INTRODUCTION — Unipolar depression is highly prevalent and disabling. Community surveys in 14 countries have estimated that the lifetime prevalence of unipolar depressive disorders is 12 percent [1], and the World Health Organization ranks unipolar major depression as the 11th greatest cause of disability and mortality in the world, among 291 diseases and causes of injury [2]. In the United States, major depression ranks second among all diseases and injuries as a cause of disability, and dysthymia ranks 20th [3].
In addition, major depression is highly recurrent. Following recovery from one episode, the estimated rate of recurrence over two years is greater than 40 percent; after two episodes, the risk of recurrence within five years is approximately 75 percent [4].
This topic reviews the general principles and prognosis for the initial treatment of depression. Choosing a therapy for the initial treatment of depression and the general evidence of efficacy of standard therapies are discussed separately, as are the evidence for therapies that are not typically used, and the evidence for standard therapies that are used for initially treating depression in primary care patients and in patients with general medical illnesses. Continuation and maintenance treatment of major depression, the treatment of resistant depression and refractory depression, and the clinical manifestations and diagnosis of depression are also discussed elsewhere.
●(See "Unipolar major depression in adults: Choosing initial treatment".)
●(See "Unipolar depression in adults and initial treatment: Investigational and nonstandard approaches".)
●(See "Unipolar depression in adults: Continuation and maintenance treatment".)
●(See "Unipolar depression in adults: Choosing treatment for resistant depression".)
●(See "Unipolar depression in adults: Management of highly resistant (refractory) depression".)
●(See "Unipolar depression in adults: Assessment and diagnosis".)
GENERAL PRINCIPLES — Depressed patients should be evaluated with a psychiatric and general medical history as well as a mental status examination. Based upon the findings, physical examination and focused laboratory testing may be indicated to rule out general medical causes. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Assessment'.)
Screening — The nine-item Patient Health Questionnaire (PHQ-9) (table 1) is a self-report, standardized depression rating scale that can be used to screen for major depression [5,6]. Scores ≥10 on the PHQ-9 suggest patients are likely suffering from major depression, whereas a score <5 indicates euthymia; however, thresholds for diagnosis of depressive disorders differ slightly between the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the World Health Organization's International Classification of Diseases-10th Revision (ICD-10). Additional information about screening for depression is discussed separately. (See "Screening for depression in adults".)
The PHQ-9 and other standardized instruments can also be used to measure response to therapy and guide treatment planning. (See 'Monitoring' below.)
Diagnosis — We diagnose unipolar major depression according to the criteria in DSM-5 (table 2) [7]. However, a reasonable alternative to DSM-5 is ICD-10 [8]. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Diagnostic criteria and classification'.)
Ruling out bipolar depression — Patients who present with major depression may have either unipolar depression or bipolar depression. Clinicians rule out bipolar disorder by ruling out a history of mania (table 3) or hypomania (table 4). Depressed patients should be assessed for bipolar disorder because treatment of bipolar depression differs from treatment of unipolar depression. (See "Bipolar disorder in adults: Assessment and diagnosis", section on 'Assessment' and "Bipolar major depression in adults: Choosing treatment".)
The types of bipolar disorder defined in DSM-5 include [7]:
●Bipolar I disorder
●Bipolar II disorder
●Cyclothymic disorder
●Other specified bipolar disorder
Bipolar depression is frequently misdiagnosed as unipolar depression, particularly in patients with either bipolar II disorder or other specified bipolar and related disorder who do not exhibit overt symptoms of mania and for whom hypomania is difficult to distinguish from anxiety or extroverted personality traits. As an example, a study of 576 primary care patients with a working diagnosis of unipolar depression found that between 10 and 22 percent met criteria for bipolar disorder (depending upon how missing data were handled) [9]. (See "Bipolar disorder in adults: Assessment and diagnosis", section on 'Unipolar major depression'.)
