Version November 2024
INTRODUCTION — Major depressive disorder (MDD, or unipolar major depression) is highly prevalent and a significant source of disability. Community surveys in 14 countries have estimated that the lifetime prevalence of depressive disorders is 12 percent [1]. In patients with other medical illnesses, such as diabetes or coronary heart disease, the estimated prevalence of MDD is 10 to 20 percent [2]. In the United States, MDD ranks second among all diseases and injuries as a cause of disability [3]. According to the World Health Organization, it is the 11th greatest cause of disability and mortality in the world [4].
MDD is undertreated. As an example, community surveys examined how many individuals with MDD in the past 12 months received minimally adequate treatment, defined as at least eight psychotherapy visits or at least four pharmacotherapy visits [5]. Among individuals with MDD in higher income countries, only 22 percent received minimally adequate treatment; in lower income countries, it was only 4 percent.
MDD is also 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 [6].
This topic reviews the use of antidepressants for the initial management of MDD, including considerations for choosing an antidepressant medication and a starting dose and monitoring outcomes to personalize dose titration and detect and minimize side effects. Other aspects of treating depression are discussed separately, including how to choose among pharmacotherapy, psychotherapy, and/or nonpharmacologic options; treatment of resistant depression; and continuation and maintenance treatment of MDD.
●(See "Major depressive disorder in adults: Approach to initial management".)
●(See "Major depressive disorder in adults: Treatment with supplemental interventions".)
●(See "Unipolar depression in adults: Choosing treatment for resistant depression".)
●(See "Unipolar depression in adults: Continuation and maintenance treatment".)
●(Related Pathway(s): Unipolar major depression: Initial pharmacologic therapy in adults.)
DEFINITIONS
●Major depressive disorder – MDD is diagnosed in patients with a history of at least one major depressive episode (table 1) and no history of mania (table 2) or hypomania (table 3) [7]. 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 symptom must be depressed mood or anhedonia, and the symptoms must cause significant distress or functional impairment. 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 [8]. 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" [8].
•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 [9,10].
-Partial response – Partial response is defined as an improvement in symptom score of >30 but <50 percent. However, definitions used in individual studies differ [9,10].
-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 cutoff) for diagnosis. Studies using the nine-item Patient Health Questionnaire (PHQ-9) often define remission as a score of <5 (table 4). 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 [11-15].
•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.
●Depression severity – The severity of depression is determined by the combination of functional impairment and the number, frequency, intensity, and duration of the individual's symptoms. (See "Major depressive disorder in adults: Approach to initial management", section on 'Determination of severity'.)
We use the self-report PHQ-9 and other features of the patient's symptoms to define the severity of a major depressive episode. The PHQ-9 classifies episodes as mild (scores of 5 to 9), moderate (10 to 14), moderately severe (15 to 19), and severe (20 or higher) (table 4). Alternative validated self-report scales for evaluating depression symptoms include the Quick Inventory of Depressive Symptomatology – Self-Report and the Clinically Useful Depression Outcome Scale [16]. Using symptom scales to monitor response to treatment and categorize symptom severity is discussed separately.
GOALS AND INDICATIONS FOR PHARMACOTHERAPY
●Indications – We include antidepressants as part of the management plan for patients with moderate to severe MDD. Other indications include some individuals with mild depression who strongly prefer treatment with medications, have lack access to psychotherapy, and/or have symptoms that have not responded to nonpharmacologic management. This is discussed in detail separately. (See "Major depressive disorder in adults: Approach to initial management", section on 'Choosing a treatment regimen for patients with major depression' and "Unipolar minor depression in adults: Management", section on 'Choosing treatment'.)
●Goals of treatment – The goals of initial treatment for depression are to restore baseline functioning, induce symptom remission, and prevent relapse [17-20]. Relapse occurs less frequently in patients whose symptoms remit with initial management, compared with those whose symptoms respond but do not remit [21].
CLASSES OF ANTIDEPRESSANTS — Second-generation antidepressants include those in the following classes (table 5):
●Selective serotonin reuptake inhibitors (see "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects")
●Serotonin-norepinephrine reuptake inhibitors (see "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects")
●Atypical antidepressants (see "Atypical antidepressants: Pharmacology, administration, and side effects")
●Serotonin modulators (see "Serotonin modulators: Pharmacology, administration, and side effects")
Older, first-generation antidepressants (table 5 and table 6) include:
●Tricyclic antidepressants (see "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects")
●Monoamine oxidase inhibitors (see "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and side effects")
SELECTING AN ANTIDEPRESSANT
Patients with mild to moderate depression — Mild to moderate depression is defined by nine-item Patient Health Questionnaire (PHQ-9) symptom scores of 5 to 9 (mild) and 10 to 19 (moderate to moderately severe) (table 4).
Treatment approach — For individuals with mild to moderate major depression who opt for antidepressants, we consider various factors other than efficacy alone because clear differences in efficacy between antidepressants have not been found. These factors include the patient's history of prior antidepressant use, specific depressive symptoms, preferences for avoiding certain antidepressant side effects, other current medications, and psychiatric and medical comorbidities (table 6) [17,22].
In most patients, we use a selective serotonin reuptake inhibitor (SSRI), such as escitalopram or sertraline, unless there is a compelling reason to avoid SSRIs or select a specific agent from a different class. SSRIs generally offer an optimal balance of efficacy and tolerability. (See 'General preference for SSRIs' below.)
Reasons to select a drug from a different class are shown in a table (table 7) and discussed in detail. (See 'Tailoring antidepressant selection' below.)
Reasonable first-line alternatives to SSRIs include other second-generation antidepressants, such as serotonin-norepinephrine reuptake inhibitors (SNRIs); atypical antidepressants, such as mirtazapine or bupropion; and serotonin modulators (table 5). Concerns about safety, particularly in overdose, and higher rates of adverse effects limit the use of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors for initial treatment. (Related Pathway(s): Unipolar major depression: Initial pharmacologic therapy in adults.)
