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Antidepressants commonly refers to family of pharmaceutical agents used in modern medicine for the treatment of major depressive disorder and other conditions, including dysthymia, anxiety disorders, obsessive-compulsive disorder, eating disorders, chronic pain, neuropathic pain and, in some cases, dysmenorrhoea, snoring, migraine, attention-deficit hyperactivity disorder (ADHD), dependence/addiction, and sleep disorders. They may be prescribed alone or in combination with other medications.[citation needed]

The major classes of antidepressants are the selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase A inhibitors (rMAO-A inhibitors), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), and noradrenergic and specific serotonergic antidepressant (NaSSAs). Herbal substances such as St. John's wort is also sometimes used in the treatment of depression[1][2]

Clinical Guidelines for Diagnosis and Prescription

Major Depressive Disorder

The UK National Institute for Health and Care Excellence( NICE) 2009 guidelines indicate that antidepressants should not be routinely used for the initial treatment of mild depression because the risk-benefit ratio is poor. The guidelines recommend that antidepressant treatment should be considered for:

  • People with a history of moderate or severe depression,
  • Those with mild depression that has been present for a long period,
  • As a second-line treatment for mild depression that persists after other interventions,
  • As a first-line treatment for moderate or severe depression.

The guidelines further note that antidepressant treatment should be used in combination with psychosocial interventions in most cases, should be continued for at least six months to reduce the risk of relapse, and that SSRIs are typically better tolerated than other antidepressants.[3]


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The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine).[4] It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters.[4] All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway.[4] Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants.[5][6] A number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses.[5][6][7][8]

Major types

Types of antidepressants


Serotonin reuptake inhibitors

Dextromethorphan[9] Because dextromethorphan can show similar antidepressant effects to ketamine in low doses (compared to common recreational doses), it is possible that dextromethorphan could be a possible treatment for treatment-resistant and severe depression. Many users of dextromethorphan claim that they do not feel any depression within a week of using dextromethorphan.[citation needed] It has a very similar mechanism of action to SSRIs. It is also useful for anxiety.

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors are believed to increase the level of extracellular serotonin, therefore allowing more serotonin to be in the brain. The reason SSRIs are used for depression is that the serotonin hypothesis, one of the most commonly accepted theories for depression, states that low serotonin in the brain causes depression. SSRIs are the most commonly prescribed antidepressant, and the most commonly prescribed anxiolytic for children. They are also the first-line treatment for panic disorder, not benzodiazepines like lorazepam and alprazolam.

Selective serotonin reuptake enhancers (SSREs)

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

Serotonin modulators and stimulators (SMSes)

Serotonin antagonists and reuptake inhibitors (SARIs)

Serotonin releasing agents (SRAs)

These agents work by directly increasing the amount of serotonin in the brain. Substances such as cocaine and MDMA can do this, but both are addictive and tolerance quickly builds to each. Additionally, the MDMA "comedown" can produce weeks to months of a low mood and motivation if the user "rolls" (doses) frequently and suddenly stops.

Norepinephrine reuptake inhibitors (NRIs)

NRIs are believed to increase the level of extracellular norepinephrine, therefore allowing more of it to be in the brain. Controversy has been sparked over the effectiveness of reboxetine, an NRI sold as Trintellix. [10]

Norepinephrine-dopamine reuptake inhibitors (NDRIs)

NDRIs are believed to increase the level of extracellular norepinephrine and dopamine, therefore allowing more of these to be in the brain. Agents such as bupropion (Wellbutrin) have been found effective for MDD with little direct effect on serotonin, and therefore it can be hypothesized that other agents are effective for it. Bupropion and other NDRIs are also effective for depression with fatigue or sleepiness.

Tricyclic antidepressants (TCAs)

Tetracyclic antidepressants (TeCAs)

Monoamine oxidase inhibitors (MAOIs)

MAOIs are usually prescribed when no other antidepressants are helping. This is because MAOIs require diet changes and have a very large amount of side effects.[11]

Reversible monoamine oxidase A inhibitors (rMAO-AI)

Psychedelics for treating depression

Psilocybin mushrooms ("Magic mushrooms")


In clinical studies, ketamine has proven to be an extremely effective and fast acting antidepressant at low doses (compared to common recreational doses).[12] It has become increasingly common for doctors to prescribe ketamine for treatment-resistant and severe depression.


[citation needed]

Adverse effects

It should be noted that many users report that the difficulty tolerating adverse effects is the primary reason for antidepressant discontinuation.


