In 2020, 18.4% of U.S. adults (one in five) reported having ever been diagnosed with depression. The prevalence of depression was higher in women, younger adults, and adults with lower education levels. Estimates of an ever diagnosis of depression ranged from 12.7% in Hawaii to 27.5% in West Virginia. Age-standardized county-level prevalence estimates ranged from 10.7% to 31.9%, with considerable state- and county-level variability [6]. Reports that focused on measures of current depression (i.e., during the prior two weeks) rather than on lifetime depression showed similar subgroup differences, including those observed both before and throughout the SARS-CoV-2 2019 (COVID-19) pandemic. Reporting from 2020 forward suggests that the COVID-19 pandemic contributed to a worsening mental health crisis in the United States, especially among adolescents and young adults [7,8,9]. Depression is more common in persons with medical illnesses, with 11% to 36% of general medical inpatients fulfilling diagnostic criteria for MDD [10,11,12,13]. Depression also is two to three times more likely in individuals with chronic diseases, including diabetes, arthritis, and cardiovascular diseases [14].

MDD is among the most costly illnesses in the world. The cost of depression in the United States was estimated at $210.5 billion in 2010, a 21.5% increase from 2005 [23]. Approximately 50% of this figure was attributed to workplace costs, 45% to direct costs, and 5% to suicide-related costs [23,24]. The economic burden of MDD was an estimated $334 billion in 2019, an increase of more than 41% since 2010 [25]. The direct cost of treating depression accounted for only 38% of the overall economic burden, or $127.3 billion [25]. In 2019, indirect costs were estimated at $206.4 billion, which included $126.3 billion in workplace costs (i.e., unemployment, productivity loss, absenteeism, presenteeism, and disability). Even low-grade depression is associated with decreased work productivity [26]. Patients who do not achieve full treatment response use twice as many healthcare services, and cost employers almost four times as much as patients achieving remission [27]. Women with early-onset depression (before 22 years of age) often fail to graduate from college and earn substantially less income than women with later-onset depression or no depression [28]. In the United States, the annual cost of suicidal behaviors (attempts and deaths) was estimated to be $93.5 billion in 2016 [29]. Depression causes an estimated 200 million lost workdays each year at a cost to employers of $17 to $44 billion [30]. However, attempts to quantify such costs on a national scale are hampered by incomplete data, such as the under-reporting of suicides [31].

Several demographic/socioeconomic, psychosocial, familial, medical, and psychologic factors are associated with higher risk for depression. Adverse early life events such as early childhood parental abandonment or death, or emotional trauma from physical, sexual or emotional abuse are major risk factors for depression and other psychiatric disorders in adulthood. In adulthood, recent loss (e.g., death, divorce), domestic abuse/violence, traumatic civilian (assault, serious car accident) or military (battlefield injury, witnessing death and dismemberment) events, and major life changes (e.g., job change, financial hardships) are all potential red flags for depression [21,32].

Certain neurologic disorders are risk factors, such as Parkinson disease, stroke, multiple sclerosis, and seizure disorders. Among persons with certain general medical conditions, such as cancer, diabetes, myocardial infarction, or stroke, 20% to 25% will go on to experience a major depressive episode (MDE) [22]. Chronic pain, medical illness, and persistent or severe psychosocial stress elevate the risk of MDD [32].

As noted, peripartum women are particularly vulnerable to depression. Risk factors for peripartum depression include [21]:

After the initial onset of MDD, around 15% of patients have a chronic and unremitting course. An additional 35% recover but experience one or more future recurrent episodes, and roughly 50% of first lifetime onsets recover and do not have future MDE episodes [10,37]. The risk of recurrence becomes progressively lower over time as the duration of remission increases. Preceding severe depressive episodes, younger age, and previous multiple depressive episodes increase the risk of recurrence [10].

Antidepressant medication can alter the disease course by reducing relapse rates, while premature antidepressant discontinuation is associated with marked increases in risk of relapse [38,39,40]. Relapse prevention is a clinical priority, and a collaborative care model with ongoing pharmacotherapy and/or psychotherapy and regular follow-up can improve treatment adherence and reduce the risk of depressive relapse [21,41]. A single episode of major depression is associated with a 50% chance of a subsequent episode, two episodes with a 70% chance, and three or more episodes with a 90% chance [42]. A greater number of depressive episodes predicts poor treatment response [22].

Depression is an illness with a potentially fatal outcome. Among persons with a mood disorder, 12% to 20% will ultimately die by suicide. The first three months is the period of highest risk for a first attempt, with the three months following the first attempt being the highest risk period for a second attempt [43].

Several similar but distinct terms are used to describe depression. The DSM-5-TR states the common feature of depressive disorders is the "presence of a sad, empty, or irritable mood, accompanied by somatic and cognitive changes that significantly affect a person's ability to function" [10]. Depressive disorder is an umbrella term that includes MDD (including major depressive episode), persistent depressive disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. A new diagnosis, disruptive mood dysregulation disorder (a chronic, severe, persistent irritability), is included in the DSM-5-TR to address concerns of potential overdiagnosis and treatment of bipolar disorder in children 12 years of age and younger [10]. MDD, formerly called major depression or clinical depression, is the classic condition in this group of disorders, characterized by discrete episodes of at least two weeks' duration involving clear-cut changes in affect, cognition, and functioning, with inter-episode remissions [10]. Persistent depressive disorder is a chronic, lower-grade depression that does not have the level of severity of MDD. A depressed mood (i.e., feeling sad) that occurs for most of the day, for more days than not, and for at least two years (or at least one year for children and adolescents) is the essential feature of this disorder [10].