For patients with mild to moderate major depression, the efficacy of different antidepressants is generally comparable across and within classes [17,23-28]. Although some systematic reviews show minor differences in the efficacy, patient acceptance, and adverse effects of different antidepressants, these are generally not considered clinically meaningful [17,23,25,28,29]. Representative examples from the literature include:
●A 2018 network meta-analysis of 522 randomized trials evaluated 21 antidepressants in more than 100,000 patients and found only small differences in response rates and acceptability (measured by medication discontinuation) [24].
●A network meta-analysis of 119 randomized trials found comparable efficacy across 16 second-generation antidepressants [30].
●Existing evidence suggests that different antidepressant agents show similar efficacy in preventing relapse and recurrence. (See "Unipolar depression in adults: Continuation and maintenance treatment", section on 'Antidepressant medications'.)
The efficacy of antidepressants compared with other treatment options (eg, placebo, psychotherapy) is discussed separately. (See "Major depressive disorder in adults: Approach to initial management", section on 'Moderate major depression' and "Major depressive disorder in adults: Approach to initial management", section on 'Antidepressant medications'.)
The utility of pharmacogenomics, machine learning tools, and electroencephalography-based models to guide antidepressant prescribing is being actively investigated; however, a clear role for these practices has not yet emerged [31-33]. The role of genetic factors in influencing an individual's response to antidepressants is discussed separately. (See "Unipolar depression: Genetics", section on 'Pharmacogenetics'.)
General preference for SSRIs — We suggest selective serotonin reuptake inhibitors (SSRIs) if other reasons to tailor antidepressant choice are not a priority (table 7). SSRIs are the most widely prescribed class of antidepressants, and their potential for overdose toxicity is low [34-37]. We typically use escitalopram or sertraline because they may offer small advantages in terms of efficacy and acceptability. Fluoxetine offers the advantage of a long half-life, which can minimize any side effects associated with intermittent adherence or discontinuation of the medication. Although paroxetine also demonstrates high efficacy and acceptability, we choose this agent less frequently due to its side effects of weight gain and higher rates of discontinuation symptoms [38]. Representative studies that support this approach include:
●A 2018 network meta-analysis of 522 trials and over 100,000 participants ranked antidepressants in terms of efficacy and acceptability. Antidepressants that ranked the highest for both efficacy and acceptability included the SSRIs escitalopram, sertraline, and paroxetine as well as the atypical agents mirtazapine and agomelatine (not available in the United States) [30].
●A second network meta-analysis of second-generation antidepressants found superior efficacy plus tolerability (dropout due to adverse effects) with escitalopram, mirtazapine, and agomelatine [39]. An earlier network meta-analysis of 10 second-generation antidepressants also reported a slightly higher rate of remission with escitalopram [40].
It is reasonable to select other SSRIs based on clinician familiarity, cost, or desire to avoid certain side effects (such as diarrhea with sertraline), particularly since the preponderance of the evidence suggests that few clinically meaningful differences exist between the SSRIs. (See 'Treatment approach' above.)
Tailoring antidepressant selection — Although we typically choose SSRIs when initiating antidepressant therapy for the initial treatment of individuals with mild to moderate depression, specific patient characteristics often inform the selection of a specific SSRI or of antidepressants from other classes.
Addressing specific symptoms — We often choose an antidepressant that can address a patient's specific symptoms or coexisting conditions (eg, pain, anxiety, and tobacco use). Approaches to common situations appear in a table (table 7) and are discussed as follows:
●Anxiety symptoms – Symptoms of anxiety (eg, ruminative thoughts, worrying, and agitation) are common in individuals with MDD. Moreover, up to 75 percent of individuals with MDD have a co-occurring anxiety disorder, such as panic disorder or generalized anxiety disorder [41].
The SSRIs are still a reasonable first choice in individuals with anxiety symptoms. SSRIs are also preferred agents for the initial pharmacotherapy of anxiety disorders (see "Generalized anxiety disorder in adults: Management" and "Social anxiety disorder in adults: Treatment overview" and "Panic disorder in adults: Treatment overview"). We typically start with one-half the usual initial antidepressant dose to minimize the transient activation that occurs with SSRIs and SNRIs.
We generally avoid the use of bupropion in patients with significant anxiety. Adding a low-dose anxiolytic, such as clonazepam (0.25 or 0.5 mg at bedtime), can also treat anxiety symptoms and may enhance antidepressant adherence, particularly during the early stages of treatment. The indications and general principles for using anxiolytics, as well as their efficacy, are discussed separately. (See "Unipolar depression in adults: Treatment with anxiolytics".)
Most evidence suggests that second-generation antidepressant agents are comparable for treating anxiety symptoms. As an example, a systematic review of 11 randomized trials of over 2300 participants with MDD found that different classes of second-generation antidepressants (SSRIs, SNRIs, atypical antidepressants, and serotonin modulators) showed similar efficacy in treating anxiety symptoms [42]. In contrast, an earlier review of 10 randomized trials of individuals with major depression and anxiety found higher response rates with SSRIs than bupropion in the subset of patients with high levels of anxiety symptoms [43].
●Insomnia – Because sleep disturbance associated with depression often improves as depression abates, most antidepressants can decrease insomnia. However, some individuals with severe insomnia may benefit from a sedating antidepressant, such as mirtazapine. Trazodone is also sedating; however, at a therapeutic antidepressant dose (200 to 400 mg daily), its side effects of sedation, nausea, and orthostatic hypotension are difficult for many individuals to tolerate.
Although many antidepressants are associated with side effects of insomnia, this side effect is usually transient (during the initial two to four weeks of treatment). As an example, in a network meta-analysis of 163 studies of 21 antidepressants, 14 were associated with an increased risk of insomnia, compared with placebo [44]; those agents most associated with insomnia included reboxetine, vilazodone, desvenlafaxine, duloxetine, and bupropion (table 6). In contrast, fluvoxamine, trazodone, and mirtazapine had the highest risk of somnolence.
However, available evidence suggests that second-generation antidepressants are comparable in treating insomnia symptoms in individuals with major depression. As an example, a systematic review of six randomized trials with over 1000 participants did not find compelling evidence that one agent or medication class was superior for the treatment of insomnia [42]. Sleep disturbance generally improves with treatment of depression, and this may partly explain the comparable efficacy of antidepressants for treating insomnia. Additional information on managing insomnia is discussed separately. (See "Overview of the treatment of insomnia in adults" and "Pharmacotherapy for insomnia in adults".)
