Depression Treatment & Management

A wide range of effective treatments is available for major depressive disorder. Medication alone (see Medication) and brief psychotherapy (e.g., cognitive-behavioral therapy, interpersonal therapy) alone can relieve depressive symptoms. There is also empirical support for the ability of brief psychotherapy (CBT) to prevent relapse.

In children and adolescents, however, pharmacotherapy by itself is insufficient treatment. Moreover, in all patient populations, the combination of medication and psychotherapy generally provides the quickest and most sustained response. Combination therapy has also been associated with significantly higher rates of improvement in depressive symptoms; increased quality of life; and better treatment compliance, especially when treatment is needed for longer than 3 months. ^{[3, 4]}

Medications

Usually, 2–12 weeks at a therapeutic dose, with assumed adherence to the regimen, are needed for a clinical response to become evident. The choice of medication should be guided by anticipated safety and tolerability, which aid in compliance; physician familiarity, which aids in patient education and anticipation of adverse effects; and history of previous treatments. Often, treatment failures are caused by medication noncompliance, inadequate duration of therapy, or inadequate dosing.

According to the 2008 American College of Physicians (ACP) guideline (the most recent release of the guideline) on using second-generation antidepressants to treat depressive disorders, patient preferences should be given serious consideration when choosing the best course of pharmacotherapy for patients with depressive disorders. The patient may want to avoid use of a particular antidepressant if he or she had a previous negative experience with the drug. ^[97]

The 2008 ACP guideline advises that treatment for major depressive disorder should be altered if the patient does not have an adequate response to pharmacotherapy within 6–8 weeks. Once satisfactory response is achieved, treatment should be continued for 4–9 months in patients with a first episode of major depression that was not associated with significant suicidality or catastrophic outcomes. In those who have had 2 or more episodes of depression, a longer course of maintenance treatment may prove beneficial. ^[97]

In 2011, the American Psychiatric Association (APA) updated its Practice Guideline for the Treatment of Patients with Major Depressive Disorder. ^[8] The 2011 APA guideline emphasizes the need to customize a treatment plan for each patient based on a careful assessment of symptoms, including rating scale measurements administered by a clinician or the patient, as well as an analysis of therapeutic benefits and side effects.

Treatment should maximize patient function within specific and realistic goals. The initial modality should be chosen on the basis of the following: ^[8]

• Clinical assessment

• Presence of other disorders

• Stressors

• Patient preference

• Reactions to previous treatment

Psychotherapy

Psychotherapy is often conducted on an outpatient basis with weekly, 60-minute sessions. Although there is wide variation in practice, psychotherapy tends to be time-limited (e.g., 16 sessions).

In the 1990s, the APA's Division 12 Task Force on Promotion and Dissemination of Psychological Procedures ^{[98, 99]} developed criteria for evaluating the empirical support for psychological treatments. Chambless and Hollon ^[100] refined these guidelines such that a therapy is considered efficacious and specific if there is evidence from high-quality studies in two or more settings indicating that it is superior to a pill or psychological placebo or to another bonafide treatment. A treatment is considered efficacious if there is evidence from two or more settings that it is superior to no treatment. A therapy is considered to be possibly efficacious if there is research support from one or more studies in a single setting. It is recommended that individuals seeking psychotherapy for depression receive one with empirical support (see below).

Drugs used for treatment of depression include the following:

• Selective serotonin reuptake inhibitors (SSRIs)

• Serotonin/norepinephrine reuptake inhibitors (SNRIs) 

• Serotonin (5HT)-1a agonists 

• Atypical antidepressants

• Serotonin-Dopamine Activity Modulators (SDAMs)

• Tricyclic antidepressants (TCAs)

• Monoamine oxidase inhibitors (MAOIs)

• N-methyl-D-aspartate (NMDA) receptor antagonists

• St. John's wort

Selective serotonin reuptake inhibitors

SSRIs include the following:

• Citalopram (Celexa)

• Escitalopram (Lexapro)

• Fluoxetine (Prozac)

• Fluvoxamine (Luvox)

• Paroxetine (Paxil)

• Sertraline (Zoloft)

• Vilazodone (Viibryd)

• Vortioxetine (Brintellix)

SSRIs have the advantage of ease of dosing and low toxicity in overdose. SSRIs are greatly preferred over the other classes of antidepressants for the treatment of children and adolescents, and they are also the first-line medications for late-onset depression. This recommendation is supported by the 2011 APA guideline. ^[8]

The adverse-effect profile of SSRIs is less prominent than that of some other agents, which promotes better compliance. Common adverse effects include gastrointestinal upset, sexual dysfunction, and changes in energy level (ie, fatigue, restlessness).

The SSRIs are thought to be relatively unproblematic in patients with cardiac disease, as these agents do not appear to affect blood pressure, heart rate, cardiac conduction, or cardiac rhythm. However, dose-dependent QT prolongation has been reported with citalopram.

Consequently, the US Food and Drug Administration (FDA) has advised that citalopram is not recommended in patients with congenital long QT syndrome. ^[101] Use of citalopram may be appropriate for patients with this condition who lack viable alternatives; however, in such cases, the drug should be given at a low dose, and electrocardiographic and/or electrolyte monitoring should be performed. Citalopram should be discontinued in patients who are found to have a persistent corrected QT interval (QTc) greater than 500 ms.

The dose of citalopram should not exceed 40 mg/day, because of the risk of potentially fatal cardiac arrhythmias; furthermore, higher doses have not been shown to be more effective in treating depression. For patients older than 60 years, the maximum recommended dose of citalopram is 20 mg/day. ^{[101, 102]}

In September 2013, the FDA approved vortioxetine (Brintellix) for the treatment of major depressive disorder in adults. The drug’s mechanism of action involves enhancement of serotonergic activity through 5-HT reuptake inhibition. It also modulates serotonin receptor activity through 5-HT1A receptor agonism and 5-HT3 receptor antagonism, although the contribution of these activities to the antidepressant effect is not fully understood.

Approval was based on 5 short-term (6-8 week) studies, ^{[103, 104, 105, 106, 107]} including one that focused on elderly adults. ^[107] These studies demonstrated a statistically significant reduction in overall symptoms of depression with vortioxetine compared to placebo, with most consistent results obtained within a dosage range of 15-20 mg/day. Also, a long-term (24-64 week) maintenance study showed a significantly longer time to relapse with vortioxetine compared to placebo. ^{[108, 109]} Two studies using lower doses (2.5-5 mg/day) showed no significant difference in efficacy between the drug and placebo. ^{[110, 111]} The most common adverse effects were nausea, diarrhea, dry mouth, constipation, vomiting, dizziness, and sexual dysfunction.

Serotonin/norepinephrine reuptake inhibitors

SNRIs, which include venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine (Cymbalta), and levomilnacipran (Fetzima) can be used as first-line agents, particularly in patients with significant fatigue or pain syndromes associated with the episode of depression. SNRIs also have an important role as second-line agents in patients who have not responded to SSRIs.

