Depressive Disorders

Etiology references

1. 1. Kendall KM, Van Assche E, Andlauer TFM, et al. The genetic basis of major depression. Psychol Med. 2021;51(13):2217-2230. doi:10.1017/S0033291721000441

2. 2. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry. 2000;157(10):1552-1562. doi:10.1176/appi.ajp.157.10.1552

3. 3. Agerbo E, Trabjerg BB, Børglum AD, et al. Risk of Early-Onset Depression Associated With Polygenic Liability, Parental Psychiatric History, and Socioeconomic Status. JAMA Psychiatry. 2021;78(4):387-397. doi:10.1001/jamapsychiatry.2020.4172

4. 4. Ghasemi M, Phillips C, Fahimi A, et al. Mechanisms of action and clinical efficacy of NMDA receptor modulators in mood disorders. Neurosci Biobehav Rev. 80:555-572, 2017. doi: 10.1016/j.neubiorev.2017.07.002

5. 5. Li S, Gao M, Mou Z, Zhang H, Wang Y, Zhang Y. Advances in neurotransmitter-mediated prefrontal circuitry in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2025;141:111475. doi:10.1016/j.pnpbp.2025.111475

6. 6. Min W, Liu C, Yang Y, et al. Alterations in hypothalamic-pituitary-adrenal/thyroid (HPA/HPT) axes correlated with the clinical manifestations of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39(1):206-211. doi:10.1016/j.pnpbp.2012.06.017

7. 7. Feng G, Kang C, Yuan J, et al. Neuroendocrine abnormalities associated with untreated first episode patients with major depressive disorder and bipolar disorder. Psychoneuroendocrinology. 2019;107:119-123. doi:10.1016/j.psyneuen.2019.05.013

8. 8. Bode H, Ivens B, Bschor T, Schwarzer G, Henssler J, Baethge C. Association of Hypothyroidism and Clinical Depression: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2021;78(12):1375-1383. doi:10.1001/jamapsychiatry.2021.2506

9. 9. Tajiri M, Suzuki Y, Tsuneyama N, Arinami H, Someya T. Hormonal Dynamics Effect of Serum Insulin-Like Growth Factor I and Cortisol/Dehydroepiandrosterone Sulfate Ratio on Symptom Severity of Major Depressive Disorder. . Hormonal Dynamics Effect of Serum Insulin-Like Growth Factor I and Cortisol/Dehydroepiandrosterone Sulfate Ratio on Symptom Severity of Major Depressive Disorder.J Clin Psychopharmacol. 2019;39(4):367-371. doi:10.1097/JCP.0000000000001071

10. 10. Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA Psychiatry. 2018;75(4):336-346. doi:10.1001/jamapsychiatry.2017.4602.

11. 11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed, Text Revision. American Psychiatric Association Publishing; 2022.

12. 12. Di Benedetto MG, Landi P, Mencacci C, Cattaneo A. Depression in Women: Potential Biological and Sociocultural Factors Driving the Sex Effect. Neuropsychobiology. 2024;83(1):2-16. doi:10.1159/000531588

13. 13. Sacher J, Rekkas PV, Wilson AA, et al. Relationship of monoamine oxidase-A distribution volume to postpartum depression and postpartum crying. Neuropsychopharmacology. 2015;40(2):429-435. doi:10.1038/npp.2014.190

14. 14. Eccles H, Abramovich A, Patte KA, et al. Mental Disorders and Suicidality in Transgender and Gender-Diverse People. JAMA Netw Open. 2024;7(10):e2436883. Published 2024 Oct 1. doi:10.1001/jamanetworkopen.2024.36883

15. 15. Bulloch A, Williams J, Lavorato D, Patten S. Recurrence of major depressive episodes is strongly dependent on the number of previous episodes. Depress Anxiety. 2014;31(1):72-76. doi:10.1002/da.22173

16. 16. Struijs SY, de Jong PJ, Jeronimus BF, van der Does W, Riese H, Spinhoven P. Psychological risk factors and the course of depression and anxiety disorders: A review of 15 years NESDA research. J Affect Disord. 2021;295:1347-1359. doi:10.1016/j.jad.2021.08.086

17. 17. Liu X, Agerbo E, Li J, Meltzer-Brody S, Bergink V, Munk-Olsen T. Depression and Anxiety in the Postpartum Period and Risk of Bipolar Disorder: A Danish Nationwide Register-Based Cohort Study. J Clin Psychiatry. 2017;78(5):e469-e476. doi:10.4088/JCP.16m10970