●Chronic pain – The SNRIs duloxetine and milnacipran and TCAs may reduce neuropathic pain and may be useful options in individuals with concomitant major depression and chronic neuropathic pain [45]. Treatment of chronic noncancer pain with antidepressants is discussed elsewhere. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Antidepressants'.)
●Tobacco use – Bupropion is effective for treating tobacco use disorder and can be useful for individuals with depression who also wish to stop smoking. (See "Pharmacotherapy for smoking cessation in adults", section on 'Bupropion'.)
Caution with certain comorbidities — In selecting an antidepressant, we consider coexisting medical conditions that can be exacerbated by certain antidepressant agents. Some antidepressants can exacerbate specific medical conditions, such hypertension and seizure disorder. Some of the most common medical conditions to consider include the following:
●Hypertension – We suggest avoiding venlafaxine in individuals with uncontrolled hypertension, especially the immediate-release formulation at higher doses. If a compelling reason exists to choose an SNRI, duloxetine or lower-dose venlafaxine can be used. Venlafaxine use in this context should be accompanied with careful blood pressure monitoring. (See 'Address side effects' below.)
Some studies have found a dose-dependent association between venlafaxine and blood pressure elevation in both normal and hypertensive individuals, and case reports exist of venlafaxine precipitating hypertensive crisis [46]. However, other studies have not confirmed this association [47]. The effects of venlafaxine on blood pressure are discussed separately. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Adverse effects'.)
●Seizure disorder – We suggest avoiding bupropion in individuals with seizure disorder or increased risk of seizure. Second-generation antidepressants can lower the seizure threshold, and bupropion is specifically contraindicated in individuals with seizure disorder or increased risk of seizure (ie, current or prior anorexia nervosa/bulimia, abrupt discontinuation of alcohol or benzodiazepines). In a population-based registry study of over 10,000 individuals, exposure to antidepressant agents was associated with an increased risk of new-onset seizure (odds ratio [OR] 1.5, 95% CI 1.3-1.6) [48]. The increase in seizure risk was highest with bupropion (OR 2.23, 95% CI 1.58-3.16) but also seen with SSRIs, SNRIs, and mirtazapine. However, even with bupropion, the absolute risk of seizures is low (0.1 percent), with the incidence increasing to 0.4 percent at higher doses. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Side effects'.)
●QTc prolongation – Citalopram and escitalopram can cause dose-dependent corrected QT interval (QTc) prolongation that is dose related. We suggest avoiding citalopram in patients with congenital long QT syndrome and using caution when prescribing citalopram to those with other medical conditions and/or on medications that cause QT prolongation. We also suggest avoiding doses of escitalopram of 30 mg/day or higher in these patients. Clinical trials suggest that escitalopram at doses less than 30 mg/day does not cause clinically significant QTc prolongation. Cardiac adverse effects of SSRIs are discussed in detail elsewhere. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Cardiac'.)
●Hyponatremia – Antidepressants (SNRIs, TCAs, mirtazapine, and particularly the SSRIs) may be associated with the syndrome of inappropriate antidiuretic hormone secretion and hyponatremia, although the absolute risk of hyponatremia appears low. In patients at high risk of hyponatremia, clinicians may choose fluvoxamine or milnacipran since hyponatremia occurs less frequently with these medications [49]. The risk of SSRI- and SNRI-induced hyponatremia is discussed elsewhere. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Hyponatremia' and "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Adverse effects'.)
●Low bone density – Some observational studies suggest an association between some classes of antidepressants (SSRIs and TCAs) and fragility fractures and/or bone loss. However, studies to date have not confirmed a causal relationship, and we do not recommend avoiding antidepressants in individuals with osteoporosis or osteopenia. This association is discussed elsewhere. (See "Drugs that affect bone metabolism", section on 'Antidepressants'.)
●Pregnancy – For females who are considering pregnancy in the next year, certain medications should be avoided because of potential risks or an inadequate record of safety. We typically avoid paroxetine in this setting because some observational studies suggest that its use may be associated with a small increased absolute risk of congenital heart defects. This is discussed elsewhere. (See "Severe antenatal unipolar major depression: Choosing treatment", section on 'Choosing an antidepressant'.)
Avoiding specific side effects — Helping individuals with depression avoid important side effects can help guide the choice of a specific antidepressant agent. Although some patients with MDD are willing to tolerate side effects from a medication that improves their symptoms, others prioritize avoiding specific side effects. Minimizing side effects helps to ensure that patients can tolerate a therapeutic dose and will adhere to pharmacotherapy. Whereas some adverse effects (eg, gastrointestinal side effects) (table 6) are common with second-generation antidepressants, others differ in frequency between different antidepressants, as described below [50].
●Weight gain – For patients who prioritize not gaining weight, we suggest bupropion, fluoxetine, escitalopram, or duloxetine. Bupropion may have a lower risk of weight gain than other antidepressants [51,52]. Because mirtazapine and paroxetine cause more weight gain than other antidepressants, we generally avoid using them in this subset of patients [25,28,52-55].
Most antidepressants are associated with weight gain. Weight gain usually starts after the first four to six months of treatment, and the magnitude of weight gain is generally small [51]. As an example, in a population-based cohort of nearly 300,000 primary care patients in the United Kingdom, antidepressant use was associated with a higher incidence of weight gain of ≥5 percent, compared with no antidepressant use (11.2 versus 8.1 per 100 person years, respectively; adjusted relative risk 1.21; 95% CI 1.19-1.22) [53]. Similarly, a retrospective cohort of patients with depression who were treated with a variety of second-generation antidepressants reported average weight gains at two-year follow-up that ranged from 1 to 7 kg [52].
Additional information about weight change with SSRIs is discussed separately. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Weight change'.)
●Weight loss – Individuals with major depression who need to avoid weight loss can use mirtazapine and most other antidepressants. They should ideally avoid bupropion. In a meta-analysis of randomized trials and cohort studies, weight loss was associated with short-term treatment with bupropion, duloxetine, fluoxetine, and sertraline [56].