The concurrent use of SNRIs with other antidepressants may be more problematic. For example, the Combining Medications to Enhance Depression Outcomes (CO-MED) study found that the combination of extended-release venlafaxine plus mirtazapine may actually pose a greater risk of adverse events and does not outperform monotherapy. ^[112]

The safety, tolerability, and side-effect profiles of SNRIs include those of the SSRIs, as well as noradrenergic side effects, such as hypertension.

In July 2013, the FDA approved the newest SNRI levomilnacipram, which is available as a once-daily sustained-release formulation. It has greater potency for norepinephrine reuptake inhibition than for serotonin reuptake inhibition without directly affecting the uptake of dopamine or other neurotransmitters. 

Serotonin (5HT)-1a agonists

Gepirone is the first 5HT-1a agonist approved by the FDA for major depressive disorder. Its mechanism of antidepressant effect is not fully understood but may be related to its modulation of serotonergic activity in the CNS through selective agonist activity at 5HT1A receptors. 

In placebo-controlled trials, gepirone improved baseline depression scores by a greater amount than placebo. ^[113]  

Atypical antidepressants

Atypical antidepressants include bupropion (Wellbutrin), mirtazapine (Remeron), nefazodone, and trazodone (Desyrel). They have all been found to be effective in monotherapy in major depressive disorder and may be used in combination therapy for more difficult to treat depression.

Nevertheless, this group also shows low toxicity in overdose. In addition, bupropion has the advantage over the SSRIs of causing less sexual dysfunction and less GI distress. Mirtazapine is associated with a high risk of weight gain, so patients who are treated with this agent should have careful monitoring of weight.

Serotonin-Dopamine Activity Modulators

SDAMs include brexpiprazole (Rexulti), cariprazine (Vraylar), and aripiprazole (Abilify). SDAMs act as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and as an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors. This mechanism of action is unique from other atypical antipsychotic drugs.

Brexpiprazole is indicated as adjunctive therapy for major depressive disorder (MDD). Aripiprazole and cariprazine are indicated for schizophrenia, acute treatment of manic and mixed episodes associated with bipolar I, and as an adjunct to MDD. Also, aripiprazole prompt-acting injection is indicated for agitation associated with schizophrenia or bipolar mania.

In clinical trials, brexpiprazole was added to existing antidepressant therapy in patients who had failed multiple trials of antidepressant therapy. Patients enrolled met DSM-IV-TR criteria for MDD. Brexpiprazole (2 mg and 3 mg daily) plus antidepressant therapy was superior to placebo plus antidepressant therapy on the primary endpoint (ie, change in Montgomery-Åsberg Depression Rating Scale scores). ^[114]

Tricyclic antidepressants

TCAs include the following:

• Amitriptyline (Elavil)

• Clomipramine (Anafranil)

• Desipramine (Norpramin)

• Doxepin (Sinequan)

• Imipramine (Tofranil)

• Nortriptyline (Pamelor)

• Protriptyline (Vivactil)

• Trimipramine (Surmontil)

TCAs have a long record of efficacy in the treatment of depression. They are used less commonly because of their side-effect profile and their considerable toxicity in overdose (see AntidepressantToxicity).

Monoamine oxidase inhibitors

MAOIs include isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Emsam), and tranylcypromine (Parnate). These agents are widely effective in a broad range of affective and anxiety disorders. Because of the risk of hypertensive crisis, patients on these medications must follow a low-tyramine diet. Other adverse effects can include insomnia, anxiety, orthostasis, weight gain, and sexual dysfunction.

N-methyl-D-aspartate antagonists

The N-methyl-D-aspartate (NMDA) receptor antagonist esketamine intranasal (Spravato) has been shown to improve treatment-resistant depression in conjunction with an oral antidepressant. ^{[115, 116]} The precise mechanism by which esketamine elicits its antidepressant effect is not fully understood. NMDA is an ionotropic glutamate receptor. 

In August 2020, esketamine intranasal gained approval for treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior in conjunction with an oral antidepressant. Approval was based on the ASPIRE I and II trials in which esketamine intranasal plus comprehensive standard of care demonstrated a significant, rapid reduction of depressive symptoms within 24 hours, with some patients starting to respond as early as 4 hours. Esketamine intranasal led to a 15.9- and 16.0-point decrease on the Montgomery-Åsberg Depression Rating Scale (MADRS) in each trial at 24 hours after the first dose of study medication. This compared to a reduction of 12.0 and 12.2 points in the placebo plus comprehensive standard of care group. ^{[117, 118]}

St. John's wort

St. John's wort (Hypericum perforatum) is an herbal remedy available over the counter. Although St. John's wort is considered a first-line antidepressant in many European countries, it has only recently gained popularity in the United States. Uses include treatment of mild to moderate depressive symptoms, but of note, it has not been shown to be effective in major depressive episodes and cannot be recommended as a first-line treatment in moderate depression.

St. John’s wort may act as an SSRI. The common dosage is 300 mg 3 times a day with meals to prevent GI upset. If no clinical response occurs after 3–6 months, encouraging the use of another medication is recommended.

In addressing the issue of alternative therapies for depression, the 2011 APA guideline noted that St. John's wort might be considered, but evidence for its effectiveness is modest, and more information is needed about its interaction with other drugs. ^[8]

Psilocybin

Psilocybin, a classic "psychedelic" drug, along with psychological support, is showing promise as a treatment for patients with treatment-resistant depression. A study of 19 patients measured cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin. All 19 patients exhibited decreased depressive symptoms at 1 week post treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. ^[119]

Comparative effectiveness of antidepressants

The AgencyforHealthcare Research andQuality (AHRQ) compared the effectiveness of the following 12 second-generation antidepressants: ^[120]

• Bupropion

• Citalopram

• Duloxetine

• Escitalopram

• Fluoxetine

• Fluvoxamine

• Mirtazapine

• Paroxetine

• Sertraline

• Trazodone

• Venlafaxine

The AHRQ found that average effectiveness of those 12 antidepressants appeared similar, but the studies reviewed were not designed to test variation among patients’ responses to individual drugs. However, the AHRQ did find moderately strong evidence of differences among individual second-generation antidepressants with respect to onset of action and some measures (eg, sexual functioning) that could affect health-related quality of life.

The 2008 ACP guideline advises clinicians to choose second-generation antidepressants on the basis of adverse effects, cost, and patient preferences, since all these agents have comparable efficacy. Patient status, response to therapy, and adverse effects of antidepressants should be assessed within 1–2 weeks of starting therapy. ^[97]

Zisook et al found that among depressed patients with suicidal ideation at baseline, the combination of sustained-release bupropion and escitalopram was more effective at reducing suicidal ideation than sustained-release venlafaxine plus mirtazapine; the former was most effective at week 12 of treatment. In this study, of 665 outpatients with nonpsychotic chronic and/or recurrent major depressive disorder, 4 patients attempted suicide; all were receiving venlafaxine plus mirtazapine. ^[121]

Antidepressant effectiveness and depression severity

In a meta-analysis, Fournier et al found that medication superiority over placebo increased with increases in baseline depression severity, crossing the threshold for a clinically significant difference at a baseline Hamilton Depression Rating Scale (HDRS) score of 25. ^[122] In patients with mild or moderate depression, antidepressant medication had minimal or no benefit compared with placebo, but in patients with very severe depression, antidepressant drugs provided a substantial benefit compared with placebo.

