Major depressive disorder (MDD) is an episodic, frequently recurring syndrome. The diagnosis requires that five of nine criteria be present for 2 wk. One of these nine criteria must be either a persistent depressed mood or pervasive anhedonia (loss of interest or pleasure in all, or almost all, usual interests or activities). Other symptoms include sleep disturbance (insomnia, hypersomnia, or interrupted sleep), appetite loss/gain or weight loss/gain, fatigue, psychomotor retardation or agitation, difficulty concentrating or indecisiveness, feelings of guilt or worthlessness, and recurrent thoughts of death or suicidal ideation.

MDD

Unipolar affective disorder

Clinical depression

Melancholia

Manic-depressive illness, depressed type

Depressive episode

Codes depend on whether the episode is single or recurrent, and also on clinical severity.

• Clinical evaluation facilitated by organizing the major symptoms into four hallmarks: (1) Depressed mood, (2) anhedonia, (3) physical symptoms (sleep disturbance, appetite problem, fatigue, psychomotor changes), and (4) psychologic symptoms (difficulty concentrating or indecisiveness, guilt or worthlessness, and suicidal ideation).
• A stressful life event, typically a serious loss, may trigger a depressive episode. DSM-5 recommends that clinical judgment be used to determine if depression in the context of a loss should be diagnosed as a major depressive episode vs. normal grief or adjustment disorder.
• Somatic complaints such as pain, fatigue, insomnia, dizziness, headache, or gastrointestinal problems occur in more than two-thirds of patients presenting to primary care with underlying depression.
• Comorbid psychiatric disorders are often present. Anxiety disorders are the most common comorbid conditions.
• Subtypes of depression include those with psychotic features. May be associated with mood-congruent delusional thinking (paranoid and melancholic themes).
• May be associated with active or passive suicidal ideation.
• May be underdiagnosed in elderly patients, with signs and symptoms attributed to normal aging or cognitive impairment.
• May be underdiagnosed in medically ill patients, with signs and symptoms attributed to medical illness or considered appropriate reaction to medical condition.

• A heterogeneous group of disorders probably arising from various etiologies.
• Genetic and environmental experiences, and their interaction, each contribute.
• Significant psychosocial stressors, including losses, trauma, and ramifications of adverse childhood events, often trigger depression, particularly for first episodes.
• Numerous biologic correlates have been identified, though none is considered causative or diagnostic. Genes that influence the production and reuptake of serotonin, norepinephrine, dopamine, and glutamate, as well as nerve cell growth in brain regions underlying memory and emotional processing, are of greatest interest. Abnormalities in brain regions underlying executive functioning, emotion regulation, and reward processing, as well as irregularities in functional connectivity have been identified. Irregularities in cortisol responding and inflammation also may play a role.
• Cognitive risk factors include a pessimistic style of explaining negative events, a tendency to ruminate, and biases in processing emotional information and events.

• Time-course and symptomatology can distinguish MDD from persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, and substance-induced mood disorder.
• Anxiety disorders, posttraumatic stress disorder (PTSD), obsessive compulsive disorder, substance abuse, and personality disorders often present with depressive symptoms or coexist with major depressive disorder.
• Important to determine if a depressive episode is part of major depression or part of bipolar disorder, which entails carefully screening for a history of manic symptoms.
• Important to distinguish from adjustment disorder. Depression in the context of a stressful life event is diagnosed as major depressive disorder if the symptom criteria are met and adjustment disorder if the symptom criteria are not met. Psychotherapy, rather than medication, is the treatment mainstay for adjustment disorder.
• Demoralization can overlap significantly with MDD, including prominent neurovegetative symptoms. Demoralization frequently lacks anhedonia and is directly related to an ongoing stressor (like a medical illness) from which escape is not seen as likely.
• Grief and bereavement can overlap with MDD. If symptoms meet criteria for MDD, MDD should still be diagnosed even in the setting of recent loss.
• Approximately 10% to 15% of depression is caused by general medical illnesses, such as Alzheimer disease, Parkinson disease, stroke, end-stage renal failure, cardiac disease, HIV infection, and cancer.⁶
• Some medical conditions can present with depressive symptoms (e.g., hypothyroidism, hyperthyroidism, pancreatic cancer, and neurosyphilis).
• Depression can coexist with dementia, though depression-related cognitive dysfunction (formerly known as “pseudodementia”) must also be considered in such populations.