●Somnolence – The less-sedating antidepressants, such as bupropion, reboxetine, or vilazodone, may be useful for patients with prominent symptoms of hypersomnia or lack of energy [44]. For individuals wishing to minimize sedation, we generally do not use fluvoxamine, trazodone, mirtazapine, or TCAs, all of which can cause somnolence (table 6).
●Sexual dysfunction – We recommend bupropion or mirtazapine for individuals who prioritize avoiding sexual dysfunction. Vortioxetine and vilazodone are also options for these patients. Sexual dysfunction is common in individuals with depression, even those who are not taking antidepressants. Sexual dysfunction occurs in over 50 percent of individuals taking SSRIs and is also seen with SNRIs. Symptoms of sexual dysfunction from antidepressants include decreased libido, difficulty achieving orgasm, and erectile dysfunction. Moreover, sexual dysfunction can persist after cessation of SSRIs and SNRIs (post-SSRI sexual dysfunction) [57,58]. The management of SSRI-induced sexual dysfunction is discussed elsewhere (algorithm 1). (See "Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Clinical features and management".)
●Gastrointestinal side effects – Gastrointestinal side effects are common with SSRIs. Nausea and vomiting occur in over 20 percent of those taking SSRIs; however, these side effects are most pronounced with medication initiation and titration and often diminish or resolve after the first several weeks of treatment. Nausea also occurs more frequently with venlafaxine than with SSRIs (33 versus 22 percent). Diarrhea is slightly more common with sertraline than with venlafaxine, mirtazapine, bupropion, and other SSRIs but generally limited to the first week (16 versus 8 percent of patients).
TCAs can also cause constipation and dyspepsia due to their anticholinergic properties. This is particularly common with the first-generation TCAs (eg, amitriptyline, imipramine).
Prior antidepressant use — Choosing an antidepressant is often based upon patient response to specific antidepressants during prior depressive episodes or family history of response to antidepressants [59]. However, robust evidence does not exist to support this practice.
Patients with 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 4). Individuals with severe major depression often report suicidal ideation and behavior, demonstrate obvious impairment of functioning, and are more likely to develop complications such as psychotic or catatonic features. Management of patients with severe major depression can require hospitalization and should ideally include referral to a psychiatrist [17].
We suggest combination treatment with psychotherapy and medication for individuals with severe major depression. Reasonable alternatives to combination treatment include medication alone or electroconvulsive therapy. Selecting a treatment regimen for patients with severe major depression, including those with psychotic features or catatonia, is discussed separately. (See "Unipolar major depression with psychotic features: Acute treatment" and "Catatonia: Treatment and prognosis" and "Major depressive disorder in adults: Approach to initial management", section on 'Choosing a treatment regimen for patients with major depression'.)
●SNRIs or SSRIs as preferred antidepressants – For the initial treatment of severe major depression, we suggest serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine or duloxetine, although selective serotonin reuptake inhibitors (SSRIs), such as escitalopram or sertraline, are a reasonable alternative. Some experts prefer SNRIs because they may be superior to SSRIs in achieving remission in those with severe major depression (table 5) [60]. Nevertheless, many patients with severe depression respond to SSRIs, which are superior to placebo for the treatment of severe major depression, are generally well tolerated, and have a low risk of life-threatening toxicity in overdose [61]. (See 'General preference for SSRIs' above.)
Clinically important differences in efficacy or tolerability between the SNRIs are not apparent. However, we suggest carefully monitoring the use of venlafaxine in persons with hypertension since venlafaxine (especially the immediate-release formulation) can occasionally cause dose-dependent increases in diastolic blood pressure. (See 'Caution with certain comorbidities' above.)
Using an SNRI is supported by meta-analyses of randomized trials that suggest severe major depression may respond better to SNRIs than SSRIs [60,62,63]. Representative studies include:
•A meta-analysis of 31 trials compared the SNRI venlafaxine with SSRIs (primarily fluoxetine and paroxetine) and stratified participants by baseline depression severity [62]. In the 656 patients with severe depression (score ≥30 on the Hamilton Rating Scale for Depression (table 8)), remission was more likely in those randomized to venlafaxine than SSRIs (OR 1.6, 95% CI 1.1-2.2, number needed to treat = 11).
•In a meta-analysis of 15 trials, remission occurred more often in the subgroup of hospitalized patients (n = 582) who received SNRIs (duloxetine, milnacipran, and venlafaxine) than SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, and sertraline; 52 versus 29 percent, respectively) [63].
●Alternative agents – TCAs and mirtazapine are alternative options for patients with severe major depression (table 5). TCAs also have demonstrated efficacy in treating severe MDD but greater safety hazards. Tailoring antidepressants to address specific depressive symptoms or patient comorbidities or avoid certain side effects is also a reasonable alternative strategy (table 7). (See 'Tailoring antidepressant selection' above.)
•Mirtazapine – Mirtazapine is effective for treating patients with severe major depression [64-66]. Although a meta-analysis comparing the efficacy of mirtazapine with SSRIs and SNRIs found that participants were more likely to achieve an early response (at two weeks) with mirtazapine, rates of remission were similar with all agents [64]. Side effects of sedation and weight gain also limit the use of mirtazapine in some patients.
•Tricyclic antidepressants – TCAs are efficacious for severely depressed patients, although they are frequently avoided due to their greater safety hazards (eg, cardiotoxicity and potential lethality with overdose), less-favorable side effect profiles, and lower tolerability (table 6) [18]. As an example, a meta-analysis of 1377 hospitalized patients found greater symptom improvement with TCAs (particularly amitriptyline) than SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine), although the clinical difference was small [67]. Moreover, treatment discontinuation due to adverse effects occurred more frequently with TCAs (14 versus 9 percent). By contrast, a subsequent meta-analysis of 54 trials of hospitalized patients with depression failed to show a significant difference in response rates among participants randomized to amitriptyline versus SSRIs (OR for SSRI 1.37, 0.87-1.96) [68]. Differences in patient populations and depression characteristics (eg, severity, chronicity) may account for these discrepant findings.
INITIAL ADMINISTRATION
Patient education — We counsel patients about the rationale for antidepressant treatment, how to take the medication and address side effects, and the importance of medication adherence and ongoing monitoring [69,70]. Specific guidance for patient education appears in a table (table 9).