Suicidal and homicidal ideation and behavior — Assessing patients for suicidal and homicidal ideation and behavior is of paramount importance in all depressed patients. Although demographic and clinical characteristics may help identify patients at increased risk for suicidal behavior [10-12], the ability of clinicians to determine which individuals are at substantial short-term risk of suicide, violence, and homicide is poor.
Evaluations for suicide and homicide risk should include the following [13,14]:
●Suicidal or homicidal ideation, plan, and intent
●Access to means for suicide and homicide, and the lethality of those means
●Psychotic symptoms (eg, delusions or command auditory hallucinations)
●Severe anxiety
●Substance-related disorders
●History and seriousness of previous suicide and homicide attempts
●Family history of or recent exposure to suicide and homicide
Brief self-report questionnaires such as the PHQ-9 [11] are not sufficient to identify imminent risk, but they can identify patients in need of further clinical assessment. Patients at immediate risk of suicide should be evaluated in an emergency department and/or hospitalized until the patient’s safety is stabilized.
Additional information about suicidal ideation and behavior, including evaluation and management, is discussed separately. (See "Suicidal ideation and behavior in adults".)
Reluctance to start treatment — Patients with mild or moderate unipolar depression (eg, PHQ-9 score 5-14 (table 1) without suicidal plans or behavior), who decline treatment, can initially be observed with support and short-term follow-up (eg, two weeks). During this period, a patient diary that records problems with mood, sleep, appetite, energy, and cognition, as well as social and occupational activities, may help patients to accept treatment. Framing medication or psychotherapy as a trial (rather than a long-term commitment) may also be useful. In addition, patients may accept treatment more readily through understanding that depression is a brain disease rather than a character defect or sign of weakness, and that as an illness, depression is analogous to other diseases such as asthma that affects the lungs or diabetes that affects the pancreas.
However, patients with more severe depression (eg, PHQ-9 score ≥15) should be informed that delaying treatment may delay recovery [15]. As an example, a meta-analysis of three studies (two observational studies and one randomized trial, total n = 486 patients with unipolar depression) found that remission was more likely in patients with a shorter duration of untreated illness, compared to patients with a longer duration (risk ratio 1.7, 95% CI 1.3-2.1) [16].
The clinical features that distinguish severe depression from mild to moderate depression are discussed separately. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Severe major depression'.)
Monitoring — Depressed outpatients started on antidepressants should generally be seen one to two weeks after starting an antidepressant and subsequently monitored (by phone, video, or in-person visit) at least every two to four weeks for six to eight weeks, depending upon the clinical urgency [17,18]. Therapeutic response, adverse effects, and adherence should be assessed, with particular attention given to symptoms of suicidal ideation and behavior, psychosis, agitation, and anxiety [19]. Following remission, the frequency of assessments can be tapered. (See "Unipolar depression in adults: Continuation and maintenance treatment", section on 'Monitoring patients'.)
Outcomes and adherence can be improved with the use of allied health professionals to proactively monitor patients, and to schedule return visits for patients with persistent symptoms [20]. Adherence may be further enhanced by facilitating telephone access or secure messaging to the clinician for patient questions about side effects. (See 'Adherence to antidepressants' below.)
At each visit, we suggest that clinicians provide measurement based care, which is the systematic, quantitative assessment of symptoms [21,22]. Tolerability of treatment, adherence, psychosocial functioning, and quality of life can also be measured. Among the standardized instruments that are available to ascertain response to pharmacotherapy or psychotherapy, the PHQ-9 (table 1) is the most widely used and studied. A decrease ≥50 percent during treatment is typically regarded as a meaningful response to treatment, and a score <5 indicates euthymia or remission. Measurement based care is consistent with multiple practice guidelines [13,14,23].
The PHQ-9 and measurement based care are discussed separately. (See "Using scales to monitor symptoms and treat depression (measurement based care)".)
