

●Active surveillance for selected patients – Initial management with active surveillance (watchful waiting) may facilitate treatment engagement for individuals who are reluctant to start medications or psychotherapy. This is a reasonable short-term choice for those with milder symptoms (eg, nine-item Patient Health Questionnaire [PHQ-9] score 5 to 14 (table 2) without suicidal plans or behavior). Active surveillance includes regular, brief follow-up visits (eg, every two to three weeks), during which clinicians monitor symptoms and provide support while helping patients link their problems with mood, motivation, sleep, appetite, energy, and cognition and impaired social and occupational functioning to depression. This, in turn, may help them accept treatment.

Active surveillance is not appropriate for depressed patients who are severely symptomatic (eg, PHQ-9 score ≥15), chronically depressed (eg, ≥2 years), or substantially impaired (eg, unemployed).

●Framing treatment as a trial – Framing medication or psychotherapy as a trial (rather than a long-term commitment) may help persuade some individuals to start treatment.

●Using monitoring to engage patients – Monitoring patients' symptoms over time using symptom scales, such as the PHQ-9, may also help to engage patients in care and active self-management (see 'Ongoing monitoring and follow-up' below) [26]. Patients who see objective improvement in their symptoms may better adhere to their treatment plans and remain engaged in treatment. Patients generally accept incorporation of symptom scales into the management of their depression, particularly if the scales are short. The acceptability and potential benefits of using scales to monitor depression care are discussed in detail separately. (See "Using scales to monitor symptoms and treat depression (measurement based care)".)

Ongoing monitoring and follow-up

●Frequency of follow-up – We arrange prompt follow-up for all patients with major depression. For initial follow-up, we see all patients within the first two weeks (in person or via telehealth) to check for treatment adherence and side effects, adjust antidepressant doses, complete any outstanding diagnostic evaluation, and plan next steps.

Subsequent follow-up frequency varies depending on the patient's symptom severity, comorbidities, psychosocial stressors, and level of support from family and friends [138,139]. Individuals with severe major depression or those initiating antidepressants should be reassessed more frequently (ie, within two to four weeks). Those with less severe, stable symptoms can have less frequent follow-up (four to eight weeks). We space out follow-up intervals as patients' symptoms improve and they are on stable medication doses and/or in psychotherapy. Following remission, the frequency of assessments can be tapered. (See "Unipolar depression in adults: Continuation and maintenance treatment", section on 'Monitoring patients'.)

●Monitoring symptoms and response to treatment – We encourage frequent follow-up to monitor symptoms, assess treatment response, ensure follow-through with referrals and/or medication adherence, and build a therapeutic alliance. We ask about new or worsening symptoms of suicidal thoughts or behavior, psychosis, agitation, and anxiety [28].

In those who are taking antidepressants, we also ask about and address medication side effects (see "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Address side effects'). Additional recommendations for monitoring initial treatment with antidepressants are discussed separately. (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Monitoring initial treatment'.)

To quantify symptoms and response to treatment, all patients should complete a symptom rating scale at each visit, such as the PHQ-9. Using symptom scales can potentially improve treatment outcomes by informing antidepressant dose adjustments, more quickly identifying response to treatment, and helping to engage patients in treatment [140,141].

•Monitor treatment response – Using symptom scales can identify those whose depression responds early, partially responds, or does not respond to antidepressant treatment. Because dysphoria and cognitive distortion that occur with depression can limit patients' capacity to sense symptom improvement, symptom scales can augment patients' subjective perception of treatment response. Conversely, identifying individuals with residual symptoms is important because they are associated with an increased risk of relapse, even in individuals whose depression has otherwise responded to treatment.

•Increase remission – Systematically monitoring depressive symptoms with a standardized scale may improve rates of remission. As an example, a meta-analysis of seven trials compared measurement-based care (using validated symptom scales [eg, PHQ-9 (table 2)] to guide treatment decisions) to standard care (clinical judgment alone) in patients taking antidepressants a depressive disorder [142]. Individuals randomized to measurement-based care were more likely to experience remission (53 versus 43 percent), symptom improvement, and adherence to pharmacotherapy (OR 1.7; 95% CI 1.2-2.3). A second meta-analysis found small improvements in mental health outcomes at nine weeks in groups receiving measurement-based care compared with usual care; however, outcomes were equivalent at 3 and 12 months [143].