• Careful medical history is required to rule out nonpsychiatric etiology. Tables 1, 2, and 3 summarize common psychologic/cognitive, behavioral, physical, and somatic symptoms encountered in unipolar depressive disorders.
• Physical examination reveals no specific diagnostic signs of depression, though psychomotor changes can be observed.
• Mental status examination.
• Self-report scales can assist in screening.
• Commonly used validated screening tools include the 15-item Geriatric Depression Scale in the elderly and the Patient Health Questionnaire (PHQ)-2 and PHQ-9. The PHQ-2 has a 97% sensitivity and 67% specificity in adults. If it is positive for depression, the PHQ-9 should be administered. The PHQ-9 has a 78% sensitivity and 87% specificity for depression in adults.⁷

• Research is underway to identify biomarkers that may be useful in diagnosis; no laboratory studies are diagnostic at present.
• The following can assist in ruling out other confounding issues:
  1. Routine blood chemistry evaluation
  2. CBC with differential
  3. Thyroid function studies
  4. Vitamin D and B₁₂ levels

With unusual presentations (e.g., associated with new-onset severe headache, focal neurologic signs, a cognitive or sensory disturbance), the following may be performed:

• Electroencephalogram (EEG) (diffuse slowing indicates metabolic encephalopathy)
• Anatomic brain imaging (computed tomography scan or MRI)

• Good evidence exists that cognitive-behavioral therapy (CBT) is as effective as antidepressant medication in achieving significant reduction or remission (Table 4). Meta-analysis indicates that combining psychotherapy with medication is modestly more effective than either modality alone.⁸
• Problem-solving and interpersonal psychotherapies are comparably efficacious.
• Various forms of CBT (e.g., acceptance and commitment, mindfulness-based [MBCT], and dialectical behavioral [DBT]), as well as traditional CBT, have demonstrated efficacy in numerous studies.
• Growing evidence indicates that internet-based CBT and brief therapy interventions integrated into primary care to expand access to therapy are efficacious, with some studies finding comparable efficacy to standard length interventions.
• By 12 wk or earlier, psychotherapy and medication approaches are equally effective.
• Augmentation of standard depression treatment with CBT to address insomnia was found to significantly improve response rates.
• Official treatment guidelines recommend that medication be used as the first-line treatment for patients with severe depression, although some studies have found equal efficacy of medication and psychotherapy in the treatment of severe depression.
• Factors, including history of adverse childhood events, presence of precipitant stressful life events, family psychiatric history, the presence of anhedonia, and depression severity, may affect treatment response and risk of recurrence. Numerous genetic and neurobiologic variables that predict treatment response have been identified, particularly in combination with one another or with clinical characteristics. However, at present, there are no universally accepted markers that can aid clinicians in matching individuals to specific medications or interventions.