Biologic measures of depression are not available for clinical practice, and diagnosis is made through psychometric findings, fulfillment of diagnostic criteria, patient history, and clinical impression [61].

Assessment of the presence of depression can also be made through signs and symptoms of the following cognitive, affective, and behavioral domains [10,21,22].

Appearance and Affect

Although most patients with MDD appear normal upon initial presentation, patients with severe symptoms can exhibit poor grooming and hygiene and changes in weight from previous contact. Psychomotor retardation may be present, reflected by a slowing or absence of spontaneous movement, flat affect, and sighs and long pauses. This represents a diminished reactivity in emotional expression. Some patients with MDD may display psychomotor agitation, reflected by pacing, hand wringing, or hair pulling [10,21,22,507].

Mood and Thought Process

Patients may appear tearful or sad and often report a dysphoric mood state expressed as sadness, heaviness, numbness, or irritability and mood swings, as well as a loss of interest or pleasure in their recreational or leisure activities, difficulty concentrating, or loss of energy and motivation. Feelings of worthlessness, hopelessness, helplessness, or other negative thoughts may pervade their thinking, and ruminative thinking is not uncommon in MDD. Eye contact may be absent [10].

In the context of MDD, psychotic thought processes are congruent in content with the patient's mood state, examples being delusions of worthlessness or progressive physical decline. Evidence of psychotic symptoms requires careful assessment to rule out other contributing conditions such as bipolar disorder, schizophrenia or schizoaffective disorder, substance abuse, or organic brain syndrome [10,22,507].

Cognition and Sensorium

Poor memory or concentration is a frequent complaint of patients with MDD, but actual cognitive deficits are infrequent and when present may represent pseudodementia. A fluctuating or depressed sensorium suggests delirium, and the patient should be evaluated for organic contributors [21,22,507].

Speech in patients with MDD may be normal, slow, monotonic, or lacking in spontaneity and content. Pressured speech and racing thoughts are suggestive of mania, and disorganized speech may reflect psychosis [10,21,22,507].

The thought content of patients with depression is usually consistent with the dysphoric mood and should always be assessed for hopelessness, suicidal ideation, or homicidal/violent ideation or intent. Previous suicide attempts or violence predicts future behavior, and command hallucinations are associated with increased suicidal and homicidal actions [21].

Depression screening instruments are used to identify patients who should undergo a fuller assessment for depressive disorders [64]. The Patient Health Questionnaire-2 (PHQ-2) is a two-question screen widely recommended for use in primary care [65]:

The Patient Health Questionnaire-9 (PHQ-9) is the most-recommended instrument following a positive screen. It consists of nine questions that ascertain depressive symptoms and symptom severity in the past two weeks and takes two minutes to complete. The PHQ-9 is recommended for use to measure severity before treatment and for periodic use during therapy to help assess response [64,66]. Positive response to the last item ("Thoughts that you would be better off dead or of hurting yourself in some way?") is associated with increased risk for suicide attempt [67].

Persistent depressive disorder is a depression of less severity than MDD that usually begins in childhood and adolescence. The depressed mood lasts for most of the day, for more days than not, must be present for at least two consecutive years (at least one year in children and adolescents), and must include the presence (while depressed) of two or more of the following symptoms [10]:

To meet the diagnosis of MDD, a person must have at least five of the following symptoms for at least two weeks' duration and represent a change from previous functioning. At least one of the symptoms must be either depressed mood or loss of interest or pleasure [10]:

The DSM-5-TR diagnostic criteria for MDD also include several specifiers to further describe the nature of the current episode of MDD. These specifiers include [10]:

In order for a patient with MDD to be classified as meeting the criteria for anxious distress, he or she must have at least two of the following symptoms during the majority of days [10]:

According to the DSM-5-TR, MDD with psychotic features includes the presence of delusions and/or hallucinations. Specifically, with mood-congruent psychotic features, the content of all delusions/hallucinations is consistent with the typical depressive themes (i.e., personal inadequacy, guilt, disease, death, nihilism, deserved punishment) [10].

Mood episodes can have their onset either during pregnancy or postpartum. Between 3% and 6% of women will experience the onset of a major depressive episode during pregnancy or in the weeks or months following delivery. Fifty percent of "postpartum" major depressive episodes actually begin prior to delivery [10]. Thus, these episodes are referred to collectively as peripartum episodes. Peripartum-onset mood episodes can present either with or without psychotic features. Postpartum mood (major depressive or manic) episodes with psychotic features appear to occur in from 1 in 500 to 1 in 1,000 deliveries. After a woman has had a postpartum episode with psychotic features, the risk of recurrence with each subsequent delivery is between 30% and 50%. This specifier may be applied to a current episode of MDD if the onset is within four weeks postpartum [10].

