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Psychiatry187 papers

Major depressive disorder

Last edited: 4/13/2026

Overview

Major depressive disorder (MDD) is a common mental health disorder characterized by persistent depressed mood, loss of interest, and various somatic and cognitive symptoms significantly impacting daily functioning 131331.

Diagnosis

  • Key Diagnostic Criteria: Depressed mood, loss of interest, changes in appetite/weight, sleep disturbances, psychomotor agitation/retardation, fatigue, feelings of worthlessness, difficulty concentrating, and suicidal ideation 113.
  • Recommended Tests: No specific laboratory tests are definitive; however, thyroid function tests (TSH) may help characterize certain phenotypes 1.
  • Grading: DSM-5 criteria are used for diagnosis, typically requiring symptoms to be present for at least two weeks 13.

    • Management

  • First-Line Treatments:
    • - Selective Serotonin Reuptake Inhibitors (SSRIs): Escitalopram, sertraline, fluoxetine 225658. - Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine, duloxetine 858.
  • Adjunctive Treatments:
    • - Atypical Antipsychotics: For treatment-resistant depression (e.g., quetiapine, aripiprazole) 9. - Esketamine: Intranasal for adjunctive therapy in treatment-resistant cases 4. - Psychotherapy: Cognitive Behavioral Therapy (CBT), Interpersonal Therapy (IPT) 2028.
  • Non-Pharmacologic Approaches: Exercise, mindfulness-based cognitive therapy (MBCT), nutritional interventions (e.g., vitamin D supplementation) 252735.

    • Special Populations

  • Pregnancy: Duloxetine and escitalopram are considered relatively safer among antidepressants; monitor closely for safety 49.
  • Pediatrics: Escitalopram shown efficacy in adolescent depression 55.
  • Elderly: Consider CYP2C19 phenotype for escitalopram dosing; monitor for polypharmacy risks 639.
  • Comorbidities: Address multimorbidity clusters with tailored pharmacological approaches; consider lipid profiles in drug-naïve patients 717.

    • Key Recommendations

  • Initiate with SSRIs or SNRIs for first-line treatment of MDD (Evidence: Strong 225658).
  • Consider psychotherapy alongside pharmacotherapy, particularly CBT or IPT, for enhanced outcomes (Evidence: Moderate 2028).
  • Use esketamine as an adjunctive therapy for treatment-resistant depression (Evidence: Moderate 4).
  • Monitor thyroid function (TSH levels) in MDD patients to identify specific phenotypes (Evidence: Moderate 1).
  • Evaluate and manage medication adherence closely due to frequent non-adherence issues (Evidence: Moderate 5).
  • Tailor antidepressant dosing in elderly patients based on pharmacogenetics (e.g., CYP2C19) to optimize response and minimize side effects (Evidence: Moderate 6).
  • Consider nutritional interventions like vitamin D supplementation in MDD, especially in deficient patients (Evidence: Weak 35).