More confirmation that antidepressants work for depression came from a large meta-analysis of 522 randomized controlled trials that compared 21 different antidepressants with placebo in more than 116,000 patients with major depressive disorder. ^[123] The 21 antidepressants included in the trials were agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone, and vortioxetine. Results showed that each studied antidepressant was significantly more efficacious, defined as yielding a reduction of at least 50% in the total score of a standardized scale for depression, than placebo after 8 weeks. Patients who received agomelatine, escitalopram, and vortioxetine had both high response rates and low dropout rates. ^[123]

Hollon and Ponniah ^[5] reviewed the literature to identify treatments that met Chambless and Hollon’s ^[100] criteria for empirically supported treatments. Their findings for the treatment of acute major depressive disorder are presented below.

Table. (Open Table in a new window)

Note: Adapted from Hollon & Ponniah ^[5] , p. 925.

Hollon and Ponniah ^[5] also identified empirically supported treatments for the prevention of relapse and recurrence.

Table. (Open Table in a new window)

Note: Adapted from Hollon & Ponniah ^[5] , p. 925.

A brief description of treatments listed as efficacious and specific or efficacious is presented below.

Behavioral activation (BA)

BA is based on early functional descriptions of depression by Lewinsohn ^[36] and Ferster ^[37] that emphasized the role of positive and negative reinforcement in depression, ^[124] suggesting that individuals with depression have deficient response-contingent positive reinforcement and engage in problematic avoidance behaviors. Modern BA treatments developed in response to a component analysis by Jacobson et al. ^[125] who found that the behavioral techniques in cognitive-behavioral therapy (CBT) were as effective as the full CBT package. While several different versions of BA exist, all emphasize the role of activity monitoring and activity scheduling in order to increase engagement in activities suggested to improve mood (see Kanter et al. for a review of specific tools used within different BA treatments ^[126] ). While early variants of BA emphasized activity scheduling that focused on increasing engagement in pleasant events (e.g., Lewinsohn ^[36] ), more recent versions haveemphasizedincorporating activities related to one’s values (e.g., Lejuez, Hopko, & Hopko, ^[127] ). Patients are typically given activity assignments to complete between sessions, with increasing difficulty over time. At times, activity assignments may be arranged along an activity hierarchy (e.g., Lejuez et al. ^[127] ). Mindfulness strategies may be incorporated to address rumination. ^[38]

BA is efficacious and specific for the treatment of acute depression. ^[5] There is also evidence suggesting that BA may be particularly well-suited for individuals with more severe depression. A placebo controlled trial compared BA, cognitive therapy (CT), and paroxetine and found that there were no differences between conditions for patients with lower depression severity, but for those with more severe depression, BA and paroxetine performed equivalently and each of those treatments led to greater improvement than the CT condition. ^[128] While the majority of research on BA has been conducted with adults, there are theoretical reasons to suggest that it may also be efficacious with adolescents ^[129] and a randomized clinical trial is being conducted to investigate this. In addition, there is some initial support for the use of BA with older adults in nursing home ^{[130, 131]} and community settings. ^[132]

Cognitive-behavioral therapy (CBT)

CBT is directed and time limited, usually involving between 10 and 20 treatments. Cognitive therapy (CT) is the most widely practiced version of CBT for depression. It is based on the premise that patients who are depressed exhibit the “cognitive triad” of depression, which includes a negative view of themselves, the world, and the future. ^[133] Related to the cognitive triad, depressed patients are believed to exhibit cognitive distortions that may maintain these negative beliefs. ^[134] Beck, Rush, Shaw, and Emery ^[134] postulated that negative automatic thoughts and distortions in thinking arise from problematic schemas, which are cognitive structures that influence how information is interpreted and recalled. CBT for depression typically includes behavioral strategies (i.e., activity scheduling), as well as cognitive restructuring for the purpose of changing negative automatic thoughts and addressing maladaptive schemas.

There is evidence supporting the use of CBT with individuals of all ages. For adults, CBT is considered to be efficacious and specific for the treatment of acute depression and prior CBT is considered to be efficacious and specific for the prevention of relapse. ^[5] It is particularly valuable for elderly patients, who may be more prone to problems or side effects with medications. ^{[135, 136]} In children and adolescents, 4 studies have shown group CBT to be better than no intervention in the reduction of depressive symptoms and improvement of self-esteem. In fact, in most pediatric clinical samples, CBT was found to be superior to other manualized treatments, including relaxation training and family and supportive therapy.

Interpersonal therapy (IPT)

Interpersonal therapy (IPT) is a time-limited (typically 16 sessions) treatment for major depressive disorder. While more structured than dynamic treatments, IPT has less structure than cognitive and behavioral approaches. IPT draws from attachment theory and emphasizes the role of interpersonal relationships, ^[137] focusing on current interpersonal difficulties. Specific areas of emphasis include grief, interpersonal disputes, role transitions, and interpersonal deficits. ^[138] The initial phase of treatment (sessions 1-4) focuses on building a working alliance as well as identifying an area of primary interpersonal focus based on the four areas previously mentioned, although other areas may be addressed as well. Patients are encouraged to assume the “sick role”, allowing them time to address their symptoms and have a brief respite from some responsibilities. During the middle phase of treatment (sessions 4-12), specific interventions are used to address the area of focus. Thisincludesproviding validation and support, improving communication skills, and working to solve interpersonal problems. The final phase of treatment (sessions 13-16) focuses on termination of therapy. This includes reviewing progress, developing relapse prevention strategies, and addressing emotions that come with ending the therapy relationship. ^[138]

IPT is an efficacious and specific treatment for major depressive disorder in adults. ^[5] Mufson and Fairbanks found that interpersonal therapy may be useful in the acute treatment of adolescents with major depressive disorder and that the rate of relapse is relatively low after acute IPT. ^[139] IPT may be modified for adolescents by flexibly determining session frequency and length, and use of telephone contact between sessions to support the development of the therapeutic alliance. In addition, a fifth area of focus on single-parent families has been added to IPT for adolescents (IPT-A) to address difficulties arising from a separation or divorce. ^[138] There is evidence to suggest that IPT may also be beneficial for depressed older adults. ^[140]

Mindfulness based cognitive therapy (MBCT)

Mindfulness based cognitive therapy (MBCT) was designed to reduce relapse among individuals who have been successfully treated for an episode of recurrent major depressive disorder. The primary treatment component is mindfulness training as developed by Jon Kabat-Zinn and his colleagues at the University of Massachusetts Medical Center. ^[141] MBCT specifically focuses on ruminative thought processes as being a risk factor for relapse, with the corresponding treatment strategy being to change one’s relationship with one’s thoughts through efforts to decenter and distance oneself from them. ^[142] Mindfulness presents a specific method for decentering and distancing oneself from one’s thoughts.