Prolonged grief disorder is defined as "intense yearning or longing for the deceased (often with intense sorrow and emotional pain) and preoccupation with thoughts or memories of the deceased. In children and adolescents, this preoccupation may focus on the circumstances of the death" [10]. In adults, this intense grief must still be present one year after a loss to be considered prolonged grief disorder; in children, the timeframe is six months. Additionally, the individual with prolonged grief disorder may experience significant distress or problems performing daily activities at home, work, or other important areas [10]. It is important for clinicians to differentiate prolonged grief disorder from usual acute grief, as well as depression and anxiety disorders [75]. Risk factors for prolonged grief disorder include past losses, separations that can impact current losses, and a history of depressive illness [10]. Symptoms include [10]:

Prolonged grief disorder is defined as "intense yearning or longing for the deceased (often with intense sorrow and emotional pain) and preoccupation with thoughts or memories of the deceased. In children and adolescents, this preoccupation may focus on the circumstances of the death" [10]. In adults, this intense grief must still be present one year after a loss to be considered prolonged grief disorder; in children, the timeframe is six months. Additionally, the individual with prolonged grief disorder may experience significant distress or problems performing daily activities at home, work, or other important areas [10]. It is important for clinicians to differentiate prolonged grief disorder from usual acute grief, as well as depression and anxiety disorders [75]. Risk factors for prolonged grief disorder include past losses, separations that can impact current losses, and a history of depressive illness [10]. Symptoms include [10]:

Healthcare providers can create a more comfortable environment for a patient of another culture by acknowledging the impact of culture and cultural differences on physical and mental health [76,77]. Symptom presentation is influenced by cultural factors, and in some cultures, depression and anxiety may be expressed through somatic symptoms, such as musculoskeletal pain and fatigue. Providers may consider starting the conversation with the patient by focusing on physical symptoms. The concept of depression also varies across cultures, and patients may not seek medical treatment unless symptoms manifest as psychosis, conversion disorders, or significant physical ailments [78].

In general, Black/African Americans are more likely than White Americans to seek help for psychologic distress in the primary care settings and are more likely to believe that mental health professionals can be helpful, but also are more likely to believe mental illness will improve on its own [80]. They tend to seek services later and, therefore, face worse outcomes [81]. When they perceive they need help for an emotional problem, African American women tend to prefer individual or group therapy over medication [79].

Major depression or persistent depressive disorder (dysthymia) with an age of onset after 60 years is referred to as late-onset depression. It is characterized by a greater presence of apathy and less lifetime presence of personality pathology than depression of earlier onset. Older patients tend to exhibit more vegetative signs and cognitive disturbance and complain less of dysphoria. In this population, major depression may be misattributed to physical illness, dementia, or the aging process itself [86]. Depression in the elderly is widespread, often undiagnosed, and usually untreated. Several factors contribute to missed diagnoses of depression in the elderly, including differences in presenting symptoms, stereotyping, provider and organizational barriers, and polypharmacy [21].

Provider-specific factors contributing to under-detection and under-treatment of depression include reluctance to inform older patients of a depression diagnosis due to uncertainty over the diagnosis and proper treatment, reluctance to stigmatize, concern regarding medication interactions, lack of access to psychiatric care, and doubts regarding treatment effectiveness and cost-effectiveness [89]. Additional factors are physician overconfidence in their ability to diagnose, treat, and manage depression in the absence of sufficient training and education and a presumption (based on their familiarity with the patient) that they have nothing new to learn about the patient [89,90,91].

As noted, women have a higher lifetime prevalence of depression and are particularly vulnerable during their childbearing years [11]. In one study, depressed women were found to mention mental symptoms when visiting a primary care provider for medical concerns (e.g., respiratory infection), giving practitioners clues as to their mental state that were not often explored [96]. Primary care providers should be alert to these clues, and screen and follow up with these women, as appropriate.

Medications that can induce mood changes include antihypertensive medications, steroids, medications that affect sex hormones, H2 histamine blockers, sedatives, muscle relaxants, appetite suppressants, and cytotoxic chemotherapy agents. Patients taking several medications are at increased risk.

Additional psychiatric disorders are present in many patients with MDD. Comorbidity rates differ between studies conducted with community compared with clinical populations. However, the most commonly occurring psychiatric comorbidities and their rates of occurrence in persons with MDD are [22,105,106,107,108]:

Cognitive impairment often accompanies MDD. Some patients have both MDD and dementia, while others have cognitive impairment that is secondary to MDD, termed pseudodementia. Pseudodementia should resolve when MDD is successfully treated. Several clinical features help differentiate pseudodementia from true dementia. When performing cognitive tasks, pseudodemented patients generally exert relatively less effort but report more incapacity than demented patients. In the latter group, especially in the advanced stages, patients typically neither recognize nor complain of their cognitive failures, as insight is impaired. In contrast, pseudodemented patients often vehemently complain that they cannot think or remember clearly. Pseudodementia also lacks the signs of cortical dysfunction (e.g., aphasia, apraxia, agnosia) that are seen in degenerative dementia. It is essential that individuals with MDD-related cognitive disturbance not be misdiagnosed and subsequently denied aggressive treatment [507].