18. 18. Levine GN, Cohen BE, Commodore-Mensah Y, et al. Psychological Health, Well-Being, and the Mind-Heart-Body Connection: A Scientific Statement From the American Heart Association. Circulation. 2021;143(10):e763-e783. doi:10.1161/CIR.0000000000000947

19. 19. Krittanawong C, Maitra NS, Qadeer YK, et al. Association of Depression and Cardiovascular Disease. Am J Med. 2023;136(9):881-895. doi:10.1016/j.amjmed.2023.04.036

Major depressive disorder (unipolar depressive disorder)

Characteristic symptoms and signs include depressed mood, anhedonia, weight change, fatigue, sleep disturbances, psychomotor agitation or slowing, feelings of worthlessness or guilt, difficulty thinking, and suicidal ideation or behavior.

Patients may appear miserable, with tearful eyes, furrowed brows, down-turned corners of the mouth, slumped posture, poor eye contact, lack of facial expression, little body movement, and speech changes (eg, soft voice, lack of prosody, use of monosyllabic words). Appearance may be confused with Parkinson disease. In some patients, depressed mood is so deep that tears dry up; they report that they are unable to experience usual emotions and feel that the world has become colorless and lifeless.

Nutrition may be severely impaired, and significant weight loss may require immediate intervention.

Some depressed patients neglect personal hygiene or their children, other loved ones, or pets.

Persistent depressive disorder

Depressive symptoms that persist for ≥ 2 years without remission are classified as persistent depressive disorder (PDD), a category that consolidates disorders formerly termed chronic major depressive disorder and dysthymic disorder.

Characteristic symptoms and signs include depressed mood, fatigue, changes in appetite, sleep disturbances, psychomotor agitation or slowing, low self-esteem, feelings of hopelessness, and difficulty thinking.

Symptoms typically begin insidiously during adolescence and may persist for many years or decades. The number of symptoms often fluctuates above and below the threshold for major depressive episode.

Affected patients may be habitually gloomy, pessimistic, humorless, passive, lethargic, introverted, hypercritical of self and others, and complaining. Patients with PDD are also more likely to have underlying anxiety disorders, substance use disorders, or personality disorders (eg, borderline personality).

Premenstrual dysphoric disorder

Premenstrual dysphoric disorder involves mood and anxiety symptoms that are clearly related to the menstrual cycle, with onset during the premenstrual phase and a symptom-free interval after menstruation. Symptoms must be present during most menstrual cycles during the past year.

Characteristic symptoms include mood swings (including depressed mood), irritability, anger, increased interpersonal conflict, feelings of hopelessness, anxiety or tension, and other symptoms of depressive disorders. Physical symptoms such as joint pain, a bloated feeling, breast tenderness, or weight gain are also present.

Manifestations are similar to those of premenstrual syndrome but are more severe, causing clinically significant distress and/or marked impairment of social or occupational functioning. The disorder may begin any time after menarche; it may worsen as menopause approaches but ceases after menopause. Prevalence is estimated at approximately 1 and 6% of menstruating women (6).

Prolonged grief disorder

Prolonged grief is persistent sadness following the loss of a loved one. It is distinct from depression in that the sadness relates to the specific loss rather than the more general feelings of failure associated with depression. In contrast to normal grief, this condition may be highly disabling and require therapy specifically designed for prolonged grief disorder.

Characteristic symptoms include emotional pain, loneliness, numbness, disbelief, a feeling that a part of oneself has died, avoidance or reminders of the loved one, and difficulty reengaging in life.

(Some useful screening tools include the Inventory of Complicated Grief and the Brief Grief Questionnaire.)

Symptoms and signs references

1. 1. Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA Psychiatry. 2018;75(4):336-346. doi:10.1001/jamapsychiatry.2017.4602

2. 2. Turner S, Mota N, Bolton J, Sareen J. Self-medication with alcohol or drugs for mood and anxiety disorders: A narrative review of the epidemiological literature. Depress Anxiety. 2018;35(9):851-860. doi:10.1002/da.22771

3. 3. Fergusson DM, Boden JM, Horwood LJ. Tests of causal links between alcohol abuse or dependence and major depression. Arch Gen Psychiatry. 2009;66(3):260-266. doi:10.1001/archgenpsychiatry.2008.543

4. 4. Weinberger AH, Chaiton MO, Zhu J, Wall MM, Hasin DS, Goodwin RD. Trends in the Prevalence of Current, Daily, and Nondaily Cigarette Smoking and Quit Ratios by Depression Status in the U.S.: 2005-2017. Am J Prev Med. 2020;58(5):691-698. doi:10.1016/j.amepre.2019.12.023

5. 5. Gorna K, Szpalik R, Rybakowski JK, Jaracz K. Health behaviours of patients with affective disorders: a cross-sectional study. BMC Psychiatry. 2023;23(1):561. Published 2023 Aug 4. doi:10.1186/s12888-023-05056-5

6. 6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed, Text Revision. American Psychiatric Association Publishing; 2022.