Peer support — Support from trained peers can be helpful. The relationship is nondirective and thus distinguished from psychotherapy and interventions that focus more on goal-setting, education, or self-help and less on developing social relationships [24]. Peer support or befriending has been used to treat symptoms that range in severity from subthreshold to depressive syndromes of minor and major depression. Evidence supporting the effectiveness of peer support or befriending includes a meta-analysis of nine randomized trials (1380 depressed patients) that compared the intervention with usual care or no treatment, and found a significant but clinically modest effect that favored befriending; heterogeneity across studies was moderate [24]. In addition, the benefit persisted for a median of 13 months.
Referral — Outcomes for the initial treatment of mild to moderate unipolar major depression appear to be comparable when the same treatments and treatment methods (measurement-based care) are employed in primary care or psychiatric specialty settings. In an observational study of depressed patients who received full doses of citalopram for up to 14 weeks in primary care settings (n = 1091 patients) or psychiatric clinics (n = 1785 patients), remission rates were nearly identical (approximately 27 percent) [25].
However, some patients who present to primary care clinicians for initial treatment of major depression are typically referred to a psychiatrist or other mental health clinician. Indications for referral include the following:
●Suspicion of bipolar disorder (eg, history of mania or hypomania). (See "Bipolar disorder in adults: Assessment and diagnosis", section on 'Assessment' and "Bipolar major depression in adults: Choosing treatment".)
●Management of unipolar major depression with mixed features. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Depressive episode subtypes (specifiers)' and "Unipolar major depression in adults: Choosing initial treatment", section on 'Depression with mixed features'.)
●Depression is severe (eg, PHQ score ≥20 (table 1) or patient has a suicide plan) or complicating features are present (eg, psychotic features such as delusions or hallucinations). (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Severe major depression'.)
●Comorbid psychiatric disorders (eg, personality or substance use disorders) are present.
●Patient preference for psychotherapy, either as the primary treatment or in combination with antidepressant medication.
Collaboration between the mental health specialist and primary care clinician can reduce patient fears about separation from or abandonment by the primary care provider.
PATIENT EDUCATION — Educating patients about depression, including the symptoms, clinical course, treatment options, and prognosis, is a useful adjunct to pharmacotherapy [13,14,23,26].
Discussing the diagnosis — Patients, especially those seen in primary care, are often reluctant to accept a diagnosis of depression, even after the signs and symptoms are explained. It may be helpful to stress that depression is [13,14]:
●Common.
●Associated with both emotional symptoms (mood changes) and physical symptoms (ie, fatigue, headache, abdominal pain, muscle tension). Depression can increase both the perception and impact of physical symptoms.
●A potentially serious illness that affects the chemistry and functioning of the brain.
●Treatable with medication and/or psychotherapy.
The clinical features and diagnosis of depression are discussed separately. (See "Unipolar depression in adults: Clinical features" and "Unipolar depression in adults: Assessment and diagnosis".)
Adherence to antidepressants — Nonadherence to medications is common. A nationally representative survey of depressed patients in the United States who initiated antidepressants (n = 829) found that the medications were discontinued within one month by 42 percent of patients, and within three months by 72 percent [27].
Poor adherence to drug therapy is associated with increased mortality. As an example, a study of an administrative claims database identified patients who were prescribed antidepressants and were either nonadherent (n >80,000) or demonstrated good adherence (n >80,000), over four years of follow-up [28]. After adjusting for potential confounding factors (eg, age, smoking status, and general medical comorbidities), the analyses found that all-cause mortality was greater in nonadherent patients than patients with good adherence (hazard ratio 1.14, 95% CI 1.10-1.18). These results are consistent with a meta-analysis of 21 studies which found that in patients with general medical illnesses (n >46,000), poor adherence to drug therapy, compared with good adherence, was associated with greater mortality [29].
Among the several factors that are associated with poor adherence to antidepressants, the one that has been identified most consistently across studies is adverse side effects [30]. Other clinical factors associated with poor adherence include comorbid substance abuse and personality disorders and a poor therapeutic alliance [30-32]. In addition, regularly missing doses or discontinuing antidepressants is more likely in patients who are reluctant to initiate pharmacotherapy, who don’t recall being told that their medication needed to be continued, and patients who feel better and believe that medications can be taken on an as-needed basis thereafter [31]. Sociodemographic risk factors include younger age (eg, less than 30 or 40 years) [30,33], fewer years of education [27,30,34], and having a race/ethnicity other than non-Hispanic White [30,33].
