Comparative efficacy and tolerability of antidepressants

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Comparative efficacy and tolerability table for antidepressants

Table

Drug Relative efficacy Tolerability Danger
in overdose 		Weight gain Ortho hypot Inactivating effects Activating effects Anti-ACh QTc i. p. GI
toxicity 		SD
[1][2][3][4][unreliable medical source?][5] [1][4][5][6] [2][3][7]
[1][4][5][6] 		[1][4][5][7][8] [1][3][4][5][7] [1][3][4][5][7][9] [1][3][4][5][7][9] [1][3][4][5][7] [3][7]
[1][4][5][9] 		[1][3][4][5][7] [1][3][4][5][7] [1][3][4][5][7]
Tricyclic antidepressants (TCAs)
Drug Relative efficacy Tolerability Danger
in overdose 		Weight gain Ortho hypot Inactivating effects Activating effects Anti-ACh QTc i. p. GI
toxicity 		SD
Amitriptyline 3 1 3 4 3 4 v 4 3 1 4/3
Amoxapine 2 2 4 2 2 2 2 2 2 v ND
Clomipramine 3 2/1 2 2 2 4/3 v 4 2 1 4
Desipramine 2 2/1 3 1 1 1/v 1 1 2 1/v ND
Dosulepin (Dothiepin) 2 1 4 ? 3/2 3/2 v 3/2 2 v 3/2
Doxepin 2 2/1 3 3 4 3 v 3 3 v 3
Imipramine 3 1 3 4 4/3 3 1 3 3 1 3
Lofepramine 2 3 1 1 1 1 1 2 1 ? ?
Maprotiline 2 2/1 4 2 2 3 v 2 3 v ND
Nortriptyline 2 2 2 1 2 1 v 1 2 v ND
Protriptyline 2 2/1 2 1 2 1 1 2 3 1 4/3
Tianeptine 2 4 ? ? ? ? ? ? ? ? ?
Trimipramine 2 1 2 4 3 4 1 4 2 2 v
Monoamine oxidase inhibitors (MAOIs)
Drug Relative efficacy Tolerability Danger
in overdose 		Weight gain Ortho hypot Inactivating effects Activating effects Anti-ACh QTc i. p. GI toxicity SD
Isocarboxazid 2 1 3 1 2 1 2 1 v 1 4
Moclobemide 2 3 1 v v v ? v v v 1/v
Phenelzine 2 1 3 2 3 1 1 1 v 1 4
Seligiline ? 3 2 v 1 v 1 1 v v v
Tranylcypromine 2 1 3 1 2 v 2 1 v 1 4
Selective serotonin reuptake inhibitors (SSRIs)
Drug Relative efficacy Tolerability Danger
in overdose 		Weight gain Ortho hypot Inactivating effects Activating effects Anti-ACh QTc i. p. GI
toxicity 		SD
Citalopram 2 3 2 1 1 v 1 v 2 1 3
Escitalopram 3 3 1 1 1 v 1 v 1 1 3
Fluoxetine 2 3 1 1 1 v 2 v 1 1 3
Fluvoxamine 2 3 2 1 1 1 1 v 1/v 2 3
Paroxetine 2 3 1 2 2 1 1 1 1/v 1 4
Sertraline 3 3 1 1 1 v 2 v 1/v 2 3
Serotonin–norepinephrine reuptake inhibitors (SNRIs)
Drug Relative efficacy Tolerability Danger
in overdose 		Weight gain Ortho hypot Inactivating effects Activating effects Anti-ACh QTc i. p. GI
toxicity 		SD
Desvenlafaxine 2 3/2 1/2 v v v 2 v v 2/1 3
Duloxetine 2 3 1 v v v 2 v v 2 3
Milnacipran 2 3 ? v v v 2 1 v 2 v
Venlafaxine 3 2 2 v v v 2 v 1 2 (IR)
1 (XR) 		3
Noradrenergic and specific serotonergic antidepressants (NaSSAs)
Drug Relative efficacy Tolerability Danger
in overdose 		Weight gain Ortho hypot Inactivating effects Activating effects Anti-ACh QTc i. p. GI
toxicity 		SD
Mianserin 2 3 ? 4 v 4 v 1 1 v 1
Mirtazapine 3 3 1 4 v 4 v 1 1 v 1
Serotonin antagonist and reuptake inhibitors (SARIs)
Drug Relative efficacy Tolerability Danger
in overdose 		Weight gain Ortho hypot Inactivating effects Activating effects Anti-ACh QTc i. p. GI
toxicity 		SD
Nefazodone 2 3 2/1 v 1 2 v 1 v 2 v
Trazodone 2 [10] 3 1 1 3 4 v v 2 3 1
Serotonin modulator and stimulators (SMSs)
Drug Relative efficacy Tolerability Danger
in overdose 		Weight gain Ortho hypot Inactivating effects Activating effects Anti-ACh QTc i. p. GI
toxicity 		SD
Vilazodone 2 3/2 ? v v v 2 v v 4 2
Vortioxetine 2 3 ? v v v 1/v v v 3 1
Other
Drug Relative efficacy Tolerability Danger
in overdose 		Weight gain Ortho hypot Inactivating effects Activating effects Anti-ACh QTc i. p. GI
toxicity 		SD
Agomelatine 2 3 1 v v 1 1 v v 1 1/v
Bupropion 2 3 3/2 v v v 2/1 v 1 1 v
Reboxetine 1 3 1 v v v 2 v v 1 1
St John's wort 3/2 4 1 1/v 1/v 1/v 1/v 1/v 1/v 1/v 1/v