General diagnostic considerations

Specific (closed-ended) questions help determine the presence, severity, and duration of symptoms. To differentiate depressive disorders from ordinary mood variations, there must be significant distress or impairment in social, occupational, or other important areas of functioning. In addition, the symptoms of a disorder should not be better explained by another psychiatric disorder, substance/medication use, or another general medical condition.

Severity is determined by the degree of pain and disability (physical, social, occupational) and by duration of symptoms. A clinician should also gently but directly ask patients about any thoughts and plans to harm themselves or others, as well as about any previous threats of and/or attempts at suicide. Psychosis and catatonia indicate severe depression, as does a melancholic syndrome . Coexisting physical conditions, substance use disorders, and anxiety disorders may add to severity.

Major depressive disorder

For diagnosis of major depressive disorder (previously called unipolar depressive disorder), ≥ 5 (1) of the following symptoms must have been present nearly every day during the same 2-week period, and at least 1 symptom must be depressed mood or loss of interest or pleasure:

• Depressed mood most of the day

• Markedly diminished interest or pleasure in all or almost all activities for most of the day

• Significant weight gain or loss (eg, a change of > 5% of body weight in a month) or decreased or increased appetite

• Insomnia (often sleep-maintenance insomnia) or hypersomnia

• Psychomotor agitation or retardation observed by others (not self-reported)

• Fatigue or loss of energy

• Feelings of worthlessness or excessive or inappropriate guilt

• Diminished ability to think or concentrate or indecisiveness

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

The history of a manic or hypomanic episode (unless caused by a substance or other medical condition) precludes the diagnosis of unipolar depression and should prompt evaluation for a bipolar disorder.

Persistent depressive disorder

For diagnosis of persistent depressive disorder (1), patients must have had a depressed mood for most of the day for more days than not for ≥ 2 years (1 year for children or adolescents) plus ≥ 2 of the following:

• Poor appetite or overeating

• Insomnia or hypersomnia

• Low energy or fatigue

• Low self-esteem

• Poor concentration or difficulty making decisions

• Feelings of hopelessness

During the 2-year period (1 year for children or adolescents), the individual has never been without the symptoms listed above for more than 2 months at a time.

The history of a manic or hypomanic episode (unless caused by a substance or other medical condition) precludes the diagnosis of persistent depressive disorder and should prompt evaluation for a bipolar disorder.

Premenstrual dysphoric disorder

For diagnosis of premenstrual dysphoric disorder (1), patients must have ≥ 5 symptoms during the week before onset of menstruation. Symptoms must begin to improve within a few days after onset of menses and become minimal or absent in the week after menstruation. Symptoms must include ≥ 1 of the following:

• Marked mood swings (eg, suddenly feeling sad or tearful)

• Marked irritability or anger or increased interpersonal conflicts

• Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts

• Marked anxiety, tension, and/or a keyed-up or on-edge feeling

In addition, ≥ 1 of the following must also be present:

• Decreased interest in usual activities

• Difficulty concentrating

• Lethargy, easy fatigability, or marked lack of energy

• Marked change in appetite, overeating, or specific food cravings

• Hypersomnia or insomnia

• Feeling overwhelmed or out of control

• Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a feeling of being bloated, and weight gain

Prolonged grief disorder

Prolonged grief is persistent sadness following the loss of a loved one. It is distinct from depression in that the sadness relates to the specific loss rather than the more general symptoms associated with depression. In contrast to normal grief, this condition may be highly disabling and require therapy specifically designed for prolonged grief disorder.