To promote adherence to treatment at the onset of therapy, patients starting pharmacotherapy should be told the following [22,35]:
●Take the medication as prescribed rather than on an as-needed basis.
●There may be a lag of several (eg, two to three) weeks before a discernible response is apparent.
●Side effects (eg, anxiety or agitation, headache, and stomach upset) (table 5) frequently occur during the first few days, but typically resolve within a week of starting the medication.
●If a dose is missed, the next scheduled dose should not be doubled.
●If medication is effective, it is important to continue treatment for several (eg, six) months to prevent relapse. (See "Unipolar depression in adults: Continuation and maintenance treatment", section on 'Continuation treatment'.)
●Call to discuss side effects or other concerns or questions.
●Talk with the prescribing clinician before stopping medications.
In addition, the following techniques can enhance medication adherence [13,14,32,36,37]:
●Help patients accept the diagnosis. (See 'Discussing the diagnosis' above.)
●Ask about prior use of pharmacotherapy.
●Take a flexible approach and customize pharmacotherapy to accommodate patient preferences to the extent that they are feasible. One option when selecting a medication is to provide a list of possibilities and allow patients to make the final choice. In addition, patients are more likely to adhere to treatment if they choose the drug formulation (eg, tablets, transdermal patches, and liquid), frequency of doses, and timing of administration. Many patients prefer simpler regimens with fewer drugs that are prescribed less often per day. Multiple reviews of different illnesses indicate that adherence is superior with medications administered once per day compared with more frequent doses.
●Discuss with patients their expectations of benefits and adverse effects.
•Elicit and emphasize benefits that are important to the patient.
•Negative expectations about the effects of medications can diminish therapeutic efficacy and amplify unwanted side effects.
●Discuss plans for dose titrations and how the clinician will monitor the use and benefit of medications.
●Provide simple and clear written instructions for taking prescribed medications.
●Suggest pill boxes to organize daily doses.
●Suggest the use of cues (eg, smart phone alarms, a written record, or pairing pill taking with another regular activity such as eating breakfast) as a reminder to take medications.
●Ask about the patient’s ability to follow the regimen and address barriers to adherence.
●Praise desirable behavior and results.
Adherence is typically monitored through patient interviews, and less often by interviewing family members and reviewing medical records (some electronic health records enable clinicians to monitor prescription refills) [13,14]. Clinicians should ask patients about adherence behavior and attitudes in a nonjudgmental manner. Patients may be more likely to discuss concerns or problems with adherence if clinicians initially ask open-ended questions (eg, “How are you taking your medications?”), normalize poor adherence (eg, “Nearly everybody has trouble taking their medications”), and explain that information about adherence is important in treatment decisions (eg, switching treatment) [38]. The last step is to explicitly ask about missed doses. For patients who acknowledge poor adherence, follow-up questions should explore the reasons (eg, “What gets in the way of taking your medications?” or “Did you feel better when you stopped the medicines?”). Clinicians may ascribe noncompliance to incorrect reasons.
Regularly-scheduled follow-up contacts, especially upon medication initiation, may improve medication continuation and allows clinicians to monitor patients and adjust doses for side effects (see 'Monitoring' above) [13,14]. The frequency of monitoring adherence depends upon the patient’s clinical status and presumed level of adherence. A lack of response to treatment, noticeable worsening in symptoms, or missed appointments should prompt an assessment. In addition, well-known patients who are thought to be fully compliant are generally assessed every one to three months. Relatively new patients who regularly adhere to treatment are monitored monthly. Patients whose adherence is problematic or who are not responding to treatment are monitored weekly.
Motivational interviewing is used to enhance adherence in many illnesses [32,39]. The basic aim of motivational interviewing is to help patients acknowledge that adherence with pharmacotherapy is problematic, make a commitment to change their behavior, and take action to change. The general approach is to initially ask questions and to give advice later. Other elements include expressing empathy (eg, “I know this is hard”), focusing upon collaboration (Let’s work together on this”), and avoiding arguments.