Using symptom scales to monitor depression care is consistent with multiple practice guidelines, including those from the American Psychiatric Association, and there is evidence suggesting that most patients like this monitoring [22,24,25,28,144-147]. Additional details regarding measurement-based care are discussed separately. (See "Using scales to monitor symptoms and treat depression (measurement based care)".)

●Using the nine-item Patient Health Questionnaire – We use the PHQ-9 scale at each visit and/or telehealth encounter to monitor symptoms and assess treatment response. The PHQ-9 is a short, self-administered, widely available scale that has been extensively validated in diverse patient populations and different languages (table 2). Its questions correspond to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) diagnostic criteria for major depression and add an item that assesses psychosocial impairment [148,149].

Patients rate each symptom item on a four-point Likert scale, indicating how often they have been bothered by the symptom over the past two weeks (0 = not at all, 1 = several days, 2 = more than half the days, 3 = nearly every day). Scores on the PHQ-9 range from 0 to 27, with higher scores indicating more severe symptoms. For monitoring depressive symptoms over time, a change of 5 or more is generally considered clinically meaningful [150]. The PHQ-9 has good reliability, internal consistency, and sensitivity to change in depression over time [151]. Its brevity makes it adaptable to use during a telephone call or secure message exchange.

Alternative options for quantifying response to treatment include the Quick Inventory of Depressive Symptomatology – Self Report 16 Item (QIDS-SR₁₆) (table 5) and the 18-item Clinically Useful Depression Outcome Scale (CUDOS) (form 1). Self-report instruments for depression monitoring are discussed in detail separately. (See "Using scales to monitor symptoms and treat depression (measurement based care)", section on 'Commonly used self-report depression scales'.)

System-level interventions and collaborative care — We suggest that patients with depression in primary care settings receive depression care in the context of system-levels interventions, such as collaborative care. Collaborative care involves treating patients with a team that usually includes a primary care clinician (who prescribes antidepressants), a case manager who provides support and outreach to patients, and a mental health specialist (eg, psychiatrist) who provides consultation and supervision [152-158]. Other elements include a structured treatment plan that involves pharmacotherapy and/or other interventions (eg, patient education or psychotherapy), scheduled follow-up visits, team-based communication, and measurement-based care (ie, using symptom scales, such as the PHQ-9, to monitor response to treatment and medication side effects).

Treating depressed primary care patients in the context of collaborative care is consistent with recommendations by the American College of Physicians and the American Psychiatric Association [7,22].

●Improved depression outcomes – Collaborative care improves depression outcomes, including rates of response and remission, psychosocial functioning, and mental and physical quality of life [156,159-165]. As an example, a 2012 meta-analysis of 79 trials of over 24,000 participants found that treatment response at six months occurred more often with collaborative care (RR 1.3, 95% CI 1.2-1.4), compared with usual care, and the benefits of collaborative care persisted for up to 24 months [156]. Collaborative care may also improve patients' engagement in treatment and medication adherence [166]. However, beneficial effects on remission rates appear small [165].

●Key components – The following components of collaborative care are associated with improved depression outcomes [160,164,167,168]:

•Case management provided by nurses or individuals with a mental health background

•Routine supervision of case managers and caseload review by a mental health specialist (typically a psychiatrist)

•At least two visits with the depression care manager within the first eight weeks of treatment

•Primary care clinician follow-up within four weeks of initial presentation

•Psychiatric intervention for patients who do not improve after eight weeks of treatment

●Who benefits – Collaborative care interventions have demonstrated efficacy across a wide range of patient populations, including those with and without additional medical comorbidities. Collaborative depression care is superior to usual care in treating individuals with chronic medical illness (eg, diabetes, cardiovascular disease, arthritis, asthma, and human immunodeficiency virus [HIV]), adolescents, military personnel, individuals attending obstetrics and gynecology clinics, patients with advanced cancer receiving palliative care, and pregnant and postpartum females with socioeconomic disadvantage [169-177].

●Improving medical comorbidities – Collaborative care can improve outcomes for general medical illnesses, such as diabetes. As an example, in a meta-analysis of seven trials of 1895 individuals with both depression and diabetes, patients randomized to collaborative care experience small but significant improvements in both depression symptom scores and hemoglobin A1C, compared with those randomized to usual care [178]. Study heterogeneity limited the strength of these findings. A subsequent open-label trial in India reported similar findings [179].