Prolonged grief disorder is diagnosed in a people who experienced the death of a someone close to them ≥ 1 year ago (for children and adolescents, ≥ 6 months ago) and have a grief response that exceeds societal, cultural, or religious norms and expectations; is persistent; is accompanied by significant functional impairment; and is characterized by 1 or both of the following symptoms nearly every day for at least the last month (1):

• Intense yearning/longing for the deceased person

• Preoccupation with thoughts or memories of the deceased person (in children and adolescents, preoccupation may focus on the circumstances of the death)

In addition, since the death, ≥ 3 of the following symptoms have been present for at least half the month:

• Feeling of identity disruption (eg, feeling as though part of oneself has died)

• Marked disbelief about the death

• Avoidance of reminders that the person is dead

• Intense emotional pain (eg, anger, bitterness, sorrow) related to the death

• Difficulty reintegrating into one’s relationships and activities

• Emotional numbness

• Feeling that life is meaningless

• Intense loneliness

Some useful screening tools include the Inventory of Complicated Grief and the Brief Grief Questionnaire.

Other depressive disorders

Clusters of symptoms with characteristics of a depressive disorder that do not meet the full criteria for other depressive disorders but that cause clinically significant distress or impairment of functioning are classified as other depressive disorder (specified or unspecified). Included are recurrent periods of dysphoria with ≥ 4 other depressive symptoms that last < 2 weeks in people who have never met criteria for another mood disorder (eg, recurrent brief depression) and depressive periods that last longer but that include insufficient symptoms for diagnosis of another depressive disorder.

When a specific cause is found for a depressive disorder, the diagnosis is usually substance-/medication-induced depressive disorder or depressive disorder due to another medical condition.

Disruptive mood regulation disorder is covered in Depressive Disorders in Children and Adolescents.

Specifiers

Major depressive disorder and persistent depressive disorder may include 1 or more specifiers that describe additional manifestations during a depressive episode, which may include:

• Anxious distress: Patients feel tense and unusually restless; they have difficulty concentrating because they worry or fear that something awful may happen, or they feel that they may lose control of themselves.

• Mixed features: Patients also have ≥ 3 manic or hypomanic symptoms (eg, elevated mood, grandiosity, greater talkativeness than usual, flight of ideas, decreased sleep). Patients who have this type of depression are at increased risk of developing bipolar disorder.

• Melancholic: Patients have lost pleasure in nearly all activities or do not respond to usually pleasurable stimuli. They may be despondent and despairing, feel excessive or inappropriate guilt, or have early morning awakenings, marked psychomotor retardation or agitation, and significant anorexia or weight loss.

• Atypical: Patients' mood temporarily brightens in response to positive events (eg, a visit from children). They also have ≥ 2 of the following: overreaction to perceived criticism or rejection, feelings of leaden paralysis (a heavy or weighted-down feeling, usually in the extremities), weight gain or increased appetite, and hypersomnia.

• Psychotic: Patients have delusions and/or hallucinations. Delusions often involve having committed unpardonable sins or crimes, harboring incurable or shameful disorders, or being persecuted. Hallucinations may be auditory (eg, hearing accusatory or condemning voices) or visual. If only voices are described, careful consideration should be given to whether the voices represent true hallucinations.

• Catatonic: Patients have severe psychomotor retardation, engage in excessive purposeless activity, and/or withdraw; some patients grimace and mimic speech (echolalia) or movement (echopraxia).

• Peripartum onset: Onset is during pregnancy or in the 4 weeks after delivery. Psychotic features may be present; infanticide is often associated with psychotic episodes involving command hallucinations to kill the infant or delusions that the infant is possessed.

• Seasonal pattern: Episodes occur at a particular time of year, most often fall or winter.

Diagnosis reference

1. 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed, Text Revision. American Psychiatric Association Publishing; 2022.

Initial support

Until definite improvement begins, a clinician may need to see patients weekly or biweekly to provide support and education and to monitor progress. Telephone calls may supplement office visits.

Patients and loved ones may be worried or embarrassed about the idea of having a psychiatric illness. The clinician can help by explaining that depression is a serious medical disorder caused by biologic disturbances, that it requires specific treatment and that the prognosis with treatment is good. Patients and loved ones should be reassured that depression does not reflect a character flaw (eg, laziness, weakness). Telling patients that the path to recovery often fluctuates helps them put feelings of hopelessness in perspective and improves adherence.

Encouraging patients to gradually increase simple activities (eg, taking walks, exercising regularly) and social interactions must be balanced with acknowledging their desire to avoid activities. The clinician can suggest that patients avoid self-blame and explain that dark thoughts are part of the disorder and will go away.

Support groups (eg, the Depression and Bipolar Support Alliance [DBSA]) can help patients by providing a forum to share their common experiences and feelings.