Almost any medication involved with serotonin regulation has the potential to cause serotonin toxicity (also known as serotonin syndrome) – an excess of serotonin that can induce mania, restlessness, agitation, emotional lability, insomnia and confusion as its primary symptoms.[13][14] Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24 hours) it is rarely fatal.[15][16]

MAOIs tend to have pronounced (sometimes fatal) interactions with a wide variety of medications and over-the-counter drugs. If taken with foods that contain very high levels of tyramine (e.g., mature cheese, cured meats, or yeast extracts), they may cause a potentially lethal hypertensive crisis. At lower doses the person may be bothered by only a headache due to an increase in blood pressure.[17]

Antidepressant-induced mania

Another possible problem with antidepressants is the chance of antidepressant-induced mania in patients with bipolar disorder. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the patient can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20–40% of bipolar patients.[18] For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.[19]


Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behaviour and thinking (suicidality) in those aged under 25.[20] This problem has been serious enough to warrant government intervention by the US Food and Drug Administration (FDA) to warn of the increased risk of suicidality during antidepressant treatment.[21] According to the FDA, the heightened risk of suicidality is within the first one to two months of treatment.[22][23] The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".[24] A meta-analysis suggests that the relationship between antidepressant use and suicidal behavior or thoughts is age-dependent.[20] Compared to placebo the use of antidepressants is associated with an increase in suicidal behavior or thoughts among those aged under 25 (OR=1.62). This increase in suicidality approaches that observed in children and adolescents. There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).[20][25]


Sexual side-effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm, and erectile dysfunction.[26] Although usually reversible, these sexual side-effects can, in rare cases, last for months or years after the drug has been completely withdrawn.[27]

In a study of 1022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1%[28] with SSRIs values between 57 and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7% and moclobemide 4%. Moclobemide, a selective reversible MAO-A inhibitor, does not cause sexual dysfunction,[29] and can actually lead to an improvement in all aspects of sexual function.[30]

Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5-HT2 and 5-HT3 receptors; decreased dopamine; decreased norepinephrine; blockade of cholinergic and α1adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels.[31] Mirtazapine is reported to have fewer sexual side-effects, most likely because it antagonizes 5-HT2 and 5-HT3 receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.[32]

Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of SSRI treatment.[33]

Discontinuation syndrome

Antidepressant discontinuation symptoms were first reported with imipramine, the first tricyclic antidepressant (TCA), in the late 1950s, and each new class of antidepressants has brought reports of similar conditions, including monoamine oxidase inhibitors (MAOIs), SSRIs, and SNRIs. As of 2001, at least 21 different antidepressants, covering all the major classes, were known to cause discontinuation syndromes.[34] The problem has been poorly studied, and most of the literature has been case reports or small clinical studies; incidence is hard to determine and controversial.[34]

People with discontinuation syndrome have been on an antidepressant for at least four weeks and have recently stopped taking the medication, either abruptly or after a fast taper.[35] Common symptoms include flu-like symptoms (nausea, vomiting, diarrhea, headaches, sweating), sleep disturbances (insomnia, nightmares, constant sleepiness), sensory/movement disturbances (imbalance, tremors, vertigo, dizziness, electric-shock-like experiences), mood disturbances (dysphoria, anxiety, agitation) and cognitive disturbances (confusion and hyperarousal).[35][36][37] Over fifty symptoms have been reported.[38]

Most cases of discontinuation syndrome last between one and four weeks, are relatively mild, and resolve on their own; in rare cases symptoms can be severe or extended.[35] Paroxetine and venlafaxine seem to be particularly difficult to discontinue and prolonged withdrawal syndrome lasting over 18 months have been reported with paroxetine.[34][39][40]

With the explosion of use and interest in SSRIs in the late 1980s and early 1990s, focused especially on Prozac, interest grew as well in discontinuation syndromes.[41] In the late 1990s, some investigators thought that symptoms that emerged when antidepressants were discontinued, might mean that antidepressants were causing addiction, and some used the term "withdrawal syndrome" to describe the symptoms. Addictive substances cause physiological dependence, so that drug withdrawal causes suffering. These theories were abandoned, since addiction leads to drug-seeking behavior, and people taking antidepressants do not exhibit drug-seeking behavior. The term "withdrawal syndrome" is no longer used with respect to antidepressants, to avoid confusion with problems that arise from addiction.[35][42][43] There are case reports of antidepressants being abused, but these are rare and are mostly limited to antidepressants with stimulant effects and to people who already had a substance use disorder.[44] A 2012 comparison of the effects of stopping therapy with benzodiazepines and SSRIs argued that because the symptoms are similar, it makes no sense to say that benzodiazepines are addictive while SSRIs are not.[45] Responses to that review noted that there is no evidence that people who stop taking SSRIs exhibit drug-seeking behavior while people who stop taking benzodiazepines do, and that the drug classes should be considered differently.[46][47]

