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].

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].

Women have greater risk of depression, with a lifetime prevalence almost twice that of men [33]. Among women, severe obesity (body mass index greater than 40) is strongly associated with depression [34]. Lower socioeconomic status and being single are also risk factors for both genders [32].

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].

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].

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].

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].

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]:

Depressed mood most of the day, nearly every day

Markedly diminished interest or pleasure in all or almost all activities most of the day or nearly every day

Significant weight loss or gain (>5% body weight) or increase or decrease in appetite

Insomnia/hypersomnia nearly every day

Psychomotor agitation or retardation nearly every day

Fatigue/loss of energy nearly every day

Feelings of worthlessness or inappropriate guilt nearly every day

Diminished concentration or indecisiveness nearly every day

Recurrent thoughts of death or suicide, suicide attempt, or a specific plan for attempting suicide

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].

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].

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]:

Generalized anxiety disorder (62%)

Social phobia (52%)

Post-traumatic stress disorder (PTSD) (50%)

Panic disorder (48%)

Specific phobia (43%)

Obsessive-compulsive disorder (42%)

Any personality disorder (30%)

Impulse control disorders (30%)

Substance use disorders (24%)

Borderline personality disorder (10% to 15%)

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]. 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].

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]:

Hypertension or cardiac conditions: Monitor vital signs and cardiac rhythm when treating with TCAs, SNRIs, or antidepressants with anticholinergic effects.

Seizure disorders: Use with caution antidepressants that lower the seizure threshold, such as bupropion, clomipramine, and maprotiline.

Parkinson disease: Serotonergic agents may worsen symptoms, and bupropion may benefit the illness but worsen psychosis if present. Selegiline may interact with L-DOPA, an agent used in the treatment of Parkinson disease.

Obesity: Monitor for weight gain with most antidepressants.

Sleep apnea: Choose an antidepressant with little daytime sedation.

HIV infection: Carefully consider the potential drug-drug interactions between psychotropics and antiretrovirals.

Chronic pain: SNRIs and TCAs are preferred over SSRIs and MAOIs.

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.

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].

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.

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].

White boys and men accounted for 70% of all suicides in the United States in 2021; the suicide rate in this population is two times greater than that for non-White boys/men. White men 45 to 64 years of age had the highest suicide rate and number of any demographic in 2021 [374]. White girls and women 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). Among adults with past-year suicidal ideation, around 1 in 4 plan suicide and 1 in 7 attempt suicide. There are 25 attempts for every suicide, increasing to 100 to 200 attempts per suicide in individuals 15 to 24 years of age and decreasing to 4 attempts per suicide among the elderly. For each male attempt are three female attempts, and there are 3.9 male suicides for each female suicide [374].

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].

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].

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.

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 2021, firearms were the most common means used in suicide deaths (54.6%), followed by suffocation/hanging (25.8%) and poisoning (11.6%) [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].

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.

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:

Suicide communication—threatening to harm or kill self

Preparations for suicide

Seeking access, or recent use, of lethal means