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Second-generation antidepressant

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Second-generation antidepressants are the most recently developed class of drugs used to treat depression. They are characterized by dissimilarity to tricyclic antidepressants and monoamine oxidase inhibitors, and heterogeneity of chemical form and pharmacological action. Most second-generation antidepressants commonly used in the practice of psychiatry inhibit the reuptake of monoamine neurotransmitters, most commonly serotonin, less frequently norepinephrine, and occasionally dopamine.[1]


Second-generation antidepressants are classified by the biogenic amine receptor that they affect.

Selective serotonin reuptake inhibitors(SSRI)

For more information, see: Selective serotonin uptake inhibitor.

Serotonin 5-HT2A–receptor antagonist

Serotonin norepinephrine reuptake inhibitors (SNRI)

Noradrenergic and specific serotonergic antidepressant (NaSSA)

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). Mirtazapine is a tetracyclic compound, is also classified as a tricyclic antidepressant by the National Library of Medicine in the United States.[4]

Norepinephrine uptake inhibitor

Dopamine reuptake inhibitor

Mechanism of action

Depression may be due to the monoamine-deficiency hypothesis, which is a "deficiency in serotonin or norepinephrine neurotransmission in the brain."[5]

By blocking the reuptake by the releasing neuron of norepinephrine, serotonin or both, second-generation antidepressants may overcome the mono-amine deficiency.[6] Some members of this class, perhaps in a dose-dependent manner, also block dopamine release.

In contrast, some first-generation antidepressants act through an alternate mechanism. Monoamine oxidase inhibitors raise levels of dopamine, norepinephrine and serotonin, in the synaptic gap between the releasing and receiving neurons, by blocking one of two subtypes of the enzyme in the receiving cell which metabolizes the three bioamines. These medications are named for the enzyme they suppress, monoamine oxidase. Tricyclic antidepressants suppress catechol-O-methyl transferase, and inhibit the reuptake of serotonin and norepinephrine, but also produce significant side effects, most prominently anticholinergic in nature.


Regarding the use of second-generation antidepressants, clinical practice guidelines by the American College of Physicians recommend:[7] [8]

  • "when clinicians choose pharmacologic therapy to treat patients with acute major depression, they select second-generation antidepressants on the basis of adverse effect profiles, cost, and patient preferences"
  • "second-generation antidepressants did not significantly differ in efficacy, effectiveness, or quality of life. Mirtazapine had a significantly faster onset of action"
  • "when treating symptom clusters in patients with accompanying depression, second-generation antidepressants did not differ in efficacy in treating accompanying anxiety, pain, and somatization. Limited evidence suggests that some agents may be more effective in treating insomnia"
  • "most of the second-generation antidepressants had similar adverse effects...paroxetine was associated with an increased risk for sexual dysfunction."

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.[9]

Second-generation antidepressants are not clearly safer than tricyclic antidepressants.[10]

The effectiveness of antidepressants depending on severity of depression[9]
American Psychiatric Association classification of severity[11] Hamilton Depression Rating Scale (HDRS) Number needed to treat Clinical significance (NICE)[12]
Mild to moderate < 19 16 No
Severe 19 - 22 11 No
Very severe > 22 4 Yes

Meta-analyses conflict about the relative effectiveness of the second-generation antidepressants with no difference reported[13] and superiority of sertraline and escitalopram reported. [14]


  1. Anonymous (2020), Second-generation antidepressants (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. anonymous (2012 [last update]). Safety Alerts for Human Medical Products > Celexa (citalopram hydrobromide) - Drug Safety Communication: Revised Recommendations, Potential Risk of Abnormal Heart Rhythms. Retrieved on March 29, 2012.
  3. 3.0 3.1 3.2 Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M et al. (2011). "Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis.". Ann Intern Med 155 (11): 772-85. DOI:10.1059/0003-4819-155-11-201112060-00009. PMID 22147715. Research Blogging.
  4. Anonymous (2020), Mirtazapine (English). Medical Subject Headings. U.S. National Library of Medicine.
  5. Belmaker RH, Agam G (2008). "Major depressive disorder". N. Engl. J. Med. 358 (1): 55–68. DOI:10.1056/NEJMra073096. PMID 18172175. Research Blogging.
  6. Katzung, Bertram G. (2006). “Antidepressant Agents”, Basic and Clinical Pharmacology, 10th. New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-145153-6. 
  7. Gartlehner, Gerald; Bradley N. Gaynes, Richard A. Hansen, Patricia Thieda, Angela DeVeaugh-Geiss, Erin E. Krebs, Charity G. Moore, Laura Morgan, Kathleen N. Lohr (2008-11-18). "Comparative Benefits and Harms of Second-Generation Antidepressants: Background Paper for the American College of Physicians". Ann Intern Med 149 (10): 734-750. Retrieved on 2008-11-18.
  8. Qaseem, Amir; Vincenza Snow, Thomas D. Denberg, Mary Ann Forciea, Douglas K. Owens, for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians (2008-11-18). "Using Second-Generation Antidepressants to Treat Depressive Disorders: A Clinical Practice Guideline from the American College of Physicians". Ann Intern Med 149 (10): 725-733. Retrieved on 2008-11-18.
  9. 9.0 9.1 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.
  10. 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.
  11. First, Michael B. (2007). Handbook of Psychiatric Measures, Second Edition. American Psychiatric Publishing, Inc. ISBN 1-58562-218-4. 
  12. National Institute for Clinical Excellence. Depression: Management of Depression in Primary and Secondary Care. London, England: National Institute for Clinical Excellence; 2004.
  13. Gartlehner, Gerald; Bradley N. Gaynes, Richard A. Hansen, Patricia Thieda, Angela DeVeaugh-Geiss, Erin E. Krebs, Charity G. Moore, Laura Morgan, Kathleen N. Lohr (2008-11-18). "Comparative Benefits and Harms of Second-Generation Antidepressants: Background Paper for the American College of Physicians". Ann Intern Med 149 (10): 734-750. Retrieved on 2008-11-18.
  14. Cipriani A. et al (2009). Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. The Lancet DOI:10.1016/s0140-6736(09)60046-5