●Role of telehealth – Collaborative care via telehealth may be effective for small practices that lack on-site mental health specialists [158]. In a trial comparing practice-based versus telemedicine-based collaborative care, telemedicine was at least as effective in achieving remission as practice-based care [180]. A second trial found that compared with usual care, online nurse case management resulted in higher rates of symptom improvement, antidepressant adherence, and patient satisfaction [181].

When to refer to specialty care

●Psychotherapy – Although psychotherapy can occur in primary care settings, most individuals who need psychotherapy will require referral to a mental health specialist, ideally a clinical psychologist with expertise in psychotherapy that has demonstrated efficacy for depression treatment (eg, cognitive behavioral therapy [CBT]). (See 'Psychotherapy' above.)

●Diagnostic uncertainty – Individuals for whom the specific depression diagnosis is uncertain should be referred to a psychiatrist, particularly those with symptoms consistent with mania, hypomania (including individuals with depression with mixed features), catatonia, or psychosis. (See 'Depression with mixed features' below and "Bipolar disorder in adults: Assessment and diagnosis", section on 'Assessment' and "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis" and "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis".)

●Comorbid psychiatric disorders – Individuals with comorbid psychiatric disorders that can complicate diagnosis and treatment can benefit from referral to a mental health professional, which could include a therapist or psychiatrist. These patients are at risk for poorer depression outcomes, even with appropriate treatment. (See "Unipolar depression in adults: Clinical features", section on 'Psychiatric'.)

●Lack of response to initial treatment – Patients who have not responded to two trials of initial treatment with antidepressants generally benefit from referral to a therapist for psychotherapy and/or a psychiatrist for medication management. Treatment-resistant depression is discussed separately. (See "Unipolar treatment-resistant depression in adults: Epidemiology, risk factors, assessment, and prognosis" and "Unipolar depression in adults: General principles of treating resistant depression".)

●Severe depression – Some individuals with severe MDD can safely be managed in primary care. However, patients with signs such as severe symptoms that are not responding to initial treatment; severe functional impairment; catatonia; suicidal behavioral or attempts; or frequent, intrusive suicidal thoughts or psychotic symptoms should be referred to a mental health specialist, especially if the primary clinician has limited experience caring for patients with depression. (See 'Severe major depression' above.)

SPECIAL CIRCUMSTANCES

●Older adults – Treatment of depression in older adults is discussed separately. (See "Diagnosis and management of late-life unipolar depression".)

●Depression in antenatal and postpartum patients – The treatment of depressive disorders that occur in the context of pregnancy and the postpartum period is discussed separately. (See "Mild to moderate episodes of antenatal unipolar major depression: Choosing treatment" and "Severe antenatal unipolar major depression: Choosing treatment" and "Postpartum unipolar major depression: General principles of treatment" and "Postpartum paternal depression".)

●Psychotic depression – The management of individuals with depression with psychotic features is discussed separately. (See "Unipolar major depression with psychotic features: Acute treatment" and "Unipolar major depression with psychotic features: Maintenance treatment and course of illness".)

OTHER DEPRESSIVE SYNDROMES

Persistent depressive disorder — Persistent depressive disorder is a depressive syndrome that lasts for at least two years. Individuals with this disorder have at least three symptoms of depression, one of which must be depressed mood (table 6) [6]. Persistent depressive disorder subsumes prior diagnoses of dysthymic disorder and chronic major depression and is discussed separately. (See "Unipolar depression in adults: Clinical features".)

For initial treatment of persistent depressive disorder, we suggest combined treatment with pharmacotherapy and psychotherapy. Pharmacotherapy alone is a reasonable alternative. Psychotherapy alone is less effective than pharmacotherapy for this group of individuals.

The choice of a specific antidepressant and/or type of psychotherapy for individuals with persistent depressive disorder is similar to that in individuals with major depression. (See 'Selecting a specific psychotherapy' above and "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Selecting an antidepressant'.)

Data supporting the efficacy of combination treatment, antidepressants, and psychotherapy derive from meta-analyses of randomized trials.