Although the DSM-5-TR criteria require the presence of five of nine symptoms for MDD diagnosis, significant impairment in functioning can occur with as few as two symptoms [10,110]. Therefore, the goal of treatment should be to achieve remission, to reduce relapse and recurrence, and to return patients to their previous level of occupational and psychosocial function. Remission is defined as the absence of depressive symptoms, response is defined as a 50% or greater reduction in symptoms, and partial response is defined as a 25% to 50% reduction in symptoms [21,111].

An essential aspect of treating major depression is the active engagement of patients and their families during the process. Engagement is the foundation for communication between providers and patients, and at the time of diagnosis, patient education represents a useful and important topic of communication. Patient education is also important to help counter the negative effects of pessimism, low motivation, low energy, social isolation, and guilt on treatment engagement and adherence [21,507].

A robust body of evidence indicates that physical activity at a dose consistent with public health recommendations can lessen or alleviate symptoms of depression. Exercise therapy is very beneficial to patients with major depression, but the exercise must be continued over time to provide maximum benefit. Greater antidepressant effects occur when training continues beyond 16 weeks. Walking is a good initial option for many patients, and physically healthy adults should be encouraged to set a goal of 30 minutes of moderate-intensity aerobic exercise, three to five days per week [21].

Combining pharmacotherapy and psychotherapy treatments should be considered for patients with MDD when practical, feasible, available, and affordable. Both approaches combined show better outcomes than either as monotherapy. When unable to combine therapy because of patient preference or problems with availability or affordability, consider psychotherapy when the presentation is mild-to-moderate, and antidepressants when depression is severe or chronic [21]. Patients with MDD with psychotic features should receive an antipsychotic and an antidepressant medication or electroconvulsive therapy (ECT). Lithium can be added in patients unresponsive to antipsychotic/antidepressant therapy [22,507]. Other specific factors should be considered in treatment planning, including the presence of substance abuse, specific features, and other comorbid disorders. If a patient displays signs of potential suicide, increasing the treatment intensity, including hospitalization if needed, should be considered, and pharmacotherapy and psychotherapy should both be provided [22,507,508].

Patients with MDD and comorbid personality disorders, especially borderline personality disorder, poorly respond to standard antidepressants, and MAOIs should not be used in patients with borderline personality disorder [22]. Psychodynamic psychotherapy may be beneficial in modifying the personality disorder in selected patients, although antisocial personality traits often interfere with treatment adherence and the psychotherapeutic relationship [22]. Other evidence suggests that comorbid personality disorders in patients with depression interfere with treatment response to interpersonal psychotherapy but not cognitive-behavioral therapy (CBT) [121].

Ethnic minority and immigrant patients can experience many barriers to accessing mental health services, including stigma, deficits in knowledge/understanding, economic hardship, and language barriers [126]. Clinicians should take steps to address their own cultural competency when working with minority patients and ensure that all communications are clear and thorough, utilizing an interpreter when necessary. Different beliefs, values, and terms for depression will impact the perceived effectiveness of treatments. In addition, some cultures may be more likely to utilize alternative treatments (e.g., saffron) [126].

As with psychiatric conditions, comorbid medical conditions can impact the treatment plan for patients with depression. Pharmacologic agents should be chosen carefully in these patients due to the increased risk for adverse events and drug-drug interactions, and the following considerations are suggested [22,507,508]:

Preventing recurrence is a key goal during the maintenance phase of 6 to 24 months or longer. Clinicians should focus on healthy life strategies, personality vulnerabilities, long-term self-management, and clinical strategies to reduce recurrence and help the patient return to full functioning and quality of life. For a significant proportion of patients with MDD, maintenance pharmacologic, psychologic, complementary and alternative medicine, and neurostimulation treatments play a role in preventing recurrence. Other key clinician activities include treating comorbidities and monitoring for recurrence [62,139,142].

CBT is a structured, circumscribed psychologic intervention that is grounded in the cognitive-behavioral model of affective disorders, which posits that irrational beliefs and distorted attitudes toward the self, the environment, and the future perpetuate depressive affects and compromise functioning [22,507]. When CBT is used for depression, the patient works collaboratively with the therapist to identify maladaptive or self-defeating thoughts, beliefs, and interpretations and their impact on current symptoms, feelings states, and/or problem-solving abilities. Therapeutic techniques include patient education and patient-therapist collaboration to choose goals, identify unhelpful thoughts, develop experiments to challenge the accuracy of such thoughts, and identify alternative beliefs through questions that explore beliefs that exacerbate depression. Treatment incorporates structured practice outside of therapy, with scheduled activities, mood tracking, thought recording and challenging, and interpersonal skills practice. CBT can be delivered via computer software and/or by group therapy format [64].

Psychotherapy is preferred as a first-line treatment for elderly patients because of potential increased toxicity and drug-drug interactions. The evidence does not support superiority of one psychotherapy modality over another in elderly patients with MDD [64].

The three most distressing side effects for patients treated with antidepressants are sleep disturbance, sexual dysfunction, and weight gain [157]. Choice of medication should be guided by knowledge of comparative side effects and patient priorities; some patients will be more concerned about sexual side effects, while for others, nausea, sleep disturbances, or weight gain may be more distressing [64]. In addition, available evidence regarding the optimal pharmacotherapeutic selection for the treatment of dimensions of depression and DSM-5-TR specifiers should be considered (Table 1).