Although the efficacy of education alone for improving depression outcomes is not supported by existing evidence, education combined with other interventions to improve depression management has been associated with improved adherence and outcomes [71]. Given that education likely has minimal harms and adherence to antidepressants is often poor, it is reasonable to provide psychoeducation to help to strengthen a therapeutic alliance and address potential adherence issues [72]. Adherence to depression management is discussed separately. (See "Unipolar depression in adults and initial treatment: General principles and prognosis", section on 'Adherence to treatment'.)
Initial low dose and dose titration — We suggest starting antidepressants at low doses to reduce side effects and improve adherence and then increasing the dose as tolerated to reach a therapeutic range [73]. Typical starting doses appear in a table (table 5).
Starting at one-half the normal initial dose may further reduce adverse effects and decrease early discontinuation of the medication. This approach may benefit patients who are older, are receiving polypharmacy, have a comorbid anxiety disorder, or are sensitive to side effects. For patients who start at one-half the normal initial dose, it is important to titrate up to the minimum usual total daily dose (therapeutic dose) over one to three weeks, depending upon tolerability. (Related Pathway(s): Unipolar major depression: Initial pharmacologic therapy in adults.)
Further dose adjustment at two to four weeks — For individuals who do not respond to the minimum therapeutic dose of an antidepressant (not the starting dose) within two to four weeks, we suggest increasing the dose as tolerated toward the upper end of the usual dosing range (table 5) [36,74,75].
Dose adjustment can proceed rapidly if the patient is tolerating the medication without significant side effects. However, patients who have side effects or reluctance to increase the medication for other reasons may need more gradual dose titration. For these individuals, continuing the initial standard dose is a reasonable alternative because some of these patients will ultimately respond. We do not consider switching antidepressants until the patient has undergone an adequate treatment trial. (See 'Ensure duration of adequate trial' below.)
●Evidence that supports increasing the antidepressant dose includes a meta-analysis of 40 randomized trials that compared different doses of selective serotonin reuptake inhibitors (SSRIs) with placebo in patients with major depression (n>10,000) [76]. Improvement with SSRIs was greater at higher doses than lower doses, and the increased efficacy with higher doses outweighed the higher rate of treatment discontinuation due to side effects. The clinical benefit of higher doses was small and appeared to plateau at the upper end of the usual dose range (eg, 50 mg/day of fluoxetine). Dose increase is consistent with suggestions in multiple practice guidelines [17,18,23,70,73].
●However, continuing the same dose is also a reasonable approach because response rates to an antidepressant generally improve the longer the patient continues treatment, and some depressive episodes remit even without treatment. As an example, a meta-analysis of nine trials included participants who did not respond to an initial standard dose of an SSRI or serotonin-norepinephrine reuptake inhibitor after three to nine weeks and were then randomized either to continue the initial dose or increase it (eg, fluoxetine 20 mg/day versus 40 to 60 mg/day) [77]. Both groups experienced comparable rates of symptom improvement and discontinuation of treatment due to adverse effects. A prior meta-analysis of six trials reported similar findings [78-80]. (See 'Address factors that can affect response' below.)
Some patients benefit from doses that exceed the maximum therapeutic dose [73]. Patients receiving high doses should be regularly monitored for adverse effects and nonadherence [81]. (See 'Address side effects' below and "Unipolar depression in adults and initial treatment: General principles and prognosis", section on 'Adherence to treatment'.)
Additional information about starting doses, titration schedules, and target doses of antidepressants (table 5) is discussed in topics that review specific classes of antidepressants.
MONITORING INITIAL TREATMENT
Frequency of monitoring — Patients who start an antidepressant should receive follow-up within one to two weeks to evaluate for side effects, monitor for early discontinuation, and assess for early improvement. The frequency of ongoing follow-up depends on the severity of the patient's symptoms, degree of functional impairment, medical complexity, and suicidal risk factors (eg, substance abuse, prior suicide attempts, etc); however, monitoring by telephone, telehealth, or in-person visits should occur every two to four weeks during the initial phase of antidepressant management to promote adherence, timely dose adjustments, and early detection of adverse events. (See "Major depressive disorder in adults: Approach to initial management", section on 'Ongoing monitoring and follow-up'.)
Assessing treatment response — Patients should complete symptom rating scales at each follow-up to monitor their response to treatment. We use the nine-item Patient Health Questionnaire (PHQ-9) scale to monitor symptoms in patients with depression because it is a short, self-administered, widely available scale that has been extensively validated in diverse patient populations and different languages (table 4) [82-87]. Using symptom scales to inform dosing adjustments can potentially improve treatment outcomes, more quickly identify nonresponse and response, recognize remission, and help to engage patients in treatment. Details regarding the use of the PHQ-9 and other symptom scales to monitor depression are discussed separately. (See "Major depressive disorder in adults: Approach to initial management", section on 'Ongoing monitoring and follow-up' and "Using scales to monitor symptoms and treat depression (measurement based care)".)
Address side effects
●Ask about side effects – We ask about side effects at each visit, particularly during the initial weeks of treatment, because they are a common reason for discontinuing antidepressants and they inform dose adjustments. Patients who develop side effects should receive education that most are temporary. With selective serotonin reuptake inhibitors (SSRIs), the most common early side effects include insomnia, increased activation or anxiety, and nausea and/or diarrhea (table 6). Given the likelihood that these will resolve after several weeks, individuals who develop but can tolerate them should continue the antidepressant if possible. Adverse effects that do not resolve with time include sexual dysfunction, corrected QT interval prolongation, hyponatremia, and blood pressure elevation. Patients whose side effects do not resolve and/or who have intolerable side effects can try a lower dose of the antidepressant or switch to an alternative antidepressant.
Over half of individuals who newly start antidepressants will have side effects; however, most of these resolve within the first two weeks. Unless clinicians ask about them specifically, side effects can go undetected and can interfere with adherence to antidepressants [88,89]. In addition, the degree to which antidepressant side effects interfere with daily functioning is associated with poorer treatment outcomes, including response and remission [90].
Symptom scales can help to identify and quantify side effects. Self-report instruments to assess side effects include the Toronto Side Effects Scale (table 10) and the Frequency, Intensity, and Burden of Side Effects Rating Scale (figure 2). Although some data indicate that side effects scales are more effective than usual practice for identifying frequent and significantly bothersome adverse effects, it is not known whether their use improves antidepressant adherence. The use of side effects scales in depression management is discussed separately. (See "Using scales to monitor symptoms and treat depression (measurement based care)", section on 'Adverse side effects scale'.)