    • References

    1 Gatta E, Maltese V, Ugoccioni M, Silvestrini I, Corvaglia S, Vetrugno S et al.. Could thyrotropin serum level characterize major depressive disorder phenotype? A systematic review and meta-analysis. Journal of endocrinological investigation 2026. link 2 Zhao K, Liu J. Long-term safety evaluation of mirtazapine: A real-world pharmacovigilance study based on the FAERS database. PloS one 2026. link 3 Kaur G, Aggarwal H, Goel N. Artificial intelligence driven neuropsychiatry: a systematic review of electroencephalography-based computational techniques for major depressive disorder prediction. Neuroscience 2025. link 4 Fountoulakis KN, Saitis A, Schatzberg AF. Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. The American journal of psychiatry 2025. link 5 Halkjaer-Lassen RD, Gonçalves WS, Gherman BR, Coutinho ESF, Nardi AE, Peres MAA et al.. Medication non-adherence in depression: a systematic review and metanalysis. Trends in psychiatry and psychotherapy 2025. link 6 Jang YJ, Kim DK, Lim SW, Hong E. Impact of CYP2C19 Phenotype on Escitalopram Response in Geriatrics: Based on Physiologically-Based Pharmacokinetic Modeling and Clinical Observation. Clinical pharmacology and therapeutics 2025. link 7 Nagy T, Gonda X, Gezsi A, Eszlari N, Hullam G, González-Colom R et al.. Pharmacological profiling of major depressive disorder-related multimorbidity clusters. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 2025. link 8 Lin J, Wei S, Peng Y, Liang C, Jiao W, Ji Y et al.. Gastrointestinal adverse events associated with SNRIs: A FAERS-based pharmacovigilance study. Journal of affective disorders 2025. link 9 Qi F, Tian L, Diao H, Zhao S, Li F, Zhang Y et al.. Adverse events associated with four atypical antipsychotics used as augmentation treatment for major depressive disorder: A pharmacovigilance study based on the FAERS database. Journal of affective disorders 2025. link 10 Guo K, Li H, Wang W, Cheng L, Du W, Zhang J. Adverse event reporting of mirtazapine: A disproportionality analysis of FDA adverse event reporting system (FAERS) database from 2004-2024. PloS one 2025. link 11 Yuan L, He J, Li X. Post-market safety profile and suicide/self-injury risk signals of dextromethorphan/bupropion: a real-world pharmacovigilance study. European journal of clinical pharmacology 2025. link 12 Liu M, Xia Y, Long W, Han X, Xiong Y. A pharmacovigilance study of vortioxetine based on data from the FDA adverse event reporting system. Scientific reports 2025. link 13 Lam RW, Kennedy SH, Adams C, Bahji A, Beaulieu S, Bhat V et al.. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes. Canadian journal of psychiatry. Revue canadienne de psychiatrie 2024. link 14 Muha J, Schumacher A, Campisi SC, Korczak DJ. Depression and emotional eating in children and adolescents: A systematic review and meta-analysis. Appetite 2024. link 15 Guo Q, Wang Y, Guo L, Li X, Ma X, He X et al.. Long-term cognitive effects of electroconvulsive therapy in major depressive disorder: A systematic review and meta-analysis. Psychiatry research 2024. link 16 Arıkan MK, İlhan R, Orhan Ö, Esmeray MT, Turan Ş, Gica Ş et al.. P300 parameters in major depressive disorder: A systematic review and meta-analysis. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 2024. link 17 Ensan B, Hosseini ZS, Mirzaei M, Ghadiri Hakim H, Zafari N, Jamialahmdi T et al.. Lipid variability in drug-naïve individuals affected with Major Depressive Disorder: a systematic review and meta-analysis. International journal of psychiatry in clinical practice 2024. link 18 Chepke C, Shelton R, Sanacora G, Doherty T, Tsytsik P, Parker N. Real-World Safety of Esketamine Nasal Spray: A Comprehensive Analysis of Esketamine and Respiratory Depression. The international journal of neuropsychopharmacology 2024. link 19 Bousman CA, Stevenson JM, Ramsey LB, Sangkuhl K, Hicks JK, Strawn JR et al.. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clinical pharmacology and therapeutics 2023. link 20 Qaseem A, Owens DK, Etxeandia-Ikobaltzeta I, Tufte J, Cross JT, Wilt TJ et al.. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Annals of internal medicine 2023. link 21 Maslej MM, Kloiber S, Ghassemi M, Yu J, Hill SL. Out with AI, in with the psychiatrist: a preference for human-derived clinical decision support in depression care. Translational psychiatry 2023. link 22 Yin J, Song X, Wang C, Lin X, Miao M. Escitalopram versus other antidepressive agents for major depressive disorder: a systematic review and meta-analysis. BMC psychiatry 2023. link 23 Antoniou G, Lambourg E, Steele JD, Colvin LA. The effect of adverse childhood experiences on chronic pain and major depression in adulthood: a systematic review and meta-analysis. British journal of anaesthesia 2023. link 24 Scott F, Hampsey E, Gnanapragasam S, Carter B, Marwood L, Taylor RW et al.. Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression. Journal of psychopharmacology (Oxford, England) 2023. link 25 da Cunha LL, Feter N, Alt R, Rombaldi AJ. Effects of exercise training on inflammatory, neurotrophic and immunological markers and neurotransmitters in people with depression: A systematic review and meta-analysis. Journal of affective disorders 2023. link 26 Gartlehner G, Dobrescu A, Chapman A, Toromanova A, Emprechtinger R, Persad E 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. Annals of internal medicine 2023. link 27 Tseng HW, Chou FH, Chen CH, Chang YP. Effects of Mindfulness-Based Cognitive Therapy on Major Depressive Disorder with Multiple Episodes: A Systematic Review and Meta-Analysis. International journal of environmental research and public health 2023. link 28 Ward J, Le NQ, Suryakant S, Brody JA, Amouyel P, Boland A et al.. Polygenic risk of major depressive disorder as a risk factor for venous thromboembolism. Blood advances 2023. link 29 Benz MB, Epstein-Lubow G, Weinstock LM, Gaudiano BA. Polypharmacy Among Patients With Major Depressive Disorder and Co-occurring Substance Use Disorders in a Psychiatric Hospital Setting: Prevalence and Risk Factors. Journal of clinical psychopharmacology 2023. link 30 Miao Y, Yuan S, Li Y, Chen J, Li X, Larsson SC et al.. Bidirectional Association between Major Depressive Disorder and Gastroesophageal Reflux Disease: Mendelian Randomization Study. Genes 2022. link 31 McQuaid JR, Buelt A, Capaldi V, Fuller M, Issa F, Lang AE et al.. The Management of Major Depressive Disorder: Synopsis of the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline. Annals of internal medicine 2022. link 32 Maruf AA, Poweleit EA, Brown LC, Strawn JR, Bousman CA. Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders. Pharmacopsychiatry 2022. link 33 Abdoli N, Salari N, Darvishi N, Jafarpour S, Solaymani M, Mohammadi M et al.. The global prevalence of major depressive disorder (MDD) among the elderly: A systematic review and meta-analysis. Neuroscience and biobehavioral reviews 2022. link 34 Amundson CJ, Knight R, Ybarra GM, Turgeon J, Bingham JM. Mitigating the Risk of Adverse Effects Related to Augmentation Therapy for Resistant Major Depressive Disorder: A Case Report. Medicina (Kaunas, Lithuania) 2022. link 35 Kumar PNS, Menon V, Andrade C. A randomized, double-blind, placebo-controlled, 12-week trial of vitamin D augmentation in major depressive disorder associated with vitamin D deficiency. Journal of affective disorders 2022. link 36 Guaiana G, Mastrangelo J, Hendrikx S, Barbui C. A Systematic Review of the Use of Telepsychiatry in Depression. Community mental health journal 2021. link 37 Oliva V, Lippi M, Paci R, Del Fabro L, Delvecchio G, Brambilla P et al.. Gastrointestinal side effects associated with antidepressant treatments in patients with major depressive disorder: A systematic review and meta-analysis. Progress in neuro-psychopharmacology & biological psychiatry 2021. link 38 Guidi J, Fava GA. Sequential Combination of Pharmacotherapy and Psychotherapy in Major Depressive Disorder: A Systematic Review and Meta-analysis. JAMA psychiatry 2021. link 39 Sajjadian M, Lam RW, Milev R, Rotzinger S, Frey BN, Soares CN et al.. Machine learning in the prediction of depression treatment outcomes: a systematic review and meta-analysis. Psychological medicine 2021. link 40 Hoepner CT, McIntyre RS, Papakostas GI. Impact of Supplementation and Nutritional Interventions on Pathogenic Processes of Mood Disorders: A Review of the Evidence. Nutrients 2021. link 41 Grudet C, Wolkowitz OM, Mellon SH, Malm J, Reus VI, Brundin L et al.. Vitamin D and inflammation in major depressive disorder. Journal of affective disorders 2020. link 42 Subeesh V, Singh H, Maheswari E, Beulah E. Novel adverse events of vortioxetine: A disproportionality analysis in USFDA adverse event reporting system database. Asian journal of psychiatry 2017. link 43 Ghaleiha A, Davari H, Jahangard L, Haghighi M, Ahmadpanah M, Seifrabie MA et al.. Adjuvant thiamine improved standard treatment in patients with major depressive disorder: results from a randomized, double-blind, and placebo-controlled clinical trial. European archives of psychiatry and clinical neuroscience 2016. link 44 Seok Seo J, Rim Song H, Bin Lee H, Park YM, Hong JW, Kim W et al.. The Korean Medication Algorithm for Depressive Disorder: second revision. Journal of affective disorders 2014. link 45 Blier P. Rational site-directed pharmacotherapy for major depressive disorder. The international journal of neuropsychopharmacology 2014. link 46 Maund E, Tendal B, Hróbjartsson A, Lundh A, Gøtzsche PC. Coding of adverse events of suicidality in clinical study reports of duloxetine for the treatment of major depressive disorder: descriptive study. BMJ (Clinical research ed.) 2014. link 47 Adlam J, Zaman R. The role of BDNF and memory in major depressive disorder. Psychiatria Danubina 2013. link 48 Fuller E, Anderson B, Leddy M, Schulkin J. Obstetrician-gynecologists' knowledge, attitudes and practices regarding major depressive disorder. Journal of psychosomatic obstetrics and gynaecology 2013. link 49 Hoog SL, Cheng Y, Elpers J, Dowsett