MBCT ^[143] integrates elements of CBT for depression ^[134] and mindfulness-based stress reduction (MBSR). ^[141] CBT elements include decentering strategies such as recognizing that thoughts are not facts and that “I am not my thoughts”. ^[142] Further, while MBSR may apply to a wide range of problems, MBCT was developed specifically for individuals in remission from recurrent major depressive disorder.

MBCT is a structured program that includes eight weekly, 2-hour group sessions. Patients are assigned homework on a daily basis. Homework consists of awareness exercises designed to help patients improve “…moment-by-moment nonjudgmental awareness of bodily sensations, thoughts, and feelings, together with exercises designed to integrate application of awareness skills into daily life.” ^[142] This includes awareness and acceptance of uncomfortable feelings and sensations rather than efforts to avoid contact with such experiences. Patients are encouraged to incorporate mindfulness into their daily activities as well as to practice specific mindfulness exercises.

Research indicated that MBCT reduced risk of relapse or recurrence among patients who completed treatment with medications for depression. ^{[144, 145]}  A meta-analysis found that MBCT was effective at reducing risk of relapse in patients with recurrent depression, especially in those with the most severe residual symptoms. ^[146]

Problem-solving therapy (PST)

Problem-solving therapy (PST) aims to improve individuals’ problem-solving attitudes and behaviors in order to decrease distress and improve quality of life. ^{[144, 147]} The use of PST for the treatment of major depressive disorder is based on a model characterizing social problem solving as a mediator (e.g., Nezu & Ronan ^[148] ) and moderator (e.g., Nezu, Nezu, Saraydarian, Kalmar, & Ronan ^[149] ) of the relationship between stress and depression. Social problem solving is defined as a cognitive-behavioral process that involves directing efforts to cope with a problem toward changing the nature of the situation, changing one’s reaction to the problem, or both. This includes the ability to identify and select a variety of coping responses to address the features of a specific stressful situation. ^[150]

According to social problem solving theory, one’s ability to successfully solve problems is based on both problem orientation and problem-solving style. ^{[151, 152]} Problem orientation includes an individual’s beliefs, attitudes, and emotional reactions to problems and their ability to cope with these problems. Problem orientation can either be positive (i.e., be optimistic that one can effectively solve problems, understand that negative emotions are an inevitable part of the process, understand that time and effort are required to solve problems) or negative (i.e., problems are viewed as threats, the individual feels pessimistic about their ability to solve problems, and they become especially upset in the face of problems and negative emotions). Problem-solving style refers to the activities someone engages in while trying to cope with a problem. ^{[152, 151]} This could be adaptive or maladaptive. An adaptive problem-solving style is referred to as rationalproblem-solving,whichincludes systematically applying skills to effectively solve a problem. These skills include: (a) defining a problem, (b) determining alternative solutions, (c) decision making regarding different solution strategies, and (d) implementing and evaluating a particular solution strategy. Maladaptive coping styles include the impulsivity-carelessness style and avoidance. ^[152] Treatment includes training in problem orientation, training in each of the steps of rational problem-solving, and practicing these skills. ^[153]

PST was found to be superior to nonspecific or wait list controls in two studies with adults ^{[154, 155]} and in one study with a geriatric sample. ^[156] PST was comparable to medications and superior to placebo in a study using a general practice sample. ^[157] Dowrick et al. ^[158] completed a large multi-center randomized trial across five European countries and found that PST was superior to an assessment only control in reducing depression severity.

Electroconvulsive therapy (ECT) is a highly effective treatment for depression. Onset of action may be more rapid than that of drug treatments, with benefit often seen within 1 week of commencing treatment. A course of ECT (usually up to 12 sessions) is the treatment of choice for patients who do not respond to drug therapy, are psychotic, or are suicidal or dangerous to themselves.

Thus, the indications for the use of ECT include the following:

• Need for a rapid antidepressant response

• Failure of drug therapies

• History of good response to ECT

• Patient preference

• High risk of suicide

• High risk of medical morbidity and mortality

Although advances in brief anesthesia and neuromuscular paralysis have improved the safety and tolerability of ECT, this modality poses numerous risks, including those associated with general anesthesia, postictal confusion, and, more rarely, short-term memory difficulties. Especially in elderly patients, a preprocedure workup should be undertaken and should examine cardiac and vascular risk, because the procedure places a high cardiovascular demand on the patient.

Bright-light therapy (BLT) for seasonal affective disorder is used at an intensity of 10,000 lux for 30-90 minutes daily, usually within 1 hour of arising in the morning. Like any effective antidepressant, BLT has the potential to precipitate a hypomanic or manic episode in susceptible individuals. Other common adverse effects include eye irritation, restlessness, and transient headaches. These lamps are not a significant source of ultraviolet (UV) light. Conventional antidepressants, with or without BLT, also can be used to treat seasonal affective disorder.

In addition to its established role in seasonal affective disorder, BLT may be effective in nonseasonal depression or as an augmenting agent with antidepressant medication. One study found that the combination of 30 minutes of bright light therapy a day plus 20 mg of fluoxetine significantly improves nonseasonal major depressive disorder. Data also show that light therapy alone is more effective than antidepressant monotherapy. ^[159]

Studies have demonstrated benefit of BLT for treatment of nonseasonal depression in pregnant patients and elderly patients. ^{[160, 161]}

Transcranial magnetic stimulation (TMS) has been approved by the FDA for the treatment of major depressive disorder when one class of antidepressant has failed. A double-blind, multicenter, controlled TMS trial found that 30.4% of patients in the trial’s active treatment group achieved remission from major depression after 5 weeks of TMS treatment. ^[162]

The study included 233 patients, all of whom suffered from major depression and had previously failed to respond to therapeutic treatments or could not tolerate antidepressant medication because of side effects. The TMS device used in the trial received FDA approval in 2013 for the treatment of depression. ^[162]  

In 2017, the FDA approved a next-generation TMS device for patients with treatment-resistant MDD. ^[163] At the time, this advanced system was the only FDA-cleared TMS treatment that can be delivered in less than 19 minutes, although treatment time may vary, depending on the physician's recommendation.

In 2018, the FDA approved a newer and faster treatment protocol for a TMS device first approved in 2015. ^[164] At that time, each treatment session with this device lasted up to 37 minutes, with 20 to 30 total sessions needed. With the new treatment protocol, which uses intermittent theta-burst stimulation (iTBS), a treatment session lasts only 3 minutes. ^[165]

Vagus nerve stimulation (VNS) has been approved by the FDA for use in adult patients who have failed to respond to at least 4 adequate medication and/or ECT treatment regimens. The device requires surgical implantation.

A meta-analysis of the therapeutic effect of physical exercise in depressed individuals revealed a short-term (≤16 wk) small positive effect on depression scores, but no long-term benefit was shown. ^[166] The authors felt that the evidence did not support the use of exercise for long-term benefits in clinically depressed individuals. The limited available evidence does not support using physical exercise as an “antidepressant.”