●Watch for new-onset mania – Because antidepressants can uncommonly precipitate mania or hypomania in individuals with undiagnosed bipolar disorder, we closely monitor for symptoms of mania or hypomania (eg, decreased need for sleep; increased irritability, aggressiveness, or agitation; euphoria; increased energy). Appearance of such symptoms should prompt an evaluation for bipolar disorder and discontinuation of the antidepressant (table 2 and table 3). The risk of "switching" from depression to mania in individuals with undiagnosed bipolar major depression who initiate treatment with antidepressants is discussed separately. (See "Bipolar major depression in adults: Efficacy and adverse effects of antidepressants", section on 'Risk of switching to mania'.)
●Monitor blood pressure – We monitor blood pressure in individuals who start venlafaxine as well as patients at risk for hypertension or hypotension. This includes patients over age 65, with medical comorbidities that predispose to orthostasis (eg, Parkinson's disease), or on antihypertensive drugs or other medication that can reduce blood pressure. Because trazodone and the SSRIs can cause orthostatic hypotension, we ask about symptoms of postural lightheadedness and check orthostatic blood pressures in those who endorse symptoms.
We check blood pressures at baseline and within two months. We typically monitor blood pressure every two to six months, especially for individuals taking higher doses of venlafaxine (≥300 mg/day). Doses of less than 300 mg per day have not been associated with significant blood pressure elevation.
●Evaluate for uncommon side effects – Given that SSRIs and serotonin-norepinephrine reuptake inhibitors can increase the risk of hyponatremia, individuals at high risk for hyponatremia should receive periodic monitoring of serum sodium levels [41]. These include patients who are older (>65 years), use diuretics, and/or have a history of hyponatremia. Other class-based side effects of antidepressants are discussed separately. (See "Major depressive disorder in adults: Approach to initial management", section on 'Safety of antidepressants'.)
●When to consider stopping an antidepressant due to side effects – Because most side effects of antidepressants are transient, we first educate about side effects and individualize medication dose titration to minimize them (see 'Initial low dose and dose titration' above). If side effects occur and are tolerable, we hold off on further dose escalation to see if they resolve or diminish. Some side effects can be adequately managed with behavioral interventions (eg, sleep hygiene for insomnia) or medications (eg, phosphodiesterase 5 inhibitors for sexual dysfunction). Side effects that persist despite these interventions and/or are severe or interfere with medication adherence warrant discontinuation of the antidepressant.
Except for patients who develop symptoms concerning for new-onset mania, most individuals who stop an antidepressant due to side effects should start an alternative antidepressant. We try to select an antidepressant with a different side effect profile either from within the same class or from a different class, depending on the specific side effect. (See 'Avoiding specific side effects' above.)
Symptoms that suggest new-onset mania or hypomania should prompt immediate discontinuation of the antidepressant.
Prognostic value of early improvement — Patients whose symptoms improve during the first two weeks of treatment should be encouraged to continue their antidepressant since early improvement suggests a likelihood of future response and remission.
Among individuals who ultimately respond to a given antidepressant, many experience improved symptoms within two weeks (ie, "early improvement," with improvement defined as reduction of baseline symptoms of ≥20 percent) [91-93]. As an example, a pooled analysis of four randomized trials found that, although improvement times with antidepressant treatment varied widely among participants, the mean time to improvement was approximately 13 days [94].
Early improvement at two weeks can predict future response and remission [94-99]. As an example, in a meta-analysis of 6562 individuals with MDD, early responders (those who had ≥20 percent reduction in baseline symptom score at two weeks) were more likely than those without an early response to have a sustained response at six to eight weeks (53 versus 11 percent, respectively) [100]. A subsequent study reported similar findings in a population of inpatients with major depression [101].
While early improvement seems to predict further benefit, patients without early improvement may subsequently respond or remit [102].
SUBSEQUENT MANAGEMENT
Defining response — We use symptom scales, such as the nine-item Patient Health Questionnaire (PHQ-9), to monitor changes in symptoms and determine subsequent management (table 4).
Patients with response — Response is usually defined as an improvement in symptom score of ≥50 percent that is still above the threshold for remission [9,10].
●Treat to remission – Clinicians should continue to monitor individuals whose symptoms respond to initial treatment to ensure that remission occurs (ie, PHQ-9 score of less than 5 that remains stable for at least one month). This may entail dose adjustment, if tolerated. Some individuals who respond to the initial treatment may ultimately require augmentation with a second medication to achieve remission. (See 'Start next-step treatment' below and "Unipolar depression in adults: Choosing treatment for resistant depression".)
●Duration of treatment – Once remission has been attained, individuals enter the continuation and maintenance phases of depression management. Patients should continue antidepressant treatment for at least six months from the time they attain remission. Factors that influence the specific duration of antidepressant treatment during the continuation and maintenance phases are discussed separately. (See "Unipolar depression in adults: Continuation and maintenance treatment", section on 'Indications'.)
Patients with incomplete response — Individuals who do not respond or have only a partial response to treatment at four weeks should undergo assessment of potential reasons for nonresponse and have a time-limited trial of continued treatment with the same agent before proceeding to next-step treatment. Although some individuals require up to 12 weeks to respond to antidepressant treatment, we typically assess patients early on for factors that can affect response, particularly for patients with more severe depressive symptoms.
Likelihood of nonresponse — Approximately 50 to 60 percent of patients with MDD do not respond to the initial antidepressant [103-107]. As an example, in a meta-analysis of 28 randomized trials of individuals with depression in primary care (n = 5940), response rates (eg, reduction of baseline symptoms ≥50 percent) at six to eight weeks were 63 percent [108]. In a second meta-analysis, pooled response rates from two trials of antidepressant treatment were 56 percent at 12 weeks [103]. Response rates in settings that more closely resemble a typical primary care practice tend to be lower than those in clinical trials. Prognosis with initial antidepressant treatment is discussed separately. (See "Unipolar depression in adults and initial treatment: General principles and prognosis", section on 'Prognosis'.)