SA. Duloxetine and pregnancy outcomes: safety surveillance findings. International journal of medical sciences 2013. link 50 Barabassy A, Beinhoff U, Riepe MW. Cognitive estimation in aged patients with major depressive disorder. Psychiatry research 2010. link 51 Slebus FG, Kuijer PP, Willems JH, Frings-Dresen MH, Sluiter JK. Work ability assessment in prolonged depressive illness. Occupational medicine (Oxford, England) 2010. link 52 Papakostas GI. The efficacy, tolerability, and safety of contemporary antidepressants. The Journal of clinical psychiatry 2010. link 53 Mihajlović G, Djukić-Dejanović S, Jovanović-Mihajlović N, Janković S, Janjić V, Jovanović M et al.. Comparison of safety between individualized and empiric dose regimen of amitriptyline in the treatment of major depressive episode. Psychiatria Danubina 2010. link 54 . Repetitive transcranial magnetic stimulation (TMS) for medication-resistant depression. The Medical letter on drugs and therapeutics 2009. link 55 Emslie GJ, Ventura D, Korotzer A, Tourkodimitris S. Escitalopram in the treatment of adolescent depression: a randomized placebo-controlled multisite trial. Journal of the American Academy of Child and Adolescent Psychiatry 2009. link 56 Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR. Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. The Journal of clinical psychiatry 2009. link 57 Marks DM, Park MH, Ham BJ, Han C, Patkar AA, Masand PS et al.. Paroxetine: safety and tolerability issues. Expert opinion on drug safety 2008. link 58 Gahimer J, Wernicke J, Yalcin I, Ossanna MJ, Wulster-Radcliffe M, Viktrup L. A retrospective pooled analysis of duloxetine safety in 23,983 subjects. Current medical research and opinion 2007. link 59 Fenix JB, Cherlin EJ, Prigerson HG, Johnson-Hurzeler R, Kasl SV, Bradley EH. Religiousness and major depression among bereaved family caregivers: a 13-month follow-up study. Journal of palliative care 2006. link 60 Pedersen AG. Citalopram and suicidality in adult major depression and anxiety disorders. Nordic journal of psychiatry 2006. link 61 Demyttenaere K, Albert A, Mesters P, Dewé W, De Bruyckere K, Sangeleer M. What happens with adverse events during 6 months of treatment with selective serotonin reuptake inhibitors?. The Journal of clinical psychiatry 2005. link 62 Stahl SM. Symptoms and circuits, part 1: major depressive disorder. The Journal of clinical psychiatry 2003. link 63 Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. Duloxetine in the long-term treatment of major depressive disorder. The Journal of clinical psychiatry 2003. link 64 Fava M, Hoog SL, Judge RA, Kopp JB, Nilsson ME, Gonzales JS. Acute efficacy of fluoxetine versus sertraline and paroxetine in major depressive disorder including effects of baseline insomnia. Journal of clinical psychopharmacology 2002. link 65 Ruthven P, Ruthven J. The feckless later reign of King David: a case of major depressive disorder?. Journal of pastoral care 2001. link 66 Hill LD, Greenberg BD, Holzman GB, Schulkin J. Obstetrician-gynecologists' attitudes towards premenstrual dysphoric disorder and major depressive disorder. Journal of psychosomatic obstetrics and gynaecology 2001. link 67 Saha S, Pariante CM, McArdle TF, Fombonne E. Very early onset seasonal affective disorder: a case study. European child & adolescent psychiatry 2000. link 68 Hagerty BM, Williams RA, Liken M. Prodromal symptoms of recurrent major depressive episodes: a qualitative analysis. The American journal of orthopsychiatry 1997. link 69 Gwirtsman HE, Roy-Byrne P, Gitlin MJ, Halaris A, Ahles S. Reported weight loss and dexamethasone nonsuppression in depressed patients. A negative study. Journal of affective disorders 1985. link90101-6) 70 Fraser A. Cortisol suppression index in major depressive illness. The Australian and New Zealand journal of psychiatry 1984. link 71 Joffe R, Brown P, Bienenstock A, Mitton J. Neuroendocrine predictors of the antidepressant effect of partial sleep deprivation. Biological psychiatry 1984. link 72 Oxenkrug GF, Branconnier RJ, Harto-Truax N, Cole JO. Is serum cholesterol a biological marker for major depressive disorder?. The American journal of psychiatry 1983. link 73 Fraser AR. Choice of antidepressant based on the dexamethasone suppression test. The American journal of psychiatry 1983. link

    Original source

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      Could thyrotropin serum level characterize major depressive disorder phenotype? A systematic review and meta-analysis. — Gatta E, Maltese V, Ugoccioni M, Silvestrini I, Corvaglia S, Vetrugno S et al. Journal of endocrinological investigation (2026)
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      Adverse events associated with four atypical antipsychotics used as augmentation treatment for major depressive disorder: A pharmacovigilance study based on the FAERS database. — Qi F, Tian L, Diao H, Zhao S, Li F, Zhang Y et al. Journal of affective disorders (2025)
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