●Combined pharmacotherapy plus psychotherapy – For patients with persistent depressive disorder, the combination of pharmacotherapy and psychotherapy is likely more effective than either intervention alone [182,183]. As an example, in a meta-analysis of 2116 individuals with chronic major depression or dysthymia, combined treatment was more effective than psychotherapy alone in achieving symptom response (standardized mean difference [SMD] 0.45; 95% CI 0.2-0.7; number needed to treat [NNT] = 4; four trials) [182]. Response rates also trended higher for combined treatment versus pharmacotherapy alone, although the results were not statistically significant. The analysis found no significant differences in drop-out rates between the three types of interventions.

●Pharmacotherapy – For most patients with persistent depressive disorder, pharmacotherapy is superior to both psychotherapy and placebo [35,37,39,43,73,182]. As an example, in the meta-analysis described above, the effectiveness of pharmacotherapy alone exceeded that of psychotherapy alone (NNT = 5.8; 10 studies) although moderate to high heterogeneity diminished the strength of this finding [182].

Pharmacotherapy alone is also superior to placebo [73,184,185]. As an example, in a pooled analysis of nine randomized trials including over 1400 participants with dysthymic disorder, response rates were higher with antidepressant treatment than placebo (52 versus 30 percent) [73].

●Psychotherapy – Although less effective than pharmacotherapy, psychotherapy is superior to control conditions in treating persistent depressive disorder. As an example, in a meta-analysis of 362 patients with chronic major depression or dysthymic disorder, psychotherapy was slightly more effective compared with control interventions (NNT = 7.7; 8 studies) [182]. Psychotherapy may also be superior for individuals with a history of childhood trauma [183].

The efficacy of interpersonal psychotherapy (IPT) in patients with persistent depressive disorder is discussed separately. (See "Interpersonal Psychotherapy (IPT) for depressed adults: Indications, theoretical foundation, general concepts, and efficacy", section on 'Dysthymic disorder'.)

Depression with mixed features — Some patients with MDD or persistent depressive disorder also exhibit symptoms of hypomania or mania that do not meet full criteria for the diagnosis of a hypomanic or manic episode (table 7 and table 8). Such individuals are diagnosed with major depression with mixed features or persistent depressive disorder with mixed features, respectively. Mixed features may be more common (though often unrecognized) in patients with depression who do not respond to antidepressants. (See "Unipolar depression in adults: Clinical features".)

We typically treat these individuals with a combination of medications and psychotherapy and choose medications used to treat bipolar I major depression, such as quetiapine or lurasidone. Other options include divalproex, lamotrigine, lithium, or other second-generation antipsychotics, such as olanzapine. (See "Bipolar major depression in adults: Choosing treatment", section on 'Choosing pharmacotherapy'.)

We prefer these agents over selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs) because patients with mixed features may have a higher risk for antidepressants to precipitate mania or hypomania. However, because major depression with mixed features was first recognized as a distinct diagnostic category in the 2013 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [186], limited evidence exists regarding its treatment. Direct comparisons of the above-mentioned medications with second-generation antidepressants (SGAs) are lacking.

One six-week trial evaluated lurasidone in 208 individuals with major depression with mixed features [187]. Compared with placebo, participants randomized to lurasidone were more likely to remit (23 versus 49 percent). Although this trial supports the use of lurasidone, it does not imply that it is superior to other agents.

Premenstrual dysphoric disorder — The management of premenstrual dysphoric disorder is discussed separately. (See "Treatment of premenstrual syndrome and premenstrual dysphoric disorder".)

Minor depression — The management of minor depression is discussed separately, as are the clinical features and diagnosis. (See "Unipolar minor depression in adults: Management" and "Unipolar minor depression in adults: Epidemiology, clinical presentation, and diagnosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Depressive disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Depression in adults (The Basics)" and "Patient education: Coping with high drug prices (The Basics)" and "Patient education: When you have depression and another health problem (The Basics)")

●Beyond the Basics topics (see "Patient education: Depression in adults (Beyond the Basics)" and "Patient education: Depression treatment options for adults (Beyond the Basics)" and "Patient education: Electroconvulsive therapy (ECT) (Beyond the Basics)" and "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Urgent management – Individuals with major depression who exhibit features of psychosis, mania, or catatonia or are at imminent risk of harming themselves or others should be referred to the emergency department for urgent evaluation and possible inpatient hospitalization. (See 'Need for urgent management' above.)

●Choosing between treatment regimens for major depression – We select treatment regimens based on depression severity, which is determined by the degree of functional impairment and the number, frequency, intensity, and duration of symptoms. Among the recommended treatment options for mild, moderate, and severe major depression, the choice between them depends primarily on patient preference and availability of high-quality, evidence-based psychotherapy. (See 'Choosing a treatment regimen for patients with major depression' above and 'Severity-based approach to treatment' above.)