History and culture

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See Also


  • Linde, K., Kriston, L., Rucker, G., Jamil, S., Schumann, I., Meissner, K., . . . Schneider, A. (2015). Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis. The Annals of Family Medicine, 13(1), 69-79. doi:10.1370/afm.1687

External links


  1. Linde, K., Kriston, L., Rucker, G., Jamil, S., Schumann, I., Meissner, K., . . . Schneider, A. (2015). Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis. The Annals of Family Medicine, 13(1), 69-79. doi:10.1370/afm.1687
  2. Linde, K., Berner, M. M., & Kriston, L. (2008). St John's wort for major depression. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd000448.pub3
  3. | Depression in adults: The treatment and management of depression in adults (National Institute for Health and Care Excellence)
  4. 4.0 4.1 4.2 Cite error: Invalid <ref> tag; no text was provided for refs named GG
  5. 5.0 5.1 Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, Kubera M, Bob P, Lerer B, Maj M (March 2009). "The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression". Metabolic Brain Disease. 24 (1): 27–53. doi:10.1007/s11011-008-9118-1. PMID 19085093. 
  6. 6.0 6.1 Sanacora G, Treccani G, Popoli M (January 2012). "Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders". Neuropharmacology. 62 (1): 63–77. doi:10.1016/j.neuropharm.2011.07.036. PMC 3205453Freely accessible. PMID 21827775. 
  7. Menke A, Klengel T, Binder EB (2012). "Epigenetics, depression and antidepressant treatment". Current Pharmaceutical Design. 18 (36): 5879–5889. doi:10.2174/138161212803523590. PMID 22681167. 
  8. Vialou V, Feng J, Robison AJ, Nestler EJ (January 2013). "Epigenetic mechanisms of depression and antidepressant action". Annual Review of Pharmacology and Toxicology. 53 (1): 59–87. doi:10.1146/annurev-pharmtox-010611-134540. PMID 23020296. 
  10. "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis." Multiple authors (2009)
  13. Birmes P, Coppin D, Schmitt L, Lauque D (2003). "Serotonin syndrome: a brief review". CMAJ. 168 (11): 1439–42. PMC 155963Freely accessible. PMID 12771076. 
  14. Boyer EW, Shannon M (2005). "The serotonin syndrome" (PDF). N. Engl. J. Med. 352 (11): 1112–20. doi:10.1056/NEJMra041867. PMID 15784664. Archived from the original (PDF) on 18 June 2013. 
  15. Mason PJ, Morris VA, Balcezak TJ (2000). "Serotonin syndrome. Presentation of 2 cases and review of the literature". Medicine. 79 (4): 201–9. doi:10.1097/00005792-200007000-00001. PMID 10941349. 
  16. Sampson E, Warner JP (1999). "Serotonin syndrome: potentially fatal but difficult to recognize". Br J Gen Pract. 49 (448): 867–8. PMC 1313553Freely accessible. PMID 10818648. 
  17. Sathyanarayana Rao TS, Yeragani VK (2009). "Hypertensive crisis and cheese". Indian J Psychiatry. 51 (1): 65–6. doi:10.4103/0019-5545.44910. PMC 2738414Freely accessible. PMID 19742203. 
  18. Goldberg JF, Truman CJ (2003). "Antidepressant-induced mania: An overview of current controversies". Bipolar Disorders. 5 (6): 407–20. doi:10.1046/j.1399-5618.2003.00067.x. PMID 14636364. 
  19. Benazzi F (1997). "Antidepressant-associated hypomania in outpatient depression: a 203-case study in private practice". J Affect Disord. 46 (1): 73–7. doi:10.1016/S0165-0327(97)00082-7. PMID 9387089. 
  20. 20.0 20.1 20.2 Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A, Hammad TA, Temple R, Rochester G (2009). "Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration". BMJ. 339: b2880. doi:10.1136/bmj.b2880. PMC 2725270Freely accessible. PMID 19671933. 
  21. Friedman RA, Leon AC (2007). "Expanding the black box – depression, antidepressants, and the risk of suicide". N. Engl. J. Med. 356 (23): 2343–6. doi:10.1056/NEJMp078015. PMID 17485726. 
  22. "Antidepressant Use in Children, Adolescents, and Adults". 
  23. "FDA Medication Guide for Antidepressants". Retrieved 5 June 2014. 
  24. "" (PDF). 
  25. Healy D, Aldred G (2005). "Antidepressant drug use and the risk of suicide" (PDF). International Review of Psychiatry. 17: 163–172. doi:10.1080/09540260500071624. 