Where

For adverse effects/overdose toxicity

4 means very strong effect/extreme toxicity.

3 strong effect; efficacious/high toxicity.

2 moderate effect/moderately toxic.

1 weak effect/weakly toxic.

v very weak/negligible effect

For tolerability

4 extremely tolerable. These drugs have proven to be better tolerated than the SSRIs.

3 very tolerable ? few, mild and transient side effects. These are drugs such as the SSRIs.

2 moderately tolerable. Some of the more tolerable of TCAs.

1 poor tolerability. TCAs and MAOIs mostly.

For efficacy

3 Superior efficacy drug, according to at least one review article.

2 Ordinary efficacy drug. Maybe some primary sources indicate superior efficacy relative to superior efficacy agents (e.g. agomelatine has shown superior efficacy to venlafaxine in one clinical trial) but insufficient data to say with much confidence.

1 Inferior efficacy compared to ordinary efficacy drugs, according to at least one review article.

Terms used in the table

Activating effects – adverse effects such as agitation, anxiety, insomnia and tremor.

AMH – Australian Medicines Handbook.[9]

GI – Gastrointestinal.

Inactivating effects – sedating effects such as drowsiness, somnolence and sedation.

IR – Immediate release tablets.

ND – No data.

Ortho hypot – Orthostatic hypotension

QTc i. p. – QTc interval prolongation

SD – Sexual dysfunction.

XR – Extended release tablets.

Per drug notes

[2][3][4][6][7][8][9]

Tricyclic antidepressants (TCAs)

Amitriptyline: Preferentially (8x over norepinephrine) inhibits the reuptake of serotonin but norepinephrine reuptake inhibition is clinically significant.[2] Listed as a more hepatotoxic antidepressant in a recent review article.[11]

Amoxapine: Sometimes classed with the tetracyclic antidepressants. Has atypical antipsychotic actions too. Not available in Australia, Canada or the UK but available in the US. May be faster acting. Antidopaminergic, which means that it can cause extrapyramidal side effects, tardive dyskinesia and neuroleptic malignant syndrome.[12] Causes kidney failure and seizures in overdose, although it usually does not cause cardiotoxic effects in overdose.[13]

Clomipramine: Highly selective (~120x) for serotonin reuptake inhibition. More epileptogenic than other TCAs.[2]

Desipramine: Preferentially inhibits the reuptake of norepinephrine (22x over serotonin).[2]

Dosulepin (Dothiepin): Not available in the US. Available in Australia (where it is still commonly referred to as dothiepin) and the UK.
Weight gain: probably 2
Danger in overdose: 4 [9]

Doxepin: Somewhat selective for inhibiting norepinephrine reuptake (2.3x over serotonin).