Psychotherapy

Numerous randomized trials have shown that psychotherapy is effective in patients with major depressive disorder, both to treat acute symptoms and to decrease the likelihood of relapse (3). Psychotherapeutic modalities with demonstrated effectiveness include the following:

• Cognitive-behavioral therapy

• Interpersonal therapy

• Behavioral activation

• Problem-solving therapy

• Psychodynamic therapy

• Mindfulness-based therapy

Patients with mild depression tend to have better outcomes than those with more severe depression, but the magnitude of improvement is greater in those with more severe depression.

Pharmacotherapy for depression

Several classes of medications can be used to treat depression:

• Selective serotonin reuptake inhibitors (SSRIs)

• Selective serotonin and norepinephrine reuptake inhibitors (SNRIs)

• Serotonin modulators (5-HT₂ blockers)

• Norepinephrine-dopamine reuptake inhibitor

• N-methyl D-aspartate (NMDA) antagonist/sigma-1 agonist

• Heterocyclic antidepressants (HCAs), including tricyclic antidepressants (TCAs)

• Monoamine oxidase inhibitors (MAOIs)

• Melatonergic antidepressant

• Psychostimulants

• Ketamine and esketamine

Choice of medication may be guided by past response to a specific antidepressant. Otherwise, SSRIs are often the initial medications of choice. Although the different SSRIs are equally effective for typical cases, certain properties make them more or less appropriate for certain patients (see table Antidepressants) and Choice and Administration of Antidepressants.

Electroconvulsive therapy (ECT)

ECT involves the electrical induction of a seizure under controlled conditions. Its mechanism of action is uncertain but the production of seizure activity appears to be integral to its antidepressant effects.

The following are often treated with ECT if medications are ineffective (4–6):

• Severe suicidal depression

• Depression with agitation or psychomotor retardation

• Delusional depression

• Depression during pregnancy

Patients who have stopped eating may need ECT to prevent death. ECT is particularly effective for psychotic depression or catatonia (4).

Response during the initial treatment of 6 to 12 ECT treatments is often rapid (4). Relapse after ECT is common, and medications are usually maintained after ECT is stopped. ECT is also tapered and sometimes given as maintenance therapy to prevent relapse.

Modern ECT, delivered under general anesthesia, is typically well tolerated but confusion and memory impairment may occur acutely. Much of this improves and is resolved by 6 months following a course of ECT, but retrograde amnesia may persist for the long term. This is particularly so for memories from the several months preceding ECT. Patients with baseline cognitive deficits, those receiving bilateral treatments, older patients, and patients receiving lithium are at higher risk for memory impairment and confusion. Modern ECT, delivered under general anesthesia, is typically well tolerated but confusion and memory impairment may occur acutely. Much of this improves and is resolved by 6 months following a course of ECT, but retrograde amnesia may persist for the long term. This is particularly so for memories from the several months preceding ECT. Patients with baseline cognitive deficits, those receiving bilateral treatments, older patients, and patients receiving lithium are at higher risk for memory impairment and confusion.

Repetitive transcranial magnetic stimulation (rTMS)

The use of repetitive transcranial magnetic stimulation (rTMS) for the acute treatment of major depressive disorder has substantial support from randomized trials (7) and consensus recommendations (8). Low-frequency rTMS may be applied to the right dorsolateral prefrontal cortex (DLPC), and high-frequency rTMS can be applied to the left DLPC. Various protocols for the administration of rTMS are under development to increase effectiveness and to decrease the time needed for a full course. The most common adverse effects are headaches and scalp discomfort; both occur more often when high-frequency rather than low-frequency rTMS is used.

Phototherapy

Phototherapy is best known for its effects on seasonal depression but appears to be effective for nonseasonal depression as well (9).

Treatment can be provided at home with a special light unit that provides 2500 to 10,000 lux at a distance of 30 to 60 cm that patients sit in front of for 30 to 60 minutes/day (longer with a less intense light source).

In patients who go to sleep late at night and rise late in the morning, light therapy is most effective in the morning, sometimes supplemented with 5 to 10 minutes of exposure between 3 PM and 7 PM. For patients who go to sleep and rise early, light therapy is most effective between 3 PM and 7 PM.

Other therapies

Ketamine and esketamine are N-methyl-D-aspartate receptor antagonists that are used to treat treatment-reistant depression.

Psychostimulants (eg, dextroamphetamine, methylphenidate) are sometimes used, often in combination with antidepressants. A number of randomized trials support their use in depressive disorders ((eg, dextroamphetamine, methylphenidate) are sometimes used, often in combination with antidepressants. A number of randomized trials support their use in depressive disorders (10).

