Major depressive disorder affects the whole body, including mood and thoughts. It is characterized by depressed mood, reduced interests, impaired cognitive function, and disturbed sleep or appetite.¹ Major depressive disorder occurs more often in women than in men, and the mean age of onset is 40 years.² However, recent data show that the incidence in younger populations is increasing, potentially because of the COVID-19 pandemic and alcohol and drug misuse.

A National Institute of Mental Health survey found that approximately 14.8 million (6.0%) US adults had at least one depressive episode in 2020.³ On average, 1 in 15 adults is affected by major depressive disorder annually, and an estimated 16.6% of people will experience depression in their lifetime.⁴

Multiple factors—including biological, genetic, environmental, and psychosocial factors—are believed to contribute to major depressive disorder.¹ An imbalance in neurotransmitters such as serotonin, major life events or illnesses, or severe stress in early life can trigger major depressive disorder, or it can develop without a clear trigger.^{1, 5}

First-degree relatives of people with depression are 3 times more likely to develop depression than those without a family history of depression.⁶ No specific gene associated with depression has been identified, but two susceptibility loci are linked to major depression in men and early onset or recurrent depressive episodes.⁷ Other genes that influence depression susceptibility are those involved in the serotonin system.

Stress and interpersonal losses can also increase the risk for depression.¹ Older adults may become distressed when experiencing illnesses such as chronic pain because of decreased independence and disruption of social networks. Other psychosocial factors contributing to depression include impaired social support, caregiver burden, loneliness, bereavement, and negative life events.¹

The 2011-2021 Youth Risk Behavior Survey Data Summary and Trends Report presents the latest monitoring information and a decade-long analysis of health behaviors and welfare of teenagers, specifically high school students, in the United States.⁸ As in previous reports, research continues to show that over 40% of high school students experience feelings of extreme sadness or hopelessness that last for at least 2 weeks, hindering their participation in everyday activities. This could be an indication of the presence of depressive symptoms.⁸ Based on the patterns observed, female students, LGBQ+ students, and those with same-sex partners were more prone to encountering mental health issues in comparison with their peers. Furthermore, Hispanic and multiracial students had higher chances of experiencing persistent feelings of sadness or hopelessness when compared with Asian, Black, and White students.⁸ Nevertheless, there was a rise in the percentage of high school students from all racial and ethnic groups who felt persistently sad or hopeless, indicating an elevated risk of major depressive disorder among this demographic.⁸

Diagnosing major depressive disorder begins by ruling out other medical causes of depression through routine laboratory tests.¹ Screening tests to rule out other causes include complete blood cell count, comprehensive metabolic panel, thyroid-stimulating hormone, free T4, vitamin D, vitamin B12, rapid plasma regain, HIV test, electrolytes, liver function tests, blood alcohol level, arterial blood gas, urinalysis, and toxicology.¹ No specific laboratory test is available to diagnose major depressive disorder, but self-reported screening instruments are available to help.^9-11 Neuroimaging can help clarify the nature of the neurologic illness among patients with neurologic deficits.¹²

Patients often present to their primary care physician with bodily manifestations that are a result of depression but deny having depressive feelings. Family or employers often encourage the person to visit health care providers because of symptoms like social withdrawal and decreased activity. The US Preventive Services Task Force recommends screening for depression in the general adult population with a simple screening test that presents the single question: “Are you depressed?” ^10,11 The single-question screening has been shown to increase the detection of depression among patients visiting their primary care providers.¹³ Longer questionnaires increase specificity in identifying patients with depression. The longer self-report screening tools include Patient Health Questionnaire-9 (PHQ-9),¹⁰ Beck Depression Inventory,⁹ Beck Depression Inventory for Primary Care,¹⁴ Zung Self-Rating Depression Scale,¹⁵ and Center for Epidemiologic Studies-Depression Scale.¹⁶ PHQ-9 uses 9 items corresponding to the DSM-5 criteria for major depressive disorder and assesses psychosocial impairment.^10,17