Address factors that can affect response — When patients do not respond or have only a partial response to initial antidepressant treatment at four weeks, it is important to ask about medication adherence, ensure that the patient is taking an adequate dose, and assess for factors that may complicate response to treatment.
●Medication adherence – It is important to assess patients' adherence to antidepressant treatment, correct patient misunderstandings about how to take the medication, troubleshoot any identified issues with adherence, and identify and treat antidepressant side effects. (See "Unipolar depression in adults and initial treatment: General principles and prognosis", section on 'Adherence to treatment'.)
●Inadequate dose – It is important to ensure that the patient is not taking a subtherapeutic antidepressant dose and, for patients taking the lower range of the usual dose, increase the dose to the upper end of that range. Therapeutic dose ranges for antidepressants appear in a table (table 5).
Additionally, individuals with increased cytochrome P450 2D6 (CYP2D6) activity may rapidly metabolize some antidepressants and require larger doses of antidepressants. Genetic polymorphisms or concomitant administration of medications that inhibit CYP2D6 enzymes can influence antidepressant pharmacokinetics and affect the dose required to achieve a therapeutic serum concentration [109,110]. As an example, in a study of individuals who were treated with escitalopram and underwent cytochrome P450 2C19 genotyping, serum escitalopram concentrations were more than three times greater in those classified as poor metabolizers compared with those classified as extensive metabolizers [111]. The role of genetic factors in response to antidepressants and drug metabolism more generally are discussed separately. (See "Unipolar depression: Genetics" and "Overview of pharmacogenomics".)
●Coexisting conditions – Because psychosocial factors and comorbid medical diagnosis may complicate response to antidepressants, they should be evaluated for and, if possible, treated. Socioeconomic factors that have been associated with poorer prognostic outcomes include social isolation, unemployment, and unstable housing conditions [112,113]. Common psychiatric comorbidities that may complicate response to treatment include substance use disorder; anxiety disorders, including panic disorder; posttraumatic stress disorder; and attention deficit hyperactivity disorder [114]. These are discussed separately. (See "Unipolar depression in adults: Clinical features", section on 'Comorbidity'.)
●Incorrect diagnosis – Individuals who do not respond to initial antidepressant treatment should also be re-evaluated to confirm a diagnosis of major depression. Some patients may have an alternative diagnosis, such as undiagnosed bipolar disorder, that requires different pharmacotherapy. (See "Unipolar depression in adults: Assessment and diagnosis".)
Ensure duration of adequate trial — After addressing factors that may contribute to an individual's lack of response, we ensure that they have had an adequate trial of therapy. The duration of an adequate trial depends in part on whether the patient has experienced a partial or no response. We suggest that clinicians engage patients in informed decision making regarding the relative merits of continuing the initial management strategy versus proceeding to next-step treatment. (See 'Start next-step treatment' below.)
●Patients with a partial response – We suggest that individuals who have had a partial response to initial antidepressant treatment continue a treatment trial for a total duration of 6 to 12 weeks before proceeding to next-step treatment [115-118]. We define partial response as a reduction in symptoms of >30 but <50 percent.
The rationale for continuing treatment in those with an initial partial response derives from evidence that some individuals require 8 to 12 weeks to achieve a response or remission. As an example, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which treated a sample that was more generalizable than those typically enrolled in clinical trials, found that nearly 25 percent of participants treated with open-label citalopram required 10 or 12 weeks of treatment to achieve remission [104]. Other observational studies have shown similar results [119,120].
Response rates to antidepressants that occur after four to six weeks still exceed those achieved with placebo. As an example, a meta-analysis of five randomized trials of second generation antidepressants found that, among participants who did not respond (reduction of baseline symptoms ≥50 percent) after four weeks of treatment, 22 percent responded at eight weeks, compared with only 11 percent of those who received placebo [103]. An earlier meta-analysis of 28 trials found that the advantage of selective serotonin reuptake inhibitors (SSRIs) over placebo continued to increase for at least six weeks of treatment [121].
This approach is consistent with multiple practice guidelines [17-19,23].
●Patients with nonresponse – We suggest that patients with minimal to no response to initial antidepressant treatment should continue the treatment trial for a total duration of four to six weeks before proceeding to next-step treatment. We define nonresponse as a reduction in symptoms of less than 30 percent.
The rationale for proceeding to next-step treatment in this subset of patients stems from the observation that rates of response and remission are low (ranging from 4 to 20 percent) among individuals who continue the same antidepressant after not responding in four weeks [100,105,122,123] (see 'Address side effects' above). Representative studies include:
•A review of 15 randomized trials and observational studies found that, among participants who demonstrated minimal improvement (eg, reduction of baseline symptoms <20 percent) at four weeks, only 20 percent responded after four additional weeks of treatment with the same agent [105].
•In a study of 566 patients with major depression who improved only minimally (<30 percent reduction of baseline symptoms) after four weeks of open-label escitalopram, those who were randomized to switch to duloxetine immediately were more likely to experience remission at week 16 than those who continued escitalopram or delayed a switch to duloxetine until eight weeks (43 versus 36 percent) [123].
Start next-step treatment — When patients have incomplete response to an initial antidepressant after addressing the above-mentioned issues (see 'Address factors that can affect response' above) and completing an adequate trial, we suggest proceeding to next-step treatment [73,117,124]. Common approaches to next-step treatment include switching to a different antidepressant, augmenting the first antidepressant with a second intervention, or referring for psychotherapy [125]. For individuals with no or minimal response to a single-antidepressant trial, we suggest switching to another antidepressant, usually one from a different class (ie, switch from an SSRI to a serotonin-norepinephrine reuptake inhibitor). For individuals who have a partial response to the initial antidepressant trial, we discuss options with the patient. These include adding a second antidepressant from a different class, such as bupropion or mirtazapine, or switching to an antidepressant from a different class. The process of switching antidepressants is discussed separately. (See "Switching antidepressant medications in adults".)
We generally reserve augmentation with agents that are not antidepressants for those who have not responded to two trials of antidepressant therapy (ie, individuals with resistant depression). Treatment of individuals with resistant depression is discussed separately. (See "Unipolar depression in adults: Choosing treatment for resistant depression".)