Imipramine: First marketed TCA. Somewhat selective for serotonin reuptake (26x over norepinephrine).
Relative efficacy: 3[14][15] More hepatotoxic than most other antidepressants.[11]

Lofepramine: Not licensed in Australia, US or Canada. Licensed in the UK and other European countries.
QTc i. p.: 1 (dose-dependent)

Maprotiline: Fairly selective (~90x over dopamine) norepinephrine reuptake inhibitor.[2]

Nortriptyline: Active metabolite of amitriptyline. Somewhat selective (4.2x) for norepinephrine reuptake inhibition.

Protriptyline: Relatively (14x over serotonin) selective norepinephrine reuptake inhibition.

Tianeptine: Enhances the reuptake of serotonin and increases dopaminergic and glutamatergic neurotransmission. Not approved for clinical use in Australia, Canada, the UK, the US and Ireland. More hepatotoxic than most other antidepressants.[11]

Trimipramine: Has antidopaminergic effects and hence can cause extrapyramidal side effects, tardive dyskinesia and neuroleptic malignant syndrome.

Monoamine oxidase inhibitors (MAOIs)

Isocarboxazid: Not licensed for use in Australia.

Moclobemide: Only clinically utilized reversible inhibitor of monoamine oxidase A (RIMA). Not approved for use in the US. Approved for clinical use in Australia, Canada, most European countries (including the Czech Republic, Finland and Ireland), New Zealand, Singapore, South Africa and the UK.
Activating effects: ? (insomnia common according to the AMH)

Phenelzine: Phenelzine is more prone than tranylcypromine and most other antidepressant to causing liver damage.[11]

Seligiline: Originally used a treatment for Parkinson's disease due to its selective, irreversible inhibition of MAO-B but at higher doses MAO-A inhibition occurs.

Tranylcypromine: Metabolized into amphetamine analogues in vivo. Can cause liver damage.[9]

Selective serotonin reuptake inhibitors (SSRIs)

Citalopram: Most likely of the SSRIs to prolong the QT interval. Also the most toxic SSRI in overdose. Less hepatotoxic than most other antidepressants.[11]
QTc i. p.: 2 (dose dependent; doses >40 mg/day are particularly dangerous)

Escitalopram: The more active S-enantiomer of citalopram. May be the most efficacious of the SSRIs (although no statistically significant difference between the efficacy of sertraline and escitalopram have been teased out to date). Based on the available evidence it is less toxic than its racemic counterpart, (R,S)-citalopram, in overdose. Less hepatotoxic than most other antidepressants.[11]

Fluoxetine: First SSRI to receive FDA approval in 1987. Some studies have shown slight (often statistically insignificant) weight reductions in those on fluoxetine. Has the longest net half-life (taking into account the effects of its active metabolite, norfluoxetine) of any antidepressant clinically used, and consequently, when abruptly stopped, withdrawal effects are usually mild and rare. Dermatologic reactions are more common than with sertraline.[4]

Fluvoxamine: Not FDA approved for major depression; FDA approved for OCD. Has the highest affinity of any SSRI towards the sigma-1 receptor at which it serves as an agonist.[16][17] Less hepatotoxic than most other antidepressants.[11]

Paroxetine: Only SSRI that's not Australian pregnancy category C but is rather category D due to an increased risk of Persistent Pulmonary Hypertension of the Newborn. The FDA of the US has placed it in category D. It is associated with a higher risk of sexual dysfunction, weight gain, anticholinergic side effects and drowsiness than the other SSRIs. Has a short half life compared to other SSRIs and hence is the most prone to causing withdrawal effects whenever a dose is missed. Paroxetine has the lowest affinity for the sigma-1 receptors of all the SSRIs.[16] It also possesses the highest propensity of any SSRI for causing extrapyramidal symptoms.[13] Less hepatotoxic than most other antidepressants.[11]

