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Am Fam Physician. 2023;107(2):173-181

Related editorial: Comparing Clinical Guidelines for the Management of Major Depressive Disorder

Patient information: See related handout on treating depression with medicine.

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

The prevalence of depression and the use of antidepressant medications have risen steadily in the United States over the past three decades. Antidepressants are the most commonly prescribed medications for U.S. adults 20 to 59 years of age. Second-generation antidepressants (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin modulators, atypical antidepressants) are first-line therapy for depression. Psychotherapy, including cognitive behavior therapy and other types of individual and group therapy, is also a first-line treatment. The combination of medication and psychotherapy is preferred for severe depression. Treatment history, comorbidities, costs, and risk of adverse effects should be considered when choosing an antidepressant medication. Although many patients use antidepressants indefinitely, few studies have examined safety and effectiveness beyond two years. There is an increased risk of relapse or recurrence of depressive symptoms when an antidepressant is discontinued, compared with continued use. Gradually tapering the dosage while concurrently providing cognitive behavior therapy can decrease this risk. High-quality evidence on antidepressant use in pregnancy is lacking. Depression and use of antidepressants are both associated with preterm birth.

The use of antidepressant medications in the United States has increased fivefold since the introduction of selective serotonin reuptake inhibitors (SSRIs) in the late 1980s.1,2 Between 2015 and 2018, the percentage of U.S. adults who reported taking an antidepressant medication in the past 30 days was 13.2%, compared with 2.4% between 1988 and 1994.1,2

Between 2015 and 2018, the percentage of U.S. adults who reported taking an antidepressant medication in the past 30 days was 13.2%, compared with 2.4% between 1988 and 1994.
Modest evidence shows that escitalopram, mirtazapine, paroxetine, venlafaxine, and amitriptyline are the most effective antidepressants for reducing acute depressive symptoms by greater than 50% at eight weeks.
A 2021 network meta-analysis demonstrated a low risk of ventricular arrhythmia or sudden cardiac death in those taking selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or tricyclic antidepressants.
Typical symptoms of antidepressant discontinuation syndrome can be described using the FINISH mnemonic (flulike symptoms, insomnia, nausea, imbalance, sensory disturbances, hyperarousal).
Clinical recommendation Evidence rating Comments
In the primary care setting, antidepressant medication and psychotherapy should be offered for the treatment of depression.1720 A Network meta-analysis, systematic reviews, clinical practice guidelines
Second-generation antidepressants, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin modulators, and atypical antidepressants, are recommended first-line medications for the treatment of depression. Choice of medication should be guided by shared decision-making, with consideration of prior treatment and response, comorbidities, costs, and risk of adverse effects.10,16,17 B Clinical practice guidelines, systematic reviews
When antidepressants are discontinued, the risk of relapse or recurrence of depressive symptoms is higher than when treatment is continued.4244 A Double-blind randomized controlled trial, systematic reviews, meta-analyses
When discontinuing antidepressants, cognitive behavior therapy should be used to help prevent relapse and recurrence of depressive symptoms.56 B Two studies included in larger meta-analysis
Pregnant and postpartum patients should be screened for depression.61 B Systematic reviews of six clinical trials (n = 11,869) showing decrease in depressive symptoms in patients who are screened, even in the absence of follow-up measures
Fluoxetine and paroxetine should be avoided in older patients. Recommended alternatives include duloxetine (Cymbalta), sertraline, and escitalopram.77 C Clinical practice guidelines

Antidepressants are the most commonly prescribed medications for U.S. adults 20 to 59 years of age.3 Rates of depression and suicide have increased, primarily among those younger than 25 years.4,5 The percentage of adults 18 to 25 years of age reporting a major depressive episode in the past year doubled from 8.8% in 2005 to 17% in 2020. During the same period, rates among adults 26 years and older increased only slightly from 6.2% to 7.1%.6,7

The definition of a major depressive episode is based on the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., criteria for major depressive disorder.6,8 Five or more depressive symptoms must be present for at least two weeks, cause distress or functional impairment, and not be due to another medical or psychiatric condition. Symptoms include depressed mood, anhedonia, changes in weight or sleep patterns, fatigue, psychomotor agitation or retardation, feelings of worthlessness or guilt, impaired concentration, and recurrent thoughts of death.6,8 Clinical trials of antidepressants often use major depressive episode as an inclusion criterion. Although most patients with clinician-identified depression do not meet diagnostic criteria for a major depressive episode, many are prescribed antidepressants.9

Second-generation antidepressants are the most common medications used to treat depression in the United States.10 These include SSRIs (e.g., escitalopram, paroxetine), serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g., duloxetine [Cymbalta], venlafaxine), serotonin modulators (e.g., nefazodone, trazodone), and atypical antidepressants (e.g., bupropion, mirtazapine).


Despite thousands of clinical trials, the effectiveness of antidepressants is not well established. High-quality reviews of randomized controlled studies show a statistically significant improvement in depression with use of antidepressant medications.11,12 A 2016 systematic review showed that the number needed to treat for response to treatment or remission is 9 for tricyclic antidepressants, 7 for SSRIs, and 6 for venlafaxine.11 Outcomes of other studies challenge these conclusions, with minimal difference in symptoms between placebo and antidepressants, publication bias favoring effectiveness, and pharmaceutical industry sponsorship of most clinical trials.11,13,14 A recent national survey of adults with depression revealed that those who used antidepressants had no improvement in health-related quality of life at two years of follow-up compared with those who did not use antidepressants.15

Psychotherapy (e.g., behavior therapy, cognitive therapy, cognitive behavior therapy, interpersonal psychotherapy, psychodynamic therapy, supportive therapy) is also a first-line treatment for depression.16,17 The effectiveness of psychotherapy is similar to that of antidepressants in the primary care setting (relative risk [RR] = 1.03; 95% CI, 0.88 to 1.22).18 Evidence for cognitive behavior therapy is more robust than for other types of therapy.10 The combination of psychotherapy and pharmacotherapy may be more effective than either treatment alone for moderate or severe depression and may reduce risk of relapse and recurrence.17,19,20

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