Among individuals who switch to a second antidepressant after nonresponse to the first agent, approximately 20 percent will have a remission with that agent. As an example, in the subset of participants in the STAR*D trial who did not respond to initial treatment with citalopram and were then randomized to a second antidepressant (bupropion, sertraline, or venlafaxine), 21 percent remitted, and an additional 9 percent responded without remission [102]. A significant proportion of participants required a long trial of treatment, with 50 percent of responses occurring after six weeks and 33 percent of responses occurring after at least nine weeks of treatment.
AVOID SUDDEN DISCONTINUATION — Because sudden discontinuation of antidepressants can cause withdrawal symptoms, patients who want or need to stop antidepressant treatment should gradually taper the medication [70]. Discontinuing antidepressants is discussed separately. (See "Discontinuing antidepressant medications in adults".)
Approximately 30 percent of individuals will have symptoms when they stop an antidepressant. The incidence of discontinuation symptoms varies with the specific antidepressant, pharmacokinetics, dose, and sensitivity of the patient to side effects. Discontinuation symptoms occur most frequently with medications that have short half-lives, such as paroxetine and venlafaxine, and less frequently with medications with longer half-lives, such as fluoxetine. Common symptoms of discontinuation include dizziness, nausea, altered sensations (eg, paresthesias, shock-like sensations), increased agitation, insomnia, anxiety, and return of depressed mood.
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: Medicines for depression (The Basics)" and "Patient education: Coping with high drug prices (The Basics)" and "Patient education: Depression in adults (The Basics)")
●Beyond the Basics topics (see "Patient education: Depression treatment options for adults (Beyond the Basics)" and "Patient education: Depression in adults (Beyond the Basics)" and "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Goals and role of antidepressant therapy – The goals of initial treatment for major depressive disorder (MDD) are to restore baseline functioning, induce symptom remission, and prevent relapse. Antidepressants can be used as monotherapy or in combination with other interventions. The overall approach to the management of MDD is discussed elsewhere. (See "Major depressive disorder in adults: Approach to initial management".)
●Antidepressant selection for mild to moderate depression – For initial pharmacotherapy of mild to moderate MDD, we suggest a selective serotonin reuptake inhibitor (SSRI), typically escitalopram or sertraline, rather than other classes of antidepressants (Grade 2C). Although efficacy is similar within and across classes of antidepressants, SSRIs optimize efficacy, safety, and tolerability for most patients. Reasonable alternatives include serotonin-norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants, and serotonin modulators (table 5). Potential reasons to use alternatives to SSRIs are listed in a table (table 7). (See 'Patients with mild to moderate depression' above and 'Tailoring antidepressant selection' above.)
●Antidepressant selection in severe depression – For patients with severe MDD, we suggest SNRIs (such as venlafaxine or duloxetine) rather than other classes of antidepressants (Grade 2C). Some data suggest that SNRIs are superior to other agents for achieving remission in this group. SSRIs are reasonable alternatives because they are safe, efficacious, and generally well tolerated in these patients. Among other agents for treating severe depression, mirtazapine and tricyclic antidepressants are the best studied (table 5). Other antidepressants may be reasonable to address specific symptoms or side effects (table 7). (See 'Patients with severe major depression' above and 'General preference for SSRIs' above and 'Tailoring antidepressant selection' above.)
Individuals with severe major depression may benefit from combination treatment with psychotherapy, require hospitalization and/or referral to a psychiatrist, or require specific therapies for symptoms of psychosis and catatonia. (See "Major depressive disorder in adults: Approach to initial management", section on 'Choosing a treatment regimen for patients with major depression' and "Major depressive disorder in adults: Approach to initial management".)
●Initiating antidepressant therapy
•Initial dosing – Typical initial doses of antidepressants are low to reduce side effects and then increased to a therapeutic range (table 5). Individuals with polypharmacy, comorbid anxiety disorders, or sensitivity to medication side effects and those who are older may benefit from starting at one-half the usual initial dose and then increasing to the usual initial dose in the first two weeks. (See 'Initial low dose and dose titration' above.)
•Dose titration – After two to four weeks, individuals who do not respond to the minimum therapeutic dose should increase the dose to the higher end of the therapeutic range, if possible. Patients who experience side effects may need slower dose up-titration. (See 'Further dose adjustment at two to four weeks' above.)
•Patient education – We counsel patients about the rationale for antidepressants, potential side effects, the importance of monitoring, and the time course of improvement (table 9). (See 'Patient education' above.)
●Monitoring
•Frequency – We have patients follow up at one to two weeks to assess for side effects, adherence, and early response to treatment. Subsequent follow-up should occur every two to four weeks during the initial phase of antidepressant management. (See 'Frequency of monitoring' above.)
•Assessments – At each visit, we use a validated self-report scale to monitor treatment response, such as the nine-item Patient Health Questionnaire (table 4). (See 'Assessing treatment response' above.)
Important or common side effects to assess include symptoms of mania or hypomania, increased agitation or anxiety, and gastrointestinal symptoms (table 6). Patients who develop symptoms of mania or hypomania should undergo evaluation for bipolar disorder, and the antidepressant should be stopped. Patients with other side effects that are intolerable or do not resolve can try a lower dose of the antidepressant or switch to an alternative antidepressant. (See 'Address side effects' above.)
●Subsequent management
•Patients who respond – Patients who respond (ie, have reduction of baseline symptoms ≥50 percent) should continue antidepressant therapy until remission and then for at least six months (continuation phases). (See "Unipolar depression in adults: Continuation and maintenance treatment".)
•Patients with incomplete response – Patients with an incomplete response (either a partial response or nonresponse) should optimize their antidepressant dose and medication adherence. Clinicians should address comorbidities that impact treatment response and ensure an adequate trial of therapy (four to twelve weeks) before proceeding to next steps. Potential next steps include switching to a different antidepressant or augmenting the first antidepressant with a second intervention. (See 'Patients with incomplete response' above.)
•Avoiding sudden discontinuation – Individuals who want or need to stop their antidepressant should gradually taper the medication to avoid discontinuation symptoms. (See "Discontinuing antidepressant medications in adults".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Gregory Simon, MD, MPH, who contributed to an earlier version of this topic review.
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