The DSM-5 criteria for major depressive disorder include at least 5 of the following depressive symptoms during the same 2-week period that are a change from previous functioning:

• Depressed mood (must be present)
• Loss of interest/pleasure (must be present)
• Weight loss or gain
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Fatigue
• Feeling worthless or excessive/inappropriate guilt
• Decreased concentration
• Thoughts of death/suicide

Additional required criteria are all 4 of the following: symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning; episode not attributable to physiological effects of a substance or another medical condition; episode not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders; and no history of manic or hypomanic episode.¹⁷

Major depressive disorder is treated with pharmacological, psychotherapeutic, interventional, and lifestyle modification methods.¹ Initial treatment includes medication or psychotherapy, or a combination of both. Combination treatments are more effective than monotherapy.¹⁸ Electroconvulsive therapy is a highly effective treatment for severe major depression.¹⁹ Antidepressants approved by the FDA are equally effective but have different adverse effects. They include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, serotonin modulators, atypical antidepressants, tricyclic antidepressants, monoamine oxidase inhibitors, mood stabilizers, and antipsychotics.¹ Treatment should maximize patient function with selected and reachable goals and be based on clinical assessment, presence of other disorders, stressors, patient preference, and reactions to previous treatment.¹ Patients should be observed monthly to determine clinical status, functioning, stressors, and treatment adherence.

Psychotherapy is conducted on an outpatient basis with weekly 60-minute sessions that occur for a set number of weeks. Psychotherapies that meet the criteria for empirically supported treatments for treating acute major depressive disorder include interpersonal psychotherapy, cognitive behavior therapy, problem-solving therapy, behavioral activation/contingency management, dynamic psychotherapy, cognitive behavioral analysis system for psychotherapy, and emotion-focused therapy.¹ Treatments for preventing relapse and recurrence include prior cognitive behavioral therapy, mindfulness-based cognitive therapy, prior dynamic psychotherapy, maintenance interpersonal psychotherapy, continuation cognitive therapy, maintenance cognitive behavioral analysis system for psychotherapy, and emotion-focused therapy.¹

Major depressive disorder is also treated with interventional and lifestyle modification.¹ In the case of a person with suicidal thoughts, hospitalization with the patient’s consent or emergency commitment should occur to ensure the patient’s safety while outpatient treatment begins. Psychiatric hospitalization is also recommended for cases of severe depression, gross disorganization, inability to care for self, and failing medical status because of depression.²⁰ Patients can also change their diet and increase activity levels to help prevent or reduce depression. Diets such as the low-sodium Dietary Approaches to Stop Hypertension (DASH) diet,²¹ the Mediterranean diet,²² and the 2 combined improve mental health.²³ Exercise and physical activity are also instrumental in helping patients recover from major depressive disorder.^1,20

The American College of Physicians compared nonpharmacologic and pharmacologic treatments for adults with major depressive disorder.²⁴ Based on the results of the systematic review, nonpharmacologic treatments were comparable in effectiveness to second-generation antidepressants as first-line treatments for adult patients with moderate to severe major depressive disorder.²⁴ As for second-line treatments, a range of augmentation and switch strategies involving cognitive therapy or pharmacological agents also exhibited similar levels of symptom alleviation. Nevertheless, individuals treated with antidepressants were more prone to experiencing adverse events or discontinuing treatment due to such events than those who opted for nonpharmacologic alternatives.²⁴

The American Academy of Child and Adolescent Psychiatry published a clinical practice guideline for assessing and treating children and adolescents with major depressive disorders.²⁵ In line with national and international recommendations, the guideline indicates that psychotherapy (such as cognitive-behavioral therapy and interpersonal therapy) and psychopharmacology (primarily selective SSRI medication, with the exception of paroxetine) have robust empirical support through randomized controlled trials and meta-analyses, and are widely accepted by experts as viable treatment options.²⁵ Given the significant role of psychological and social-environmental factors in the development of depression, it is important to consider supportive interventions as a first-line treatment for mild depression in children and adolescents. For moderate-to-severe depression, evidence-based psychotherapies and SSRI medications, either alone or in combination, can be considered, with the continuation of treatment for a sufficient duration to minimize the risk of relapse or recurrence.²⁵ Since accurate diagnosis, comprehensive clinical formulation, and an evidence-based treatment plan are critical for successful treatment outcomes, a thorough, evidence-based assessment can enhance the efficacy of evidence-based treatments.²⁵