SSRIs are thought to act by inhibiting serotonin transporters (SERT) that reuptake serotonin (5-HT) into the presynaptic cell, increasing 5-HT in the synaptic cleft. SSRIs have advantages of low overdose lethality and better tolerability than first-generation antidepressants, which can improve adherence. SSRIs are particularly effective in patients with obsessive-compulsive symptoms but may initially worsen anxiety or panic symptoms [21,22,122]. This class includes the agents fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox) (off-label for MDD), citalopram (Celexa), escitalopram (Lexapro), and vortioxetine (Trintellix). Escitalopram may have fewer drug-drug interactions than other SSRIs, and fluoxetine may be a better choice in patients with poorer adherence due to its long half-life [21,22,122].

Most MAOIs appear broadly effective in a range of depressive and anxiety disorders and may be more effective than other antidepressant classes in MDD with pronounced anxiety or panic symptoms [21,22,122]. MDD with atypical features may preferentially respond to MAOIs over other antidepressant classes. Although effective, MAOIs are rarely the first- or second-line treatment choice due to serious side effect potential from medication interactions and dietary restriction. The selegiline transdermal patch (Emsam) used at the lowest strength (6 mg delivered over 24 hours) may lack the dietary restrictions required of oral MAOIs [168]. Moclobemide is a reversible inhibitor of monoamine oxidase type A, greatly improving its safety, including overdose safety (i.e., 20,000 mg ingestion was non-fatal). This drug lacks TCA side effects or SSRI/SNRI sexual side effects; improved libido, erection, or orgasm is more commonly reported [169,170]. Moclobemide may be superior to other antidepressants in treatment-resistant depression [171]. This drug is approved for use in Canada and throughout Europe and Asia but is not available in the United States [169].

With oral ingestion, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed, the individual may suffer from hypertensive crisis (Table 2) [166]. If foods containing tryptophan are consumed, hyperserotonemia may result. The amount required to cause a reaction varies greatly from individual to individual and depends on the degree of inhibition, which in turn depends on dosage and selectivity.

In general, CNS stimulants are associated with side effects related to hyperarousal (e.g., agitation, aggression, tachycardia, restlessness, insomnia). Other potential side effects include headache, anorexia, nausea, and irritability [175]. Modafinil is associated with markedly lower subjective stimulation.

Antidepressant discontinuation (more appropriately termed withdrawal) symptoms are described by the FINISH mnemonic (flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, hyperarousal), may be experienced by up to 40% of patients when antidepressants are stopped abruptly, and may occur with any antidepressant [158,189,190,191]. SSRI withdrawal symptoms are far more frequent with paroxetine. Common symptoms include dizziness, nausea, headache, confusion, low energy, weakness, sleep disturbance, flu-like symptoms, restlessness, agitation, anxiety, panic, anger, and irritability. Less common and more severe symptoms include electric-shock sensations, vertigo, paresthesia, intensified suicidal ideation, aggression, derealization, depersonalization, and visual/auditory hallucinations. Gradual tapering is a reasonable strategy but does not prevent the onset of SSRI withdrawal [192]. SSRI withdrawal syndrome is least likely with fluoxetine and vortioxetine [158].

Symptoms usually begin within five days of treatment cessation or occasionally during taper or after missed doses [193,194]. Symptoms are usually mild and self-limiting but may also be severe and prolonged, particularly following abrupt withdrawal. Some symptoms occur more frequently with specific drugs, such as dizziness and electric shock-like sensations with SSRIs and sweating and headache with TCAs [189,195]. Risk factors include taking antidepressants longer than eight weeks, development of anxiety symptoms during antidepressant initiation (particularly with SSRIs), use of other medications with CNS activity (e.g., antihypertensives, antihistamines, antipsychotics), and a history of previous discontinuation symptoms [195,196]. Outpatients who discontinued escitalopram and developed a withdrawal syndrome (56%) had significantly higher mean escitalopram doses and higher plasma concentrations reflecting delayed clearance of escitalopram, than patients without withdrawal. Escitalopram treatment duration, age, and sex were unrelated to withdrawal risk [197].

From a clinical perspective, it is unrealistic to expect patients with MDD and minimal treatment response to continue with their antidepressant beyond two to four weeks. Integrating best evidence with pragmatism, intervention is recommended with insufficient outcome (symptom reduction ≤20%) after two to four weeks of treatment [62,150]. With minimal improvement by two to four weeks, the recommended approach is to increase the dose, if the initial antidepressant is tolerated, or switch to another antidepressant if side effects are problematic [158].

Bright-light therapy is effective in patients with MDD with season variation (i.e., seasonal affective disorder) and may also be efficacious as monotherapy treatment of MDD without season variation. The correct intensity of light is essential and should be 3,000 to 10,000 lux-hours of white light, administered at least 30 minutes per day [22]. Results of a systematic review suggest that bright-light therapy at 5,000 lux or greater for periods of 30 minutes or more may be useful as an augmentation to standard antidepressant pharmacotherapy for treatment of MDD [233].

If a patient fails to adequately respond to an initial antidepressant and/or psychotherapy trial, the clinician should consider adjusting the treatment plan, re-evaluating the initial diagnosis, and/or optimizing the prescribed therapy. If the patient remains unresponsive to treatment, referral to a psychiatrist may be indicated.

