Depression

Depression is the most common psychiatric disorder in adults. You will encounter patients with depression on the wards and in the outpatient setting. In both situations, but particularly in the outpatient setting, screening for depression is important because it is often undiagnosed, and consequently, untreated. Depression is associated with poorer health outcomes and is a leading cause of disability. In this section, we cover screening, diagnosis, and treatment of depression as well as suicidality and late-life depression.

Screening

The U.S. Preventive Services Task Force (USPSTF) recommends screening for depression when staff-assisted depression-care supports are in place to assure accurate diagnosis, effective treatment, and follow-up. Several screening tools exist, including the following:

• The Patient Health Questionnaire-2 (PHQ-2): Screening Instrument for Depression

• The Patient Health Questionnaire-9 (PHQ-9): Screening Instrument for Depression

The PHQ-2 is an initial, brief screening tool to identify the frequency of depressed mood and anhedonia over the past 2 weeks and includes the first two items of the PHQ-9. Patients who screen positive on the PHQ-2 should then be evaluated with the PHQ-9 to determine if they meet the criteria for a depressive disorder.

Diagnosis

The following table provides a summary of The Diagnostic and Statistical Manual of Mental Disorders, fifth edition, text revision (DSM-5-TR) criteria for diagnosis of major depressive disorder:

Treatment

Treatment of major depressive disorder includes both psychotherapeutic and pharmacologic approaches.

• Moderate-to-severe symptoms or history of a positive response to antidepressant therapy may suggest the use of medication treatment.

• Co-occurring disorders, significant stressors or psychological factors, or history of a positive response to psychotherapy may suggest the use of psychotherapeutic treatment.

• The American Psychiatric Association (APA) recommends the following modalities for acute treatment of major depressive disorder based on illness severity:

  • mild-to-moderate severity: pharmacotherapy, depression-focused psychotherapy, or both; electroconvulsive therapy (ECT) for certain patients

  • severe depression without psychotic features: pharmacotherapy with or without depression-focused psychotherapy; ECT

  • severe depression with psychotic features: pharmacotherapy with both antidepressant and antipsychotic medications with or without depression-focused psychotherapy; ECT

Antidepressants

Antidepressant medications have been a mainstay of treatment for moderate-to-severe depression. The choice of treatment depends on associated side effects, the presence of coexisting conditions, specific symptoms, and the patient’s history of response.

The classes of antidepressants are:

• First-generation

  • tricyclic antidepressants (TCAs; e.g., amitriptyline)

  • monoamine oxidase inhibitors (MAOIs)

• Second-generation

  • selective serotonin-reuptake inhibitors (SSRIs; e.g., fluoxetine, paroxetine)

  • serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine, duloxetine)

  • dopamine re-uptake inhibitors (e.g., bupropion)

  • 5-HT2 receptor antagonists (e.g., nefazodone)

  • other (e.g., bupropion, mirtazapine and trazodone-dopamine reuptake inhibitor, noradrenergic and specific serotonergic antidepressant, and serotonin antagonist and reuptake inhibitor)

The following table summarizes first-line antidepressant medications for major depressive disorder:

(Source: Depression in the Primary Care Setting. N Engl J Med 2019.)

TCAs and MAOIs: In recent years, these first-generation antidepressants have been prescribed less often than SSRIs/SNRIs because of the perceived undesirable side-effect profiles, potential for drug interactions, and potential lethality of overdose.

SSRIs and SNRIs: These classes of second-generation antidepressants are first-line treatment for moderate-to-severe depression; however, no single antidepressant or class of antidepressants has proven more efficacious than others in clinical trials. Selection of an antidepressant is often based on safety, side-effect profile, and cost.

Efficacy and Safety of Antidepressants

Second-generation antidepressants have laid the foundation of treatment for major depressive disorder. Meta-analyses of the comparative efficacy and safety of second-generation antidepressants have had conflicting results. A 2011 meta-analysis showed no significant difference in efficacy among second-generation antidepressants in the treatment of major depressive disorder, challenging the result of an earlier meta-analysis that found some differences. In a more recent 2018 meta-analysis, all 21 first- and second-generation antidepressant drugs examined were more effective than placebo in adults with major depressive disorder. Given the likelihood of similar efficacy among second-generation antidepressants, treatment choice is often based on dosing frequency, side-effect profile, and cost.

A reported 15% to 23% of patients experience depressive episodes following acute myocardial infarction or unstable angina. In 2002, the double-blind, randomized, placebo-controlled SADHART study evaluated the efficacy and safety of sertraline in patients with major depressive disorder following acute coronary syndrome (ACS) and found no significant differences in cardiac safety between patients treated with sertraline or placebo. The study was not designed to detect differences in depression scores. The American College of Cardiology has published an expert analysis of antidepressant prescribing in cardiovascular disease.