The FDA has recently granted approval to multiple medications for treating major depressive disorder. On August 19, 2022, the FDA approved dextromethorphan HBr and bupropion HCl, the first rapid-acting oral treatment for major depressive disorder that improves depressive symptoms in 1 week when compared with placebo.²⁶ On December 16, 2022, cariprazine was approved as an adjunctive treatment to antidepressants for major depressive disorder in adults based on a phase 3 study. Results from this study showed a significant change from baseline to week 6 in the Montgomery-Åsberg Depression Rating Scale total score for patients treated with cariprazine at 1.5 mg per day and antidepressant therapy, when compared with placebo and antidepressant therapy. Cariprazine was safe and well tolerated.²⁷ More treatments may be approved in the future as the FDA has accepted a new drug application for an oral treatment for major depressive disorder.²⁸

Major depressive disorder is a serious mood disorder that is improved with the right treatment. Depression often runs in families and is diagnosed after a psychiatric examination and medical history analysis, which are usually performed by a mental health professional. Patients feel better within a few weeks when undergoing the appropriate treatment. Exercise and physical activity are instrumental in lessening symptoms like exhaustion and hopelessness. Ongoing research is seeking new therapeutics to quickly improve depressive symptoms and enhance the quality of life in patients who are affected by the disorder.

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3. Major depression. National Institute of Mental Health. Updated January 2022. Accessed July 29, 2022. https://www.nimh.nih.gov/health/statistics/major-depression

4. Torres F. What is depression? American Psychiatric Association. Reviewed October 2020. Accessed July 29, 2022. https://psychiatry.org/patients-families/depression/what-is-depression

5. Pérez-Granado J, Piñero J, Medina-Rivera A, Furlong LI. Functional genomics analysis to disentangle the role of genetic variants in major depression. Genes (Basel). 2022;13(7):1259. doi:10.3390/genes13071259

6. Levinson DF. Major depression and genetics. Stanford Medicine. Accessed July 29, 2022. https://med.stanford.edu/depressiongenetics/mddandgenes.html

7. Shadrina M, Bondarenko EA, Slominsky PA. Genetics factors in major depression disease. Front Psychiatry. Published online July 23, 2018. doi:10.3389/fpsyt.2018.00334

8. Youth risk behavior survey data summary and trends report: 2011-2021. Centers for Disease Control and Prevention. Accessed April 17, 2023. https://www.cdc.gov/healthyyouth/data/yrbs/pdf/YRBS_Data-Summary-Trends_Report2023_508.pdf

9. Beck Depression Inventory. https://www.ismanet.org/doctoryourspirit/pdfs/Beck-Depression-Inventory-BDI.pdf

10. Patient Health Questionnaire-9. https://www.apa.org/depression-guideline/patient-health-questionnaire.pdf

11. Depression in adults: screening. US Preventive Services Task Force. Published online January 26, 2016. https://www.uspreventiveservicestaskforce.org/uspstf/document/RecommendationStatementFinal/depression-in-adults-screening

12. Winter NR, Leenings R, Ernsting J, et al. Quantifying deviations of brain structure and function in major depressive disorder across neuroimaging modalities. JAMA Psychiatry. Published online July 27, 2022. doi:10.1001/jamapsychiatry.2022.1780

13. Pfoh ER, Janmey I, Anand A, Martinez KA, Katzan I, Rothberg MB. The impact of systematic depression screening in primary care on depression identification and treatment in a large health care system: a cohort study. J Gen Intern Med. 2020;35(11):3141-3147. doi:10.1007/s11606-020-05856-5

14. Bellis C. The Beck Depression Inventory for Primary Care accurately screened for major depressive disorders. Evid Based Nurs. 1999;2(4):126. doi.10.1136/ebn.2.4.126