• Concurrent medical or psychiatric illnesses, history of prior response, cost, patient preference, and side effects should be considered when selecting initial treatment.
• Antidepressants are helpful in approximately 60% to 70% of cases, though sustained remission rates are lower.⁵
• Selective serotonin reuptake inhibitors (SSRIs) are generally first line. According to the Sequenced Treatment Alternatives to Relieve Depression (STAR-D) trial, approximately 30% achieve remission with the first prescribed medication after 3 mo of treatment.⁵ Another 25% to 30% respond to treatment but do not achieve remission. Treatment-refractory patients may be switched to another SSRI or another class of medication may be more helpful, offered adjunctive medication such as bupropion, or referred for evidence-based counseling. Approximately 25% more patients will achieve remission with this secondary intervention.
• According to a network meta-analysis of 21 antidepressants, escitalopram, mirtazapine, paroxetine, and sertraline had higher response and lower dropout rates than other antidepressants, and all antidepressants were more effective than placebo.⁹
• Response to antidepressants for many patients is seen as early as 2 wk, and among patients showing little to no response, the odds of later response decrease the longer patients remain unimproved. Conversely, rapid response to treatment predicted improved outcomes in multiple studies.
• Antidepressants may transiently increase suicidality and aggression in patients under 25, an important side effect to discuss prior to treatment initiation. Other side effects include gastrointestinal distress, sexual dysfunction, sleep disturbance, and weight gain. Characteristics of antidepressant drugs are summarized in Table 5.
• To date, there are no data to support combining antidepressants as first-line treatment. There is also no clear advantage to switching medications within vs. across different classes, or to switching vs. augmentation. The Veterans Affairs (VA) Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) trial found that switching to the antipsychotic aripiprazole resulted in statistically significant, though modest, improvement in remission rates compared with switching or augmenting with an antidepressant, although greater side effects resulted.¹⁰
• Treatment should be continued for 4 to 9 mo after the full remission of depressive symptoms.¹⁰
• Electroconvulsive therapy (ECT) is the most effective means available for the treatment of severe, refractory depression. Transcranial magnetic stimulation (TMS) has also shown evidence of efficacy, though the magnitude of effects is more variable and overall smaller than ECT. Research is underway to investigate mechanisms to increase the efficacy of TMS.¹¹
• Antipsychotic medication should be added for psychotic depression. Antipsychotic medication has also been shown to be helpful in augmenting antidepressants for nonpsychotic depression, and it may be beneficial for individuals with mixed manic-depressive features, although more research is needed.
• Ketamine intravenous has been found to be rapidly effective in treatment-resistant and suicidal depression.¹² Intranasal esketamine (Spravato) is approved for use in treatment-resistant depression. Further research is needed to determine whether positive effects are maintained, as effectiveness appears to fade without repeated use.
• Early data from open-label trials of psilocybin for treatment-resistant depression suggest sustained improvement of depressive symptoms at 3 and 6 mo, though the first randomized trial directly comparing psilocybin vs. conventional pharmacologic treatment for depression did not show a significant difference.¹³

Long-term treatment, in some cases lifelong, is recommended for multiple depressive episodes, an episode duration longer than 2 yr, a severe episode or significant suicidality, or a strong family history of severe depression or bipolar disorder.

St. John’s wort (Hypericum perforatum) is sold as a dietary supplement in the United States and is used for depression in the community. It is not consistently effective and should not be used in combination with antidepressants given the possibility of severe serotonin-related side effects, as well as effects on the metabolism of other drugs.

• Major depression is often a relapsing and remitting illness.
• Additional episodes are experienced by >50% of patients after one episode, with each additional episode linked to increased risk for subsequent episodes.⁵
• Without treatment, episodes last an average of 6 to 12 mo; risk of recurrence higher without treatment.⁵
• For many depressed individuals, subthreshold residual symptoms are present between episodes and define the majority of an individual’s course of depression. Such symptoms may lead to impairment and warrant prolonged treatment.

• If treatment-refractory
• If patient is suicidal or psychotic
• For suspected bipolar depression

• All threats of suicide should be taken very seriously. Clinicians can use the mnemonic SAL: Is the method specific? Is it available? Is it lethal?
• Rule out bipolar affective disorder before initiating antidepressant medication. Screening scales for bipolar disorder can be helpful in primary care settings to identify patients at increased risk for bipolar disorder. Antidepressants can induce mania in susceptible patients.
• Comorbid or diagnostically-related entities such as OCD, generalized anxiety, and PTSD, while sometimes difficult to differentiate from MDD, share similar pharmacologic and therapy-based treatment principles.
• Various rating scales (e.g., Montgomery-Asberg Depression Rating Scale [MADRS], Hamilton Rating Scale for Depression [HAM-D] [Table 6], Beck Depression Inventory [BDI] [Table 7]) are available for diagnostic screen to measure improvement over time.
• A two-question screener (PHQ2) is as effective as longer instruments.¹⁴ A positive answer to either question warrants a full assessment.
  1. Over the past 2 wk, have you ever felt down, depressed, or hopeless?
  2. Over the past 2 wk, have you felt little interest or pleasure in doing things?
• Depression screening programs without treatment programs are unlikely to improve depression outcomes.
• Strict monitoring of patients who initiate antidepressant therapy is necessary both for safety and to ensure optimal treatment. Use of self-report scales to measure symptom severity is helpful in monitoring outcomes and may result in improved outcomes.

Depression (Patient Information)

Bipolar Disorder (Related Key Topic)