  26. Grant JE, Potenza MN, eds. (2012). The Oxford handbook of impulse control disorders. Oxford: Oxford University Press. ISBN 978-0-19-538971-5. 
  27. Csoka AB, Csoka A, Bahrick A, Mehtonen OP (2008). "Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors". J Sex Med. 5 (1): 227–33. doi:10.1111/j.1743-6109.2007.00630.x. PMID 18173768. 
  28. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F (2001). "Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction". J Clin Psychiatry. 62 Suppl 3: 10–21. PMID 11229449. 
  29. Serretti A, Chiesa A (2009). "Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis". J Clin Psychopharmacol. 29 (3): 259–66. doi:10.1097/JCP.0b013e3181a5233f. PMID 19440080. 
  30. Chebili S, Abaoub A, Mezouane B, Le Goff JF (1998). "[Antidepressants and sexual stimulation: the correlation]". Encephale (in French). 24 (3): 180–4. PMID 9696909. 
  31. Keltner NL, McAfee KM, Taylor CL (2009). "Biological Perspectives". Perspectives in Psychiatric Care. 38 (3): 111–6. doi:10.1111/j.1744-6163.2002.tb00665.x. PMID 12385082. 
  32. Ozmenler NK, Karlidere T, Bozkurt A, Yetkin S, Doruk A, Sutcigil L, Cansever A, Uzun O, Ozgen F, Ozsahin A (2008). "Mirtazapine augmentation in depressed patients with sexual dysfunction due to selective serotonin reuptake inhibitors". Hum Psychopharmacol. 23 (4): 321–6. doi:10.1002/hup.929. PMID 18278806. 
  33. Labbate LA, Grimes JB, Hines A, Pollack MH (December 1997). "Bupropion treatment of serotonin reuptake antidepressant-associated sexual dysfunction". Annals of Clinical Psychiatry. 9 (4): 241–5. doi:10.3109/10401239709147804. PMID 9511948. 
  34. 34.0 34.1 34.2 Haddad, P. (2001). "Antidepressant discontinuation syndromes". Drug Saf. 24 (3): 183–97. doi:10.2165/00002018-200124030-00003. PMID 11347722. 
  35. 35.0 35.1 35.2 35.3 Warner CH, Bobo W, Warner C, Reid S, Rachal J (August 2006). "Antidepressant discontinuation syndrome". Am Fam Physician. 74 (3): 449–56. PMID 16913164. 
  36. Haddad, P.M.; Anderson, I.M. (2007). "Recognising and managing antidepressant discontinuation symptoms". Advances in Psychiatric Treatment. 13 (6): 447–457. doi:10.1192/apt.bp.105.001966. 
  37. Renoir T (April 2013). "Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved". Front Pharmacol. 4: 45. doi:10.3389/fphar.2013.00045. PMC 3627130Freely accessible. PMID 23596418. 
  38. Haddad PM, Dursun SM (January 2008). "Neurological complications of psychiatric drugs: clinical features and management". Hum Psychopharmacol. 23 (Suppl 1): 15–26. doi:10.1002/hup.918. PMID 18098217. 
  39. Tamam, L.; Ozpoyraz, N. (January–February 2002). "Selective Serotonin Reuptake Inhibitor Discontinuation Syndrome: A Review". Advances in Therapy. 19 (1): 17–26. doi:10.1007/BF02850015. PMID 12008858. Retrieved 28 November 2012. 
  40. Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review [Internet]. Comparative Effectiveness Reviews, No. 46. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Dec.
  41. Stutz, Bruce (6 May 2007). "Self-Nonmedication". New York Times. Retrieved 24 May 2010. 
  42. Shelton RC (2006). "The nature of the discontinuation syndrome associated with antidepressant drugs". J Clin Psychiatry. 67 (Suppl 4): 3–7. PMID 16683856. 
  43. WHO (2003) WHO Expert Committee on Drug Dependence – WHO Technical Report Series, No. 915 – Thirty-third Report
  44. Evans EA, Sullivan MA (Aug 2014). "Abuse and misuse of antidepressants". Subst Abuse Rehabil. 5: 107–20. doi:10.2147/SAR.S37917. PMID 25187753. 
  45. Nielsen M, et al. (May 2012). "What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors". Addiction. 107 (5): 900–8. doi:10.1111/j.1360-0443.2011.03686.x. PMID 21992148. 
  46. Brady K (May 2012). "Withdrawal or dependence: a matter of context. Comment on: What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors". Addiction. 107 (5): 910–1. doi:10.1111/j.1360-0443.2012.03862.x. PMID 22471576. 
  47. Lader M (May 2012). "Dependence and withdrawal: comparison of the benzodiazepines and selective serotonin re-uptake inhibitors. Comment on: What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors". Addiction. 107 (5): 909–10. doi:10.1111/j.1360-0443.2011.03736.x. PMID 22471575.