Antidepressants are associated with significant side effects and potential interactions with other medications. Common drug interactions with antidepressants are important to note when starting new medications in hospitalized patients who are already taking antidepressants. One potentially severe adverse effect associated with SSRIs and SNRIs is the serotonin syndrome.

The serotonin syndrome is the most serious consequence of drug interactions related to antidepressants. Signs of excess serotonin range from tremor and diarrhea in mild cases to delirium, neuromuscular rigidity, and hyperthermia in life-threatening cases. The spectrum of clinical findings is demonstrated in the following figure:

(Source: The Serotonin Syndrome. N Engl J Med 2005.)

Many medications that target psychiatric and nonpsychiatric symptoms can be associated with the serotonin syndrome, as detailed in the table below. When initiating a new serotonergic drug, be aware of recently used agents that are no longer on a patient’s medication list. Medications with long half-lives or prolonged activity (e.g., the SSRI fluoxetine and MAOIs) can precipitate the serotonin syndrome days or weeks after they are discontinued.

(Source: The Serotonin Syndrome. N Engl J Med 2005.)

Other Treatments for Depression

• Lithium, lamotrigine, and atypical antipsychotic agents (e.g., quetiapine and lurasidone) are sometimes prescribed for treatment of depression in patients with bipolar disorder (bipolar depression). An estimated 20% of patients with clinical depression have bipolar disorder.

• ECT and other neurostimulation modalities (e.g., transcranial magnetic stimulation and deep-brain stimulation) can be highly effective in certain patients, including those with treatment-refractory or treatment-resistant depression.

• Esketamine and ketamine are also used for treating treatment-resistant depression in adults.

Late-Life Depression

Older adults are at increased risk for depression. Therefore, careful evaluation of this population is important, keeping in mind the following key points:

• Late-life depression (age ≥60 years) is common and often associated with coexisting medical illness, cognitive dysfunction, or both.

• The inflammation hypothesis is a prominent theory to explain the biology behind late-life depression. It suggests that age-related changes lead to a chronic proinflammatory environment over time. This inflammatory process, along with increases in peripheral immune responses and disruption of the periphery-brain communication mechanisms, leads to dysregulation of brain responses, particularly with respect to serotonin and glutamate.

• The severity of depression and presence of cognitive symptoms have been associated with a chronic proinflammatory state with elevated peripheral markers of inflammation.

• Depressed older adults are at increased risk for suicide.

• A positive screening result should be followed by a thorough evaluation to assess patient safety and ensure that treatment is warranted.

Treatment of late-life depression: Pharmacotherapy or psychotherapy are first-line treatments in older patients with moderate levels of depression. Standardized psychotherapy techniques are effective in older adults with depression. Patients with more-severe depression should receive pharmacotherapy.

• Currently available antidepressants are effective in depressed older populations, but older adults may be at increased risk for medication side effects and often require lower doses.

• SSRIs are considered first-line pharmacotherapy.

• When antidepressants fail to achieve a response, augmentation with lithium or aripiprazole may improve effectiveness.

• ECT is associated with faster remission than medication in the elderly and may be the most effective modality for treatment of severe late-life major depression.

• See a summary table of evidence-based and novel therapies for the treatment of late-life depression.

Suicidality

Evaluation of depression should include assessment of warning signs as well as risk factors for suicide, including suicidal thoughts, intent, or plan.

Urgent warning signs associated with suicide

• intense negative emotion and escalating psychological pain

• feelings of being irreversibly trapped or abandoned

• increasing frequency and intensity of suicidal preoccupations and ideation

• giving away one’s possessions

• specificity of suicide plans

Risk Factors

The risk factors associated with suicide can be genetic, psychological, and personality-based; can occur at the individual and community level; and can be present at different times throughout life.

The strength of the association between each risk factor and suicide is indicated by the shading (darker shading indicates a stronger association). (Source: Suicide. N Engl J Med 2020.)

Assessment of Suicide Risk

The following table summarizes the various tools for evaluating suicide risk:

(Source: Suicide. N Engl J Med 2020.)

Suicide Prevention

Risk-mitigation and safety-planning suicide-prevention strategies that have been advocated worldwide include:

• careful assessment

• ongoing monitoring

• psychological and psychosocial interventions

• pharmacological interventions

In a systematic review of suicide prevention strategies, no one method emerged as the most successful intervention; however, a more recent systematic review showed a modest benefit from cognitive behavioral and dialectical behavior therapy in reducing suicidal ideation. Although meta-analyses have indicated that antidepressants prevent suicide attempts, individual randomized controlled trials appear to be underpowered. Among pharmacological modalities being explored for prevention of suicide, ketamine has been shown in both meta-analyses and randomized control trials to be particularly effective in the reduction of suicidal ideation, based on both clinician- and patient-reported assessments. Lithium has been shown to actually reduce suicide rates, as compared with placebo.

Targeted suicide-prevention interventions acknowledge differences in stressors and risk factors for subgroups of patients at high risk for suicide, as described in the following table:

(Source: Suicide. N Engl J Med 2020.)