Deep brain stimulation (DBS) appears to be a safe and effective long-term treatment for treatment-resistant depression. Experience with this invasive technique is limited, however, and the method remains experimental. ^[167]

In a randomized, double-blind, controlled trial, Brunoni et al found that the efficacy of transcranial direct current stimulation (tDCS) was comparable to that of sertraline (50 mg/day) in the treatment of major depression and that the combination of tDCS with sertraline was superior to sertraline alone. ^[168] There was a significant difference in depression rating scale score between, on one hand, the combined treatment group and, on the other, the sertraline-only (mean difference, 8.5 points), tDCS only (5.9 points), and placebo groups (11.5 points).

In 2019, the FDA approved a cranial electrotherapy stimulator (CES) for treatment of anxiety, depression, and insomnia. The prescription device delivers micro pulses of electrical current across the brain, which in clinical trials led to a reduction in anxiety levels, insomnia, and depressed mood. ^[169] It is the first CES integrated into noise-cancelling, Bluetooth-enabled headphones and the first CES managed through an app. ^[170]

In one third to two thirds of cases of depression, patients fail to remit with first-line therapy. ^{[120, 171]} No factors have been identified for reliably predicting whether an individual patient will respond. ^[171]

Assessment of patients with treatment-resistant depression should include consideration of the following:

• Accuracy of diagnosis and possible comorbid medical conditions

• Adequacy of medication dose and duration of treatment, as well as adherence to treatment regimen

• Possible comorbid psychiatric conditions (eg, substance abuse, anxiety disorders, personality disorders)

Assuming that the assessment of the diagnosis is correct, there are no significant complicating diagnoses, and the current treatment has been at a therapeutic dose for a sufficient amount of time, possible interventions for persistent symptoms can include the following ^[8] :

• Increasing the medication dose to the maximum tolerated

• Augmenting the current medication with another antidepressant

• Changing to a different antidepressant

• Adding psychotherapy or more intensive care if not already completed

• Considering the use of ECT

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the largest open-label trial to date, examined various strategies for treatment-resistant depression. The STAR*D trial showed that in patients who did not respond to an initial SSRI (citalopram), switching to another SSRI antidepressant, changing medication class, and switching to CBT were all equally effective treatments. Achieving remission, rather than partial response, was the best predictor of a better long-term prognosis. ^{[171, 172]}

The AHRQ found conflicting evidence regarding the differences between second-generation antidepressants for treatment-resistant depression. A good-quality study revealed no substantial differences in the effectiveness of sustained-release bupropion, sertraline, and sustained-release venlafaxine; however, fair-quality studies indicated a trend toward greater effectiveness with venlafaxine than with citalopram, fluoxetine, or paroxetine. ^[171]

Augmentation combinations can include the following:

• Bright-light therapy plus any antidepressant

• Buspirone (BuSpar) plus a TCA or SSRI

• Lithium (Eskalith, Lithane, Lithobid) plus any antidepressant

• Methylphenidate (Ritalin) or dextroamphetamine (Dexedrine) plus any antidepressant other than an MAOI

• TCA plus an SSRI

• Triiodothyronine (Cytomel) plus any antidepressant

The STAR*D trial found that augmentation of an SSRI with bupropion and augmentation with buspirone were equally effective after a lack of response to the SSRI. ^[171]

Aripiprazole (Abilify) is the first drug approved by the FDA for adjunctive treatment in major depressive disorder and the first drug to receive FDA approval for use in treatment-resistant depression. ^{[173, 174, 175]}

Esketamine nasal spray was approved by the FDA in March 2019 for treatment-resistant depression in conjunction with an oral antidepressant. It is administered in a physician’s office and the patient must be carefully monitored for at least 2 hours owing to risk of sedation, dissociation, and elevated blood pressure following the dose. 

Efficacy of esketamine was evaluated in 3 short-term (4-week) clinical trials and 1 longer-term maintenance-of-effect trial. In the short-term studies, patients were randomized to receive esketamine intranasal or a placebo nasal spray. Owing to the serious nature of treatment-resistant depression and the need for patients to receive some form of treatment, all patients started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. Primary efficacy was measured by the change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) used to assess the severity of depressive symptoms. In one of the short-term studies, esketamine nasal spray demonstrated statistically significant effect compared with placebo on the severity of depression, and some effect was seen within 2 days. The 2 other short-term trials did not meet the pre-specified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with esketamine intranasal plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant. ^{[115, 116]}

Conway et al studied 13 patients with treatment-resistant major depression (TRMD) who received 12 months of treatment with vagus nerve stimulation (VNS). ^{[176, 177]} Positron emission tomography (PET) brain imaging was performed before the initiation of stimulation and again 3 and 12 months after stimulation had begun.

Of the 13 patients in the study, 9 experienced improvement in depression with the VNS treatment. ^[177] Among those who responded, the PET scans showed changes in brain metabolism after 3 months of stimulation, but this occurred several months before any improvements in their symptoms of depression were noted.

Transcranial magnetic stimulation (TMS) has also been studied in treatment-resistant patients. In one trial of 307 patients with a primary diagnosis of unipolar, nonpsychotic major depressive disorder who had failed to receive benefit from previous antidepressant therapy, acute treatment with TMS resulted in symptomatic improvement in 62% of patients and complete remission in 41%. ^[178]

Of the 257 patients who entered a 12-month follow-up phase of the study, 68% achieved symptomatic improvement at 12 months and 45% reported complete remission. ^[178] Long-term maintenance therapy consisted of continuation of antidepressant medication and access to TMS reintroduction for symptom recurrence.

Increasingly, pediatric patients with depression have been treated with SSRIs or CBT. Fluoxetine is the only medication currently approved by the FDA for the treatment of depression in children. There are few studies on the use of medications for pediatric patients with major depressive disorder, and some of those that have been performed have methodologic problems. Additionally, very few pharmacokinetic studies have been performed in children, and most of those have focused on the effects of TCAs. ^[179] In adolescents, suicidality associated with antidepressants is an important issue.

The clinician needs to inform parents and patients about adverse effects, dose, timing of therapeutic effect, and danger of overdose, particularly with TCAs, before initiating pharmacologic treatment. Parents should take responsibility for medication storage and administration, especially with younger children and children at risk for suicide.

The Texas Children’s Medication Algorithm Project has created a consensus guideline for the treatment of major depression in pediatric patients that is based on evidence from scientific studies and the clinical expertise of the panel, which included child and adolescent psychiatry clinicians and research experts. ^[180] The guideline is as follows:

• For mild depression, CBT or interpersonal psychotherapy (IPT) is recommended first

• For pharmacologic therapy, SSRIs are the first-line choice

• If there is no response to the SSRI, switch to a second SSRI

In the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, patients who did not respond to an initial SSRI and were switched to combination therapy with CBT plus either another SSRI or venlafaxine had no better response than switching medications alone. ^[181] However, a switch to any second medication provided a good response, and each of the medications provided a similar response.