•Mild major depression – For individuals with mild major depression (table 2) and a brief duration of symptoms without major functional impairment, we suggest active surveillance rather than specific interventions (Grade 2C). Psychotherapy is a reasonable alternative. Given the mild, possibly transient nature of symptoms in such individuals, we favor minimizing overtreatment.

For those with prolonged symptoms, significant functional impairment, or prior depressive episodes, we suggest initial treatment with psychotherapy or antidepressants rather than active surveillance (Grade 2C). (See 'Mild major depression' above.)

•Moderate major depression – For patients with moderate major depression (table 2), we suggest antidepressants or psychotherapy rather than combination therapy (Grade 2C). However, combination therapy (ie, antidepressants and psychotherapy) is an acceptable alternative, especially for those with marked functional impairment, prior depressive episodes, or persistent symptoms (eg, >6 months). Antidepressants and psychotherapy are more efficacious than placebo and have comparable efficacy. Combination therapy is not clearly superior in this population. (See 'Moderate major depression' above.)

•Severe major depression – For patients with severe major depression (table 2), we suggest combination therapy rather than other treatment regimens (Grade 2C). Combination therapy may be superior to monotherapy with antidepressants or psychotherapy in this population. Nevertheless, use of pharmacotherapy or psychotherapy alone is reasonable, given that multiple treatment modalities may negatively affect adherence. Adding treatment modalities sequentially may make combination treatment more feasible. (See 'Severe major depression' above.)

For the subset of patients who require a rapid onset of treatment (eg, those with suicidal ideation, catatonia, or dehydration or malnutrition due to food refusal), electroconvulsive therapy (ECT) is also an option. (See 'Severe major depression' above and "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)".)

●Supplemental treatments – We encourage all individuals with depression to exercise or increase their physical activity. Exercise and other supplemental interventions can be used as an adjunct to standard treatment (ie, antidepressants and/or psychotherapy) for all individuals with major depressive disorder (MDD) and as an alternative to standard treatment in some individuals with mild MDD. (See 'Severity-based approach to treatment' above.)

The efficacy and safety of supplemental treatments for depression are discussed separately. (See "Major depressive disorder in adults: Treatment with supplemental interventions".)

●Choosing an antidepressant – The choice of a specific antidepressant agent for the initial management of major depression is discussed separately. (See "Major depressive disorder in adults: Initial treatment with antidepressants".)

●Choosing a psychotherapy – For patients with major depression who are initially treated with psychotherapy, we select among psychotherapies that have demonstrated efficacy in randomized trials. These include cognitive-behavioral therapy (CBT), interpersonal psychotherapy (IPT), problem-solving therapy (PST), behavioral activation therapy, and short-term dynamic psychotherapy. We prioritize the skill of the therapist, therapy availability, and patient preferences over a specific psychotherapy modality. (See 'Efficacy of psychotherapy' above and 'Psychotherapy' above.)

●Optimizing treatment

•Engagement and education – To enhance treatment engagement, we assess the patient's perception of disease and provide tailored education to address any concerns or misconceptions (table 4). (See 'Education and engagement' above.)

•Monitoring and follow-up – The frequency of follow-up depends on symptom severity, comorbidities, and psychosocial stressors and support. Initial follow-up ranges from one to two weeks for those with severe major depression or who are initiating antidepressants to four to eight weeks for those with milder, stable symptoms.

At each visit, we monitor response to treatment with a validated, self-rated symptom scale, such as the nine-item Patient Health Questionnaire (PHQ-9) (table 2). (See 'Ongoing monitoring and follow-up' above and "Using scales to monitor symptoms and treat depression (measurement based care)".)

●Patients with persistent depressive disorder – Persistent depressive disorder is characterized by dysphoria and at least two other depressive symptoms lasting for two or more years (table 1). For patients with persistent depressive disorder, we suggest antidepressants plus psychotherapy rather than antidepressants alone or psychotherapy alone (Grade 2C). However, monotherapy with antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs]) or psychotherapy are reasonable alternatives based on considerations of feasibility and patient preference. (See 'Persistent depressive disorder' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Gregory Simon and Wayne Katon, MD, who both contributed to an earlier version of this topic review.