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Antidepressant medications, also called antidepressive agents, are "mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several monoamine oxidase inhibitors are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (tricyclic antidepressant) also appear to act through brain catecholamine systems. A third group (second-generation antidepressant agents) is a diverse group of drugs including some that act specifically on serotonergic systems."[1]

Mechanism of action

Depression may be due to the monoamine-deficiency hypothesis, which is a "deficiency in serotonin or norepinephrine neurotransmission in the brain."[2]


Tricyclic antidepressants

For more information, see: Tricyclic antidepressant.

Tricyclic antidepressants are "substances that contain a fused three-ring moiety and are used in the treatment of depression. These drugs block the uptake of norepinephrine and serotonin into axon terminals and may block some subtypes of serotonin, adrenergic, and histamine receptors. However the mechanism of their antidepressant effects is not clear because the therapeutic effects usually take weeks to develop and may reflect compensatory changes in the central nervous system."[3]

Heterocyclic antidepressants

Heterocyclic antidepressants include trazadone and bupropion, and more recently, mirtazapine and nefazadone which are based on trazadone[4]

Second-generation antidepressants

For more information, see: Second-generation antidepressant.

Second-generation antidepressants are a "structurally and mechanistically diverse group of drugs that are not tricyclics or monoamine oxidase inhibitors. The most clinically important appear to act selectively on serotonergic systems, especially by inhibiting serotonin reuptake."[5]

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors are a "chemically heterogeneous group of drugs that have in common the ability to block oxidative deamination of naturally occurring monoamines".[6]


The effectiveness is antidepressants depends on the severity of a patient's depression. This relationship may be due to thedeclining effect of placebo among more severely depressed patients.[7]

The effectiveness of antidepressants depending on severity of depression[7]
American Psychiatric Association classification of severity[8] Hamilton Depression Rating Scale (HDRS) Number needed to treat Clinical significance (NICE)[9]
Mild to moderate < 19 16 No
Severe 19 - 22 11 No
Very severe > 22 4 Yes

"The clinical response of our patients underscores the usefulness of mirtazapine in the treatment of the comorbid symptoms of weight loss, insomnia, and anxiety". [10]

Amitriptyline, mirtazapine, and paroxetine may case more weight gain than other antidepressents according to a meta-analysis.[11]

Drug toxicity

Second-generation antidepressants are not clearly safer than tricyclic antidepressants.[12]

Neuroleptic malignant syndrome

For more information, see: Neuroleptic malignant syndrome.

Serotonin syndrome

For more information, see: serotonin syndrome.

Recurrence of illness after discontinuation

The recurrence risk for depression or panic was shorter if antidepressants were discontinued over 7 days or less.[13]


  1. Anonymous (2023), Antidepressant (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Belmaker RH, Agam G (2008). "Major depressive disorder". N. Engl. J. Med. 358 (1): 55–68. DOI:10.1056/NEJMra073096. PMID 18172175. Research Blogging.
  3. Anonymous (2023), Tricyclic Antidepressive Agents (English). Medical Subject Headings. U.S. National Library of Medicine.
  4. Katzung, Bertram G. (2006). “Antidepressant Agents”, Basic and Clinical Pharmacology, 10th. New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-145153-6. 
  5. Anonymous (2023), Second-generation antidepressants (English). Medical Subject Headings. U.S. National Library of Medicine.
  6. Anonymous (2023), Monoamine Oxidase Inhibitors (English). Medical Subject Headings. U.S. National Library of Medicine.
  7. 7.0 7.1 Lo B (2010). "Commentary: Conflict of interest policies: an opportunity for the medical profession to take the lead.". Acad Med 85 (1): 9-11. DOI:10.1097/ACM.0b013e3181c46e96. PMID 20042812. Research Blogging. Cite error: Invalid <ref> tag; name "pmid20042812" defined multiple times with different content
  8. First, Michael B. (2007). Handbook of Psychiatric Measures, Second Edition. American Psychiatric Publishing, Inc. ISBN 1-58562-218-4. 
  9. National Institute for Clinical Excellence. Depression: Management of Depression in Primary and Secondary Care. London, England: National Institute for Clinical Excellence; 2004.
  10. Raji MA, Brady SR (2001). "Mirtazapine for treatment of depression and comorbidities in Alzheimer disease.". Ann Pharmacother 35 (9): 1024-7. PMID 11573849[e]
  11. Serretti A, Mandelli L (2010). "Antidepressants and body weight: a comprehensive review and meta-analysis.". J Clin Psychiatry 71 (10): 1259-72. DOI:10.4088/JCP.09r05346blu. PMID 21062615. Research Blogging.
  12. Coupland CA, Dhiman P, Barton G, Morriss R, Arthur A, Sach T et al. (2011). "A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database.". Health Technol Assess 15 (28): 1-202, iii-iv. DOI:10.3310/hta15280. PMID 21810375. Research Blogging.
  13. Baldessarini RJ, Tondo L, Ghiani C, Lepri B (2010). "Illness risk following rapid versus gradual discontinuation of antidepressants.". Am J Psychiatry 167 (8): 934-41. DOI:10.1176/appi.ajp.2010.09060880. PMID 20478876. Research Blogging.

See also