Options for patients lacking benefit from their initial antidepressant include switching antidepressants, switching to or adding psychotherapy, and adjunctive strategies (i.e., adding a second medication). The decisions to switch or add medications should be individualized and based on clinical factors [158]. Clinicians may consider switching to another antidepressant when [158]:

Treatment-resistant depression is a problem increasingly encountered by primary care and mental health providers. Contributors to treatment-resistant depression include illness severity, medical and psychiatric comorbidity, and the limitations of FDA-approved drug options. The definition of treatment resistance lacks consensus, but the most common definition is inadequate response to two or more antidepressants. This does not consider adjunctive strategies or distinguish patients with partial versus non-response [158,180].

As first-line treatment, ECT is used for severe melancholic, catatonic, psychotic, or refractory depression and for patients who refuse to eat or drink, have very high suicide risk or severe distress, pregnant women with severe depression, or who have a previous positive ECT response [64,281,284]. A large study reported 95% remission in study completers [285].

Ketamine is an N-methyl-D-aspartate receptor (NMDA-R) antagonist that was approved for use as an anesthetic in 1970. Demonstration that a single IV dose in patients with treatment-resistant depression reliably produced rapid, robust antidepressant effects for one week was a breakthrough discovery for research and a turning point for patients for whom all other treatment approaches had failed [311]. The short-term efficacy of ketamine treatment of refractory MDD and bipolar depression is now established; over a dozen placebo-controlled trials have shown that patients with refractory MDD or bipolar depression have significantly greater response, remission, and depressive symptom reduction to single-dose IV ketamine than placebo from 40 minutes through days 10 to 12 post-treatment [312,313]. The approach has become standardized, using a sub-anesthetic dose: 0.5 mg/kg IV over a 40-minute infusion. In a 2015 analysis, ketamine was designated as one of two psychiatric treatments that had the highest potential impact on patient outcomes. This designation was based on the serious unmet need for fast-acting, well-tolerated antidepressants with efficacy in refractory MDD and bipolar depression [47].

Several non-drug therapies effective in mild-to-moderate depression are available for pregnant and breastfeeding women, including interpersonal psychotherapy, bright-light therapy, and CBT [332,333,334]. Interpersonal therapy is efficacious in postpartum depression and can improve functioning for six months postpartum [334]. While these interventions are more efficacious than routine care for postpartum depression, there is little indication of superiority for any one intervention [334]. Other nonpharmacologic treatments that may be effective include acupuncture, progressive relaxation, music therapy, sleep deprivation, and exercise [331]. Empirical support for nutritional or supplemental omega-3 fatty acids is lacking, although they pose little to no risk of adverse effects [335]. Progesterone is ineffective in postpartum depression and may intensify depressive symptoms in some patients [331].

Acute suicide risk is now thought to result from recent psychosocial stressors superimposed on non-modifiable (traditional) risk factors, with psychosocial stressors the precipitants or "triggering events" to suicidal behaviors [364,368]. Warning signs, or the acute patient response to precipitants, are considered more useful to assess than risk factors [368]. The strongest suicide risk factor—previous suicide attempts—is a static, non-acute factor with low predictive power [369]. While nearly half of suicides made previous attempts, only 5% to 15% of attempters ultimately die by suicide [370,371]. This seems a robust predictor, but with distribution of risk across the lifespan, even this risk factor does little to inform of acute patient risk level in any given contact [369].

White boys and men accounted for 68.6% of all suicides in the United States in 2024; the suicide rate in this population is two times greater than that for non-White boys/men [374]. White girls and women (8,233 suicides in 2024) also have markedly higher suicide rates than their non-White counterparts [374].

Aside from measures of suicide-related deaths, various levels of suicidality among adults have been studied, with suicidal thoughts, plans, and attempts quantified (Table 6). In the general population, there are 60 attempts for every suicide. Among adults with past-year suicidal ideation, around 1 in 4 plan suicide and 1 in 7 attempt suicide. For each male attempt are three female attempts, and there are 3.96 male suicides for each female suicide [374].

Suicide is the second most common cause of death among college students, with an estimated 1,000 students taking their lives on college campuses each year. More than 50% of college students report having had suicidal thoughts, and another 10% report a serious suicide attempt. An estimated 80% to 90% of college students who died by suicide were not receiving help from college counseling centers [387]. A study published in 2019 from the American College Health Association/National College Health Assessment survey assessed mental health diagnoses and suicidality from more than 67,000 undergraduate students across 108 institutions [388]. According to the results, one in five students have had thoughts of suicide, with 9% making a suicide attempt and 20% reporting self-injury [388]. Students leaving home for college face unique challenges that may increase suicide risk in vulnerable students, including separation from support systems and social networks, academic stress, pressure to succeed, feelings of isolation, poor coping skills, and mental health stigma.

Sexual orientation or gender identity harassment and being threatened or injured with a weapon at school are the most damaging forms of school-based victimization for sexual minority adolescents, and these factors have the greatest association with suicidality [390]. For sexual minority youth, risk factors for bullying and violence include social isolation, lack of parental support, lack of safety or support at school, and harmful norms about masculinity and femininity associated with violence against those seen as not masculine or feminine enough [389].