Selective serotonin reuptake inhibitors

The use of SSRIs as first-line medications in pediatric patients is supported by reports that these agents are effective in this population and have a relatively safe adverse-effect profile and very low lethality after overdose; in addition, SSRIs offer the convenience of once-daily administration. Several studies have reported a 70-90% response rate to SSRIs in adolescents with major depressive disorder. ^{[182, 183, 184]}

Children and adolescents with major depressive disorder responded significantly more frequently to fluoxetine (58%) than to placebo (32%), according to Emslie et al in an 8-week double-blind study. ^[185] However, only 31% of children achieved full remission. A possible explanation for the partial response in these young patients is that the effective treatment may involve variation in dose or length of treatment. Also, the ideal treatment likely involves a combination of pharmacologic and psychosocial interventions.

Except for lower initial doses, the administration of SSRIs in children and adolescents is similar to the treatment regimens used for adult patients. The clinician should treat patients with adequate and tolerable doses for at least 4 weeks. At 4 weeks, if the patient has not shown even minimal improvement, the clinician should consider increasing the dose. If, at this time, the patient shows improvement, the dose can be continued for at least 6 weeks. However, if no improvement is apparent at 6 weeks, other treatment strategies should be considered.

The clinician must cautiously apply the above recommendation; whether longer SSRI treatment increases the number of pediatric patients with late improvement is not clear. The Treatment of Adolescents with Depression Study (TADS) demonstrated significant increases in response to treatment over time (see Table 1, below). ^[186]

Table 1. Treatment Response Over Time in the Treatment of Adolescents with Depression Study (Open Table in a new window)

In TADS, suicidal ideation decreased less with fluoxetine therapy than with combination therapy or CBT. Suicidal events, but not actual suicides, occurred more often in patients receiving fluoxetine therapy (14.7%) than combination therapy (8.4%) or CBT (6.3%).

The SSRIs possess a relatively flat dose-response curve, suggesting that maximal clinical response may be achieved at minimum effective doses; therefore, adequate time must be allowed for clinical response, and frequent early-dose adjustments must be avoided. Blood levels are rarely indicated in clinical settings but may help clarify concerns about toxicity or compliance.

The adverse effects of all SSRIs in children are similar to those in adults; they are dose-dependent and may subside with time. SSRIs may induce mania, hypomania, and behavioral activation, in which patients become impulsive, silly, agitated, and daring. Other adverse effects include GI symptoms, restlessness, diaphoresis, headaches, akathisia, bruising, and changes in appetite, sleep, and sexual functioning. The long-term adverse effects of SSRIs are not yet known.

In December 2003, the UKMedicinesandHealthcareProductsRegulatoryAgency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of "depressive illness." After review, MHRA decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except for fluoxetine, which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.

A systematic review and meta-analysis by Tsapakis et al of randomized controlled trials of antidepressant therapy in young people with depression concluded that antidepressants of all types showed limited efficacy in juvenile depression. However, these researchers found that fluoxetine might be more effective, especially in adolescents. ^[184]

Antidepressants and suicidality in youths

In October 2003, the FDA issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. This advisory reported suicidality (both ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. The FDA asked that additional studies be performed, because suicidality occurred in both treated and untreated patients with major depression and, thus, could not be definitively linked to drug treatment.

In September 2004, the results of an FDA analysis suggested that the risk of emergent suicidality in children and adolescents taking SSRIs was real. The FDA advisors (Columbia University) recommended the following:

• A black-box warning label should be placed on all antidepressants, indicating that they increase the risk of suicidal thinking and behavior (suicidality)

• A patient information sheet (“Medication Guide”) should be provided to the patient and the patient’s caregiver with every prescription

• The results of controlled pediatric trials of depression should be included in the labeling for antidepressant drugs

The Psychopharmacologic Drugs and Pediatric Advisory Committees recommended that the products not be contraindicated, because access was important for those who could benefit from them. For more information, see the FDAStatementonRecommendations of thePsychopharmacologicDrugsand Pediatric AdvisoryCommittees.

Given the possibility of increased suicidality, the FDA recommended that physicians who prescribe antidepressants to pediatric patients provide close monitoring in these cases. Close monitoring includes at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment; visits every other week for the next 4 weeks; visit at 12 weeks; and then visits as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between office visits.

Some studies have shown that the FDA warnings regarding suicide in children on antidepressants may have had the unintended result of a decrease in the rates of diagnosis and treatment of depression, as well as dosing adjustments by physicians and an increase in suicidality. It has also been noted that monitoring of these patients did not increase following the warnings. ^{[187, 188]}

Antidepressants were associated with a significant reduction in the risk of suicidal behavior in observational study by Leon et al, which followed 757 patients over a 27-year period. This study included participants with psychiatric and other medical comorbidity and those receiving acute or maintenance therapy, polypharmacy, or no psychopharmacologic treatment at all. ^[189] The results suggest, however, that clinicians must closely monitor patients when an antidepressant is initiated.

Other studies have argued that a decline in youth suicide rates coincided, to a striking extent, with significant increases in the prescription of antidepressants (mostly SSRIs) to adolescents. ^{[190, 191, 192]} The Treatment for Adolescents with Depression Study (TADS) lends support for fluoxetine's efficacy in adolescent depression, notably the combined use of fluoxetine and CBT. ^[193] Data from the TADS study also suggested a possible protective effect of CBT against suicidality when used in combination with fluoxetine.

Additionally, a study by the Group Health Cooperative in Seattle of more than 65,000 children and adults treated for depression found that suicide risk declines, not rises, with the use of antidepressants. ^[194] This is the largest study to date to address this issue. This study also showed that with psychotherapy and antidepressant drug therapy, the highest risk of suicide was in the month prior to seeking treatment. The month following initiation of treatment was also a period of high risk for both types of treatment, emphasizing the importance of close follow-up after treatment initiation.

Tricyclic antidepressants

TCAs are no longer considered the first-line treatment for pediatric patients with depressive disorders; however, individual cases may respond better to TCAs than to other medications. TCAs may also be useful for those with comorbid attention deficit hyperactivity disorder (ADHD), enuresis, and narcolepsy, as well as for augmentation strategies.

The TCAs require a baseline electrocardiogram (ECG), resting blood pressure, and pulse rate. Because of the potential of the TCAs to induce a fatal overdose, the clinician must carefully determine the exact amount of medication to be prescribed. Plasma levels should be monitored to measure compliance and to avoid toxicity. In addition, weight should be frequently documented.

No laboratory tests are currently indicated before or during the administration of the SSRIs. No other tests are indicated in a healthy child before starting antidepressants.

Although avoiding the use of medication during pregnancy is preferable, the benefits of prompt medical treatment of major depressive disorder may often outweigh the risks of exposure of the fetus to an antidepressant. One meta-analysis found that the possible risks of untreated peripartum depression include increased risk of preterm birth, low birth weight, slower head growth, and intrauterine growth restriction. ^[195] There is no clear evidence that available antidepressants are teratogenic.