15. Zung Self-Rating Depression Scale. http://www.mentalhealthministries.net/resources/flyers/zung_scale/zung_scale.pdf

16. Center for Epidemiologic Studies-Depression Scale. http://www.chcr.brown.edu/pcoc/cesdscale.pdf

17. DSM-5 criteria for major depressive disorder. MDCalc. Accessed July 29, 2022. https://www.mdcalc.com/calc/10195/dsm-5-criteria-major-depressive-disorder

18. Henssler J, Alexander D, Schwarzer G, Bschor T, Baethge C. Combining antidepressants vs antidepressant monotherapy for treatment of patients with acute depression: a systematic review and meta-analysis. JAMA Psychiatry. 2022;79(4):300-312. doi:10.1001/jamapsychiatry.2021.4313

19. Li M, Yao X, Sun L, et al. Effects of electroconvulsive therapy on depression and its potential mechanism. Front Psychol. Published online February 20, 2020. doi:10.3389/fpsyg.2020.00080

20. Chand SP, Arif H. Depression. In: StatPearls. StatPearls Publishing; July 18, 2022. http://www.ncbi.nlm.nih.gov/books/nbk430847/

21. Saharkhiz M, Khorasanchi Z, Karbasi S, et al. The association between adherence to a dietary approaches to stop hypertension (DASH) diet and neuro-psychological function in young women. BMC Nutr. 2021;7(1):21. doi:10.1186/s40795-021-00429-z

22. Oddo VM, Welke L, McLeod A, et al. Adherence to a Mediterranean diet is associated with lower depressive symptoms among U.S. adults. Nutrients. 2022;14(2):278. doi:10.3390/nu14020278

23. Cherian L, Wang Y, Holland T, Agarwal P, Aggarwal N, Morris MC. DASH and Mediterranean-dash intervention for neurodegenerative delay (MIND) diets are associated with fewer depressive symptoms over time. J Gerontol A Biol Sci Med Sci. 2021;76(1):151-156. doi:10.1093/gerona/glaa044

24. Gartlehner G, Dobrescu A, Chapman A, et al. Nonpharmacologic and pharmacologic treatments of adult patients with major depressive disorder: a systematic review and network meta-analysis for a clinical guideline by the American College of Physicians. Ann Intern Med. 2023;176(2):196-211. doi:10.7326/M22-1845

25. Walter HJ, Abright AR, Bukstein OG, et al. Clinical practice guideline for the assessment and treatment of children and adolescents with major and persistent depressive disorders. J Am Acad Child Adolesc Psychiatry. 2022;S0890-8567(22)01852-4. doi:10.1016/j.jaac.2022.10.001

26. Auvelity Prescribing Information. Axsome Therapeutics. Published December 2022. Accessed April 17, 2023. https://www.axsome.com/auvelity-prescribing-information.pdf?_gl=1*3t1h7i*_ga*MTQ2MTExODkyNi4xNjgyNDUxMDc2*_ga_R7GN1HNP9B*MTY4Mzc0NDYxOC4yLjEuMTY4Mzc0NDcyOS42MC4wLjA.*_ga_LVY4YVJJ3H*MTY4Mzc0NDYxOC4zLjEuMTY4Mzc0NDc1MS4zOC4wLjA.

27. US FDA approves VRAYLAR® (cariprazine) as an adjunctive treatment for major depressive disorder. News Release. Abbvie; December 16, 2022. Accessed April 17, 2023. https://news.abbvie.com/news/press-releases/us-fda-approves-vraylar-cariprazine-as-an-adjunctive-treatment-for-major-depressive-disorder.htm

28. Biogen and Sage Therapeutics announce FDA accepts filing of new drug application and grants priority review of zuranolone in the treatment of major depressive disorder and postpartum depression. News Release. Biogen; February 6, 2023. Accessed April 17, 2023. https://investors.biogen.com/news-releases/news-release-details/biogen-and-sage-therapeutics-announce-fda-accepts-filing-new