Suicidality disproportionately affects gender minorities, who may represent up to 0.5% of the adult population. Transgender men and women are roughly 5 times more likely to attempt suicide and 19 times more likely to die by suicide than cisgender adults [404]. The suicide attempt prevalence in trans populations is 22% to 43% for lifetime and 9% to 11.2% for past-year [405]. Violent victimization, experienced by 43% to 60% of transgender persons, predicts a fourfold increase in suicide risk [404]. Physical assault increases the odds of attempting suicide, but physical abuse directed at gender identity or expression has greater relative impact on suicidal behavior [404]. Experiencing fewer transphobia events has been associated with a 66% reduction in ideation and a 76% reduction in suicide attempts among ideators [405].

In one study, veterans during the Iraq and Afghanistan war era (317,581 deployed to war zones, 964,493 nondeployed) were followed from the time of discharge to 2010. With 1,868 suicide deaths, both veteran cohorts had 41% to 61% higher risk of suicide relative to the general population, but suicide risk was not associated with a history of war zone deployment and multiple deployments were not associated with greater suicide risk among deployed veterans [407].

Among U.S. Armed Forces veterans, the estimated lifetime prevalence of suicide ideation was 12.7% for men and 20.1% for women, and the prevalence of lifetime suicide attempts was 2.5% and 5.1%, respectively [408]. Among active Armed Forces suicide decedents, roughly 50% accessed health care in the month before their death and more than 25% accessed care in the week before their death. Male, never married, and non-Hispanic Black individuals were less likely to access care prior to death. The number of mental health encounters was the only predictor of suicide risk documentation among decedents at 4 weeks and 52 weeks prior to death [409].

The Interpersonal-Psychological Theory of Suicide posits that persons will not make lethal suicide attempts unless they have developed the desire (i.e., low belongingness, high burdensomeness) and ability to do so [377]. Thwarted belongingness is defined as the experience of having little or no social connectedness, a result of living alone, death of a spouse, or disabling physical or psychiatric illness. The need to belong is a core aspect of human nature; when unfulfilled, suicide risk increases [428]. Perceived burdensomeness is evident when persons feel their family members and the world in general would be better off if they were no longer living, and this can initiate suicidal ideation [428]. Acquired capability for suicide refers to reaching the point at which a patient overcomes his or her innate fears of pain, injury, and death with suicide. Opponent process theory suggests with repeated exposure, the effects of previously noxious, aversive, or provocative stimuli may recede, and the opposite effect of the stimuli becomes strengthened and amplified [429]. Persons can habituate to pain, injury, or death through previous suicide attempts, exposure to trauma, armed combat, violence, or death and diverse experiences related to psychologic and physical pain [350,351].

Non-suicidal self-injury (NSSI) is intentional, non-socially accepted damage to the bodily surface, without suicidal intent, by cutting, scratching, hitting/banging, carving, or scraping. Roughly 17% to 18% of teens have one or more NSSI event; up to 60% of adolescent psychiatric patients have one NSSI event and 50% have repetitive NSSI [431,432]. NSSI prevalence is higher in girls and women. It rises from late childhood to early adolescence, peaks in mid- to late-adolescence, and generally declines by young adulthood [383]. NSSI can occur without a psychiatric diagnosis [433].

NSSI serves as a means to escape aversive emotional (e.g., sadness, anxiety) or cognitive (e.g., negative thoughts or memories) states, relieve tension or anger, or regain perception of control [383,434]. Adolescents with repetitive NSSI remain at high risk of dysfunctional emotion regulation strategies after ceasing the behaviors and show increased substance abuse as the behaviors decrease [435]. Those who cut themselves on body areas other than arms or wrists have the greatest risk of subsequent suicide [436]. Identifying with "goth" or "emo" youth subculture, sexual minority status, social media exposure to self-injury behaviors, bullying, and childhood emotional abuse are risk factors for NSSI [437].

Chronic uncontrolled pain is second only to bipolar disorder as a medical cause of suicide [439,440,441]. The distress, exhaustion, and hopelessness of chronic unrelieved pain can invite intended overdose. Death is no longer feared, but instead becomes a welcome prospect of permanent relief from suffering and anguish [442]. Individuals with physical pain are substantially more likely than those without pain to report lifetime death wish; to have current and lifetime suicidal ideation, plans, and attempts; and to die from suicide. Chronic uncontrolled pain is a consistent risk factor for suicidality, even after controlling for demographics and psychiatric and substance use disorders [443,444].

Suicide is viewed as behavior motivated by the desire to escape from unbearable pain, and suicide risk research implicates two related constructs: psychache and pain tolerance, defined as the greatest duration or intensity of painful stimuli one can withstand before pain is intolerable and unbearable [447,448]. Psychache is a crucial link between suicidal risk and behavior and mediates the relationship between depression or other psychologic conditions and suicidality [447,448,449,450,451]. As discussed, numerous studies indicate that psychache highly predicts suicidality and distinguishes attempters from ideators. Changes in suicide preparation and intent over three years significantly correlates with changes in psychache but not depression or hopelessness [452]. Evidence links pain tolerance to self-injurious behaviors and suicide risk. Psychache and physical pain are linked to other predictors of suicide, including impaired reward processing, hopelessness, and depression [448].