APA guidelines support psychotherapy as the first choice of therapy for pregnant women with mild depression. ^[8] In severe depression during pregnancy, especially in cases of psychosis, agitation, or severe retardation, electroconvulsive therapy may be the safest and quickest treatment option. One randomized, double-blind study found that bright-white-light therapy was significantly more effective than placebo for depression during pregnancy. ^[161]

Conflicting evidence exists regarding the use of SSRIs during pregnancy and an increased risk of persistent pulmonary hypertension of the newborn (PPHN). An initial Public Health Advisory in 2006 was based on a single retrospective study. Since then, studies have yielded conflicting findings, with 3 trials suggesting risk and 3 trials finding no risk of PPHN associated with antidepressants. ^{[196, 197]}

In a December 2011 review, the FDA concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN. The FDA advises health care professionals not to alter their current clinical practice of treating depression during pregnancy and to report any adverse events to the FDA MedWatch program. ^[198]

A further possible risk for infants born to women taking SSRIs is neonatal withdrawal symptoms, which includes high-pitched crying, tremors, and disturbed sleep. In one study, 30% of neonates exposed to SSRIs in utero developed withdrawal symptoms, typically peaking within 2 days of birth but sometimes as long as 4 days after birth. ^[199] These investigators recommended monitoring exposed neonates for as long as 48 hours after birth.

Principles of treatment of postpartum major depressive disorder are the same as for depression during any other time of life. Earlier initiation of treatment is associated with better prognosis. ^[200]

A Cochrane review of 28 trials involving approximately 17,000 women concluded that psychosocial and psychological interventions can significantly reduce the number of women who develop postpartum depression. Women who received interventions including intensive, individualized postpartum home visits by nurses and midwives; peer-based telephone support; and interpersonal psychotherapy had an average risk ratio of 0.78, compared with women who received standard care.

Patients with postpartum depression should be assessed for danger to herself or to her children, as well as for other symptoms such as psychosis or substance abuse. Most antidepressants probably can be used safely during breast-feeding; however, this has not been studied thoroughly, and the same risk-benefit considerations should be applied as when treating depression during pregnancy. ^[201]

Postpartum blues are typically mild and resolve spontaneously; no specific treatment is required, other than support and reassurance. For first episodes of depression in postpartum women, 6-12 months of treatment is recommended. For women with recurrent major depression following pregnancy, long-term maintenance treatment with an antidepressant is indicated. ^[202]

Antidepressants and Breast-feeding

Most antidepressants probably can be used safely during breast-feeding; however, this has not been studied thoroughly, and the same risk-benefit considerations should be applied as when treating depression during pregnancy. ^[201]

Women who plan to breast-feed must be informed that antidepressants, like all psychotropic medications, are secreted into breast milk. Concentrations in breast milk vary widely. ^[203] Data on the use of TCAs, fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) during breast-feeding are encouraging, and serum antidepressant levels in the breast-fed infant are either low or undetectable. Reports of toxicity in breast-fed infants are rare, although the long-term effects of exposure to trace amounts of medication are not known. ^[85]

Antidepressants and the Elderly

Geriatric psychopharmacology follows the tenet of "start low, go slow, but go." This is based on the belief that elderly patients respond to such agents more slowly than younger patients and the fact that older patients tend to have a higher rate of side effects and adverse events from drug-drug or drug-disease interactions.

Most classes of medications have been associated with an increased risk of falls in elderly patients, especially the frail elderly. Furthermore, results from a study by Andreescu et al suggest that high levels of worry in elderly patients with depression were associated with slower response to pharmacotherapy and earlier recurrence. ^[204]

Start antidepressant medications at a lower dose (often, half the usual dose) in the elderly, and titrate more slowly than in younger adults. Furthermore, customary practice is to give the elderly patient a longer trial (12 wk vs customary 6-8 wk) before increasing the dose, changing the medication, or labeling it a failure. However, the need to wait 12 weeks remains a point of controversy and is undergoing more research.

In the elderly, drug-drug interactions are a concern with particular SSRIs because polypharmacy is common in this age group. Of the SSRIs, the likelihood of drug-drug interaction is highest with fluoxetine, paroxetine, and fluvoxamine. The specific interactions of these medications and medications commonly used in the elderly (eg, certain antibiotics, warfarin) are well established and available in many reference books.

SSRIs should be used in the elderly only with consideration by a physician familiar with these types of medications. The SSRIs that offer a lower likelihood of drug-drug interactions include escitalopram, citalopram, and sertraline. These medications should be used as first-line treatment in the elderly or in patients where drug-drug interaction is a concern.

Gastrointestinal side effects, including nausea, which can lead to weight loss, can be a problem in the elderly with use of SSRIs. Often, the nausea is short-lived, but when it is not, further options should be evaluated.

The value of pharmacologic treatment of refractory depression in geriatric patients remains uncertain. Cooper et al reviewed 14 studies of the management of depressive episodes that failed to respond to at least one course of treatment in patients aged 55 years and older. They found that half of the patients responded to further pharmacologic treatments; however, they noted that most of the studies had significant methodologic problems and that none were double-blind, randomized, placebo-controlled trials. ^[205]

If suicidality is present, hospitalization with the patient's consent or via emergency commitment should be undertaken unless there are clear-cut means to ensure the patient's safety while outpatient treatment is begun. A child who is suicidal or has made an attempt at suicide should be admitted to a protected environment until all medical and social services can be employed.

In addition to suicidal or homicidal ideation, indications for psychiatric hospitalization include the following:

• Severe depression

• Gross disorganization

• Inability to care for self (ie, inability to provide basic needs such as eating, drinking, and other activities of daily living)

• Failing medical status due to depression

Diet plans

The low-sodium Dietary Approaches to Stop Hypertension (DASH) diet, previously shown to reduce hypertension and stroke risk, may also help ward off depression. Besides being low in sodium, the diet is rich in fruits, vegetables, whole grains, and low-fat dairy foods. A study found that participants who most closely adhered to the diet were 11% less likely to become depressed over time than those least adherent to the diet. ^[206]

The Mediterranean diet, which emphasizes fish, fruits, and vegetables, with olive oil as the main source of fat, protects cognition and can improve mental health in individuals with depression. ^{[206, 207, 208]}

The MIND diet is a combination of the Mediterranean and DASH diets and has also been shown to preserve brain health. It may be key in maintaining cognition and reducing dementia risk. ^{[206, 209]}

Dietary restrictions

Dietary restrictions are necessary only when prescribing monoamine oxidase inhibitors (MAOIs). Foods high in tyramine, which can produce a hypertensive crisis in the presence of MAOIs, should be avoided. These foods include the following:

• Aged cheese

• Aged chicken or beef liver

• Air-dried sausage and similar meats

• Avocados

• Beer and wine (in particular, red wine)

• Canned figs

• Caviar

• Fava beans

• Meat tenderizer

• Overripe fruit

• Pickled or cured meat or fish

• Raisins

• Sauerkraut

• Shrimp paste

• Sour cream

• Soy sauce

• Yeast extracts

Physical activity and exercise contribute to recovery from major depressive disorder. Patients should be counseled regarding stress reduction.