Herbs or other supplements are used by some patients. St. John’s wort may be effective for mild depression, although data are contradictory (11). St. John’s wort may interact with other antidepressants and other medications. Some randomized trials of omega-3 supplementation, used as augmentation or as monotherapy, have suggested that eicosapentaenoic acid has useful antidepressant effects (12).

Vagus nerve stimulation involves intermittently stimulating the vagus nerve via an implanted pulse generator. It may be useful for depression refractory to other treatments but usually takes 3 to 6 months to be effective (13, 14).

Deep brain stimulation using implanted electrodes that target the subgenual cingulate or the anterior ventral internal capsule/ventral striatum has had promising results in uncontrolled case series (15). Randomized trials are underway.

Treatment references

1. 1. Bulloch A, Williams J, Lavorato D, Patten S. Recurrence of major depressive episodes is strongly dependent on the number of previous episodes. Depress Anxiety. 2014;31(1):72-76. doi:10.1002/da.22173

2. 2. Rosner R, Bartl H, Pfoh G, et al. Efficacy of an integrative CBT for prolonged grief disorder: A long-term follow-up. J Affect Disord. 183:106-112, 2015. doi: 10.1016/j.jad.2015.04.051

3. 3. Cuijpers P, Karyotaki E, Weitz E, et al. The effects of psychotherapies for major depression in adults on remission, recovery and improvement: A meta-analysis. J Affect Disord. 159:118-126, 2014. doi: 10.1016/j.jad.2014.02.026

4. 4. Espinoza RT, Kellner CH. Electroconvulsive Therapy. N Engl J Med. 2022;386(7):667-672. doi:10.1056/NEJMra2034954

5. 5. Ross EL, Zivin K, Maixner DF. Cost-effectiveness of Electroconvulsive Therapy vs Pharmacotherapy/Psychotherapy for Treatment-Resistant Depression in the United States. JAMA Psychiatry. 2018;75(7):713-722. doi:10.1001/jamapsychiatry.2018.0768

6. 6. Rose S, Dotters-Katz SK, Kuller JA. Electroconvulsive Therapy in Pregnancy: Safety, Best Practices, and Barriers to Care. Obstet Gynecol Surv. 2020;75(3):199-203. doi:10.1097/OGX.0000000000000763

7. 7. Berlim MT, van den Eynde F, Tovar-Perdomo S, et al. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: A systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol Med. 44(2):225-239, 2014. doi: 10.1017/S0033291713000512

8. 8. McClintock SM, Reti IM, Carpenter LL, et al. Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression. J Clin Psychiatry. 2018;79(1):16cs10905. doi:10.4088/JCP.16cs10905

9. 9. Dong C, Shi H, Liu P, et al. A critical overview of systematic reviews and meta-analyses of light therapy for non-seasonal depression. Psychiatry Res. 314:114686, 2022. doi: 10.1016/j.psychres.2022.114686

10. 10. McIntyre RS, Lee y, Zhou AJ, et al. The efficacy of psychostimulants in major depressive episodes: A systematic review and meta-analysis. J Clin Psychopharmacol. 37(4):412-418, 2017. doi: 10.1097/JCP.0000000000000723

11. 11. Simon GE, Moise N, Mohr DC. Management of Depression in Adults: A Review. JAMA. 2024;332(2):141-152. doi:10.1001/jama.2024.5756

12. 12. Bazinet RP, Metherel AH, Chen CT, et al. Brain eicosapentaenoic acid metabolism as a lead for novel therapeutics in major depression. Brain Behav Immun. 85:21-28, 2020. doi: 10.1016/j.bbi.2019.07.001

13. 13. Kamel LY, Xiong W, Gott BM, Kumar A, Conway CR. Vagus nerve stimulation: An update on a novel treatment for treatment-resistant depression. J Neurol Sci. 2022;434:120171. doi:10.1016/j.jns.2022.120171

14. 14. Müller HHO, Moeller S, Lücke C, Lam AP, Braun N, Philipsen A. Vagus Nerve Stimulation (VNS) and Other Augmentation Strategies for Therapy-Resistant Depression (TRD): Review of the Evidence and Clinical Advice for Use. Front Neurosci. 2018;12:239. Published 2018 Apr 10. doi:10.3389/fnins.2018.00239

15. 15. Bergfeld IO, Mantione M, Hoogendoorn MLC, et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry. 73(5):456-64, 2016. doi: 10.1001/jamapsychiatry.2016.0152