Traditional suicide risk factors include mood (e.g., bipolar disorder, MDD), anxiety, impulse control, personality, psychotic, and alcohol/substance use disorders [368]. There is little evidence that trait impulsivity increases risk of attempts in ideators, although suicidal behavior can occur during transient impulsive states [456]. In patients with MDD (the condition most associated with suicide), the lifetime suicide prevalence is 4% for hospitalized individuals, 2.2% in mixed inpatient/outpatient populations, and 8.6% if hospitalized for suicidality [66]. However, it is important to remember that MDD alone does predict acute risk of suicide, and depression and most psychiatric disorders alone do not predict transition from ideation to suicidal plans or attempts.

While symptomatic panic disorder, PTSD, and generalized anxiety disorder influence suicide behavior more than any other psychiatric disorders, it is the acute state of anxious agitated distress (not an anxiety disorder diagnosis) that greatly increases risk of ideators moving to suicide attempts [368,457]. Among inpatient suicides, 79% met diagnostic criteria for severe or extreme anxiety and/or agitation.

More than 33% of suicides occur during alcohol use, typically at high levels of ingestion, and controlled trials confirm that acute alcohol use is a potent suicidal risk factor [461,462,463,464]. Alcohol intoxication significantly increases suicide risk and may heighten psychologic distress and aggression, encourage suicide attempts, and inhibit adaptive coping strategies [465]. During intoxication, disinhibition facilitates movement from ideation to impulsive action, and alcohol intoxication predicts use of lethal means in suicide [465,466]. However, substance use disorder and suicidality can be temporarily linked, as patients are likely to deny suicidality after intoxication has resolved [467,468].

In 2024, firearms were the most common means used in suicide deaths (56.5%), followed by suffocation/hanging (23.5%), other (11%), and poisoning (9%) [373,374]. In the United States, the rate of suicide by firearm is eight times greater than the rates in other economically developed countries [472]. Household gun ownership strongly correlates with firearm suicide, and storage practices impact suicide rates, which are higher in geographic areas with greater household prevalence of loaded guns. The presence of loaded, unlocked firearms within reach is a risk factor for fatal outcomes from suicidal behavior [473]. Firearm suicides reached an all-time high in 2024, increasing 13% since 2020 [373].

Most suicides and attempts are driven by the motivation to escape unbearable pain. Other motives include revenge, shame, humiliation, delusional guilt, command hallucinations, gaining attention or reaction from others, loneliness, self-hatred, or a sense of being a burden, not belonging, feeling trapped, or having no purpose [364]. Individuals have a unique balance between their personal motivations for suicide and their reasons for living. Reasons for living can include religious beliefs, a sense of responsibility to children or others, plans for the future, or a sense of purpose in life. A strong social support network is also protective against suicide [364]. Importantly, "reasons for living" become irrelevant when suicidal intent is moderate or greater.

The elevated suicide risk in the elderly is influenced by the prevalence of isolation, chronic pain, chronic illness, and/or depression (often undiagnosed). Many at-risk elderly adults suffer from intense loneliness, bereavement, or loss of social roles; fears of disability, dependency, or burdensomeness to others are common [481]. Enhancing connectedness to others is a suicide protective factor and formal strategy to prevent suicide in the elderly [480].

Dialectical behavioral therapy is the most thoroughly studied and effective psychotherapy for suicidal behavior. It has been shown in multiple studies to decrease suicide attempts, self-harm, and other suicide-relevant markers such as suicidal ideation and hopelessness. This psychotherapy emphasizes skills training and mindfulness-based emotion regulation [482].

Effective pharmacotherapy for suicidality has been elusive. Antidepressants are standard treatment for acutely suicidal patients, but delayed onset imposes unacceptable distress and elevates risk of lethal self-harm [47]. In MDD and bipolar disorder, lithium is protective against suicidal behavior and has extensive evidence support, but it is underprescribed for this purpose. In schizophrenia, clozapine is superior to other antipsychotic agents in lowering suicide rates. However, the need for close toxicity monitoring has limited its use in preventing suicide. In severe MDD with high suicide risk, ECT is established as rapid, effective treatment, but practical issues and stigma constrain its use [47,483,484].

Standard suicide risk assessment intends to gather clinical information sufficient to determine patient risk level for suicide, culminating with clinician estimation of risk based on suicide thoughts, intent, behaviors; protective and risk factors, precipitants, warning signs; and behavioral observation during assessment [364,366,368]. Patients with any of the following conditions should be assessed for suicide risk, although many are nonspecific factors that do not predict current risk [364,366,368]:

Suicide warning signs are recent, unusual changes in the patient, often an acute response to precipitants, and proximally associated with imminent suicide risk. Intent may be signaled through emotions, thoughts, or behaviors. Danger is elevated with previous suicide attempts, family history of suicide, or possession of a lethal method. Presence of any of the following warning signs requires immediate attention, mental health evaluation, and possibly hospitalization to ensure patient safety, stability, and security:

Survivors may struggle to comprehend why the suicide occurred and how they could have intervened, and the guilt over perceiving missed opportunities with hindsight can be agonizing. Relief may be felt if the loved one was prone to difficult mood or temperament. The stigma and shame surrounding suicide may inhibit family members and friends from contacting survivors and can prevent survivors from reaching out for help. Ongoing support remains important to maintain family and relationships during the grieving process [481].