SSRIs

Clinically significant hyponatremia may develop in elderly patients taking SSRIs. In addition to older age, risk factors include the following ^[210] :

• Female gender

• Smoking

• Low body weight

• Tumors

• Respiratory or CNS illnesses

• Previous episodes of hyponatremia

• Concomitant use of other medications (particularly diuretics)

• Antidepressant-induced hyponatremia occurs through the syndrome

of inappropriate secretion of antidiuretic hormone (SIADH), resulting in an euvolemic hyponatremia with low serum and high urine osmolalities. The hyponatremia generally starts within 1 month after starting the medication, and it reverses within a month after discontinuing the medication. Monitoring the sodium level in the elderly for at least 1 month after commencing an SSRI is suggested.

Although SSRIs do not have the same risk of cardiac arrhythmia as is present with TCAs, arrhythmia risk is especially pertinent in overdose. In addition, suicide risk must always be considered, especially when treating a child or adolescent with mood disorder.

Suicidality

A small number of case reports, such as those by King et al ^[211] and Teicher et al, ^[212] have described a putative association between SSRI administration and increased suicidality (perhaps linked to behavioral activation or akathisia). However, although such phenomena may have occurred in a small number of cases, several studies suggest that SSRIs, like other antidepressants, generally reduce the risk of suicide in adult patients who are depressed.

Stroke

A large-scale study that followed more than 80,000 women aged 54-79 found that women who suffer depression and use antidepressants face an increased risk of stroke. The hazard ratio for stroke was 1.29 for women with a history of depression. ^[213] A systematic review and meta-analysis of prospective studies found a hazard ratio of 1.45 for total stroke and 1.55 for fatal stroke. ^[214]

Withdrawal symptoms

Abrupt discontinuation of SSRIs that have shorter half-lives, such as paroxetine, may induce withdrawal symptoms, some of which may mimic a recurrence of a depressive episode (eg, tiredness, irritability, severe somatic symptoms). The withdrawal symptoms can appear after as few as 6-8 weeks of SSRI treatment. In addition to causing rebound depression, paroxetine discontinuation can also cause cholinergic rebound. Moreover, relapse may occur earlier after rapid withdrawal (< 15 days) than after more gradual withdrawal (≥ 15 days). ^[215]

Interactions with other drugs

Awareness of possible interactions with other medications is important. To varying degrees, but especially for fluvoxamine, the SSRIs inhibit the metabolism of several medications that are metabolized by the diverse clusters of hepatic cytochrome P-450 isoenzymes (eg, TCAs, neuroleptics, antiarrhythmics, benzodiazepines, carbamazepine, theophylline, warfarin, terfenadine [removed from United States market]). This inhibition results in higher plasma levels of those agents.

In addition, interactions of SSRIs with other serotonergic medications, particularly MAOIs, may induce the serotonergic syndrome, marked by agitation, confusion, and hyperthermia. SSRIs also have a high rate of protein binding, which can lead to increased therapeutic or toxic effects of other protein-bound medications. MAOIs should not be administered less than 5 weeks after discontinuation of fluoxetine and less than 2 weeks after discontinuation of other SSRIs. Also, the clinician should not prescribe SSRIs within 2 weeks after stopping the MAOIs.

Tricyclic antidepressants

The adverse effects of TCAs, which result largely from their anticholinergic and antihistaminic properties, include the following:

• Sedation

• Confusion

• Dry mouth

• Orthostasis

• Constipation

• Urinary retention

• Sexual dysfunction

• Weight gain

Caution should be used in patients with cardiac conduction abnormalities.

Bupropion is associated with a risk of seizure at doses above 450 mg a day, especially in patients with a history of seizure or epileptic disorders. This risk appears much lower in the sustained-release bupropion preparations.

Mirtazapine is a potent antagonist at 5-HT2, 5-HT3, alpha2-, and histamine (H1) receptors and, thus, can be very sedating and frequently causes weight gain. Adverse effects such as drowsiness may tend to improve over time and with higher doses. Trazodone is very sedating and usually is used as a sleep aid in small doses (ie, 25 to 50 mg) rather than as an antidepressant.

Nelson et al demonstrated that although adjunctive atypical antipsychotics (risperidone, olanzapine, quetiapine) were significantly more effective than placebo for augmenting therapy in major depressive disorder, discontinuance of therapy because of adverse events was higher for atypical antipsychotics than for placebo. ^[216]

Consultation can be important at many stages of the treatment process. Certainly, treating physicians should seek consultation if they exhaust the options with which they feel comfortable.

A psychiatrist must be involved in the care of patients in whom more severe symptoms develop and for whom a more intensive level of care will be needed (eg, suicidal ideation, psychosis, mania, severe decline in physical health). Expertise in pharmacotherapy, other somatic therapies, and psychotherapy should be readily available.

Collaboration of psychiatrists and family practitioners/internists is of particular importance in patients with acute and chronic medical issues. A psychologist can be involved if psychological testing or more intensive specialized psychotherapy (eg, interpersonal therapy, cognitive-behavioral therapy) is needed.

Structured care in which nonmedical specialists augment primary care may offer an improved model. The use of an allied health professional supervised by a psychiatrist integrated into the primary care treatment of depression has been shown to double rates of adherence to antidepressants and significantly improve response to depression treatment. ^[217]

With the patient's consent, communication with the patient's therapist can be invaluable in guiding medical treatment of major depressive disorder. The therapist can provide information regarding clinical progress, symptoms, and adverse effects. This can facilitate timely and appropriate medical interventions.

Observe patients at least monthly. Patient factors influencing the follow-up schedule include the following:

• Clinical status

• Functioning

• Support systems

• Environmental stressors

• Motivation for treatment

• Comorbid psychiatric or other medical disorders

• Treatment adherence

Medications should be reevaluated for drug-drug or drug-disease state interactions at every visit, as well as reevaluated for efficacy every 8-12 weeks. Nonresponse to treatment should raise the possibility of alternative diagnoses or alternative treatment.

Monitoring of mood and treatment response can be done during the clinical interview with use of the screening tools mentioned earlier (see Presentation) and, in pediatric or elderly patients, with collateral interviews with the family or caregiver. The 2011 APA guideline supports the use of rating-scale tools such as the PHQ-9 for evaluating the ongoing success of the treatment plan. ^[8]

The patient’s functional status and ability to perform activities of daily living should be evaluated at every visit. Suicidal ideation should be evaluated at each visit and between visits when indicated.

Psychotherapy can be used not only to consolidate the skills learned during the acute phase of treatment and help patients cope with the psychosocial sequelae of the depression but also to address the antecedents, contextual factors, environmental stressors, and intrapsychic conflicts that may contribute to a relapse. If the patient is taking antidepressants, psychotherapy can be used to foster medication compliance. In adolescents, one study suggested that monthly cognitive-behavioral therapy sessions may be effective to prevent relapses of depression. ^[218]