Treatment sessions explore the:
●Physical, psychological, and psychosocial effects of major depression and nonadherence upon the patient’s life
●Pros and cons of nonadherence
●Value and meaning of nonadherence in the patient’s life
●Patient’s goals in life
●Motivations for changing medication behavior (potential benefits)
●Ambivalence about and barriers to changing medication behaviors
●Discrepancy between the patient’s current state of functioning and desired future state
It may also be possible to enhance adherence by focusing upon the therapeutic alliance (relationship) with patients and encouraging them to actively participate in treatment as partners [13,14,23,30,32].
PROGNOSIS — Initial treatment of mild to moderate unipolar major depression (eg, Patient Health Questionnaire score <15 (table 1), or no psychotic features and no suicidal behavior) with antidepressants leads to response or remission in roughly 50 to 60 percent of patients:
●A pooled analysis of 182 randomized trials (n >23,000 patients treated with antidepressants for an average of seven weeks) found that response (reduction of baseline symptoms ≥50 percent) occurred in 54 percent of patients [40].
●In a pooled analysis of 93 randomized trials that included more than 20,000 patients who were treated with second-generation antidepressants (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine) for 6 to 12 weeks [41]:
•Response occurred in 63 percent of patients
•Remission in 47 percent
●In the prospective, observational Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 2876 outpatients (nearly 80 percent had chronic or recurrent unipolar major depression) were initially treated with full doses of citalopram for up to 14 weeks [42]. Remission occurred in 33 percent, with a mean time to remission of seven weeks. In addition, response without remission occurred in another 15 percent [43].
Remission may be more likely if treatment commences soon after onset of symptoms [16] (see 'Reluctance to start treatment' above). However, the prior number of major depressive episodes is not related to outcome of antidepressant treatment for an acute episode, based upon a pooled analysis of 15 randomized trials (n >5600 patients treated with antidepressants or placebo) [44].
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 5th to 6th 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 10th to 12th 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 (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
●Unipolar depression is highly prevalent, disabling, and recurrent. (See 'Introduction' above.)
●The general principles of treating unipolar major depression include:
•Screening for the disorder; we typically use the nine-item Patient Health Questionnaire (table 1)
•Diagnosing the disorder; we typically use the criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (table 2)
•Ruling out bipolar disorder by ruling out a history of mania (table 3) or hypomania (table 4)
•Assessing patients for suicidal and homicidal ideation and behavior
•Addressing reluctance to start pharmacotherapy or psychotherapy
•Monitoring patients during treatment
•Encouraging patients to pursue social support
•Referring patients who need specialty care
(See 'General principles' above.)
●Education about treatment of depression includes discussing the diagnosis by explaining the symptoms of the disorder and clarifying that depression is common, associated with both emotional and physical symptoms, and is treatable. (See 'Discussing the diagnosis' above and 'Information for patients' above.)
●To promote adherence to treatment at the onset of therapy, patients starting pharmacotherapy should be told the following: take the medication as prescribed; there may be a lag of several weeks before a discernible response is apparent; side effects (table 5) frequently occur during the first few days, but typically resolve within a week of starting the medication; continue treatment despite feeling better; and call to discuss side effects or other concerns or questions.
Other techniques for promoting adherence include taking a flexible approach and customizing pharmacotherapy to accommodate patient preferences to the extent that they are feasible, discussing expectations of benefits and adverse effects, providing simple and clear written instructions for taking prescribed medications, and motivational interviewing. (See 'Adherence to antidepressants' above.)
●Initial treatment of mild to moderate unipolar major depression with antidepressants leads to response or remission in roughly 50 percent of patients. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Wayne Katon, MD, now deceased, who contributed to an earlier version of this topic review. The UpToDate editorial staff also acknowledges Dr. Gregory Simon, who contributed to an earlier version of this topic review.