Sertraline: Highest risk of psychiatric side effects (e.g. mania, suicidal behavior/ideation, psychosis, etc.)[4] Has slight (but clinically significant) inhibitory effects on dopamine reuptake.[18][19] Has the second highest affinity of the SSRIs towards the sigma-1 receptor where it may serve as a sigma-1 receptor antagonist.[17]
GI toxicity: 2 (mostly diarrhoea)[7]

Serotonin–norepinephrine reuptake inhibitors (SNRIs)

Desvenlafaxine: Active metabolite of venlafaxine.

Duloxetine: Unlike the other SNRIs listed here duloxetine does not cause dose-dependent hypertension as a common adverse effect. Used to relieve neuropathic pain too. More hepatotoxic than most other antidepressants.[11]

Milnacipran: Primarily used as a treatment for neuropathic pain.
Danger in overdose: ? (No single-drug fatal overdoses reported yet)

Venlafaxine: Relatively selective (116x) for serotonin reuptake inhibition over norepinephrine.
GI toxicity: 2 (IR) / 1 (XR)

Noradrenergic and specific serotonergic antidepressants (NaSSAs)

Mianserin: Not licensed for use in the US and Canada. Licensed for use in Australia and the UK. Can cause blood dyscrasias (including agranulocytosis) and consequently both the BNF and AMH recommend regular complete blood count monitoring.[9][20]

Mirtazapine: Licensed for use in the US, UK, Australia and Canada. Mianserin's successor and analogue.

Serotonin antagonist and reuptake inhibitors (SARIs)

Nefazodone: Risk of hepatotoxicity. Available in the US but not in Canada, Australia or Europe.

Trazodone: Not available in Australia. More hepatotoxic than other antidepressants.[11]
Relative efficacy: 2 [10]

Serotonin modulator and stimulators (SMSs)

Vilazodone: Potential for serotonin syndrome as an adverse effect.
Danger in overdose: ? (probably low aside from an increased risk of serotonin syndrome)

Vortioxetine: Introduced to the US market in September 2013 and hence data on its adverse effects may be lagging behind. Serotonin syndrome is a possible (rare) adverse effect.

Other

Agomelatine: Not licensed in the US or Canada. Licensed in Australia and the UK.
Relative efficacy: 2 [21]

Bupropion: Only licensed in the UK and Australia as a smoking cessation aid, but in the US it is licensed for the treatment of major depressive disorder. More hepatotoxic than most other antidepressants.[11]

Reboxetine: Not licensed in the US or Canada. Licensed in Australia and the UK.

St John's wort: Not a prescription drug in most countries; available as an over-the-counter herbal supplement.

References

  1. ^ a b c d e f g h i j k l Linde K, Berner MM, Kriston L (2008). "St John's wort for major depression". Cochrane Database Syst Rev (4): CD000448. doi:10.1002/14651858.CD000448.pub3. PMID 18843608.
  2. ^ a b c d e f g Brunton, Laurence L.; Chabner, Bruce; Knollmann, Björn C., eds. (2011). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  3. ^ a b c d e f g h i j k "Side effects of antidepressant medications". UpToDate. Wolters Kluwer Health. Archived from the original on 2 November 2013. Retrieved 24 October 2013. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  4. ^ a b c d e f g h i j k l m n o Royal Pharmaceutical Society of Great Britain. MARTINDALE – The Complete Drug Reference. Pharmaceutical Press. Archived from the original on 26 July 2013. Retrieved 31 October 2013. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help); Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  5. ^ a b c d e f g h i j k l Ernst E; Rand JI; Barnes J; Stevinson C (1998). "Adverse effects profile of the herbal antidepressant St. John's wort (Hypericum perforatum L.)". European Journal of Clinical Pharmacology. 54 (8): 589–94. doi:10.1007/s002280050519. PMID 9860144. Collectively, the data suggest that hypericum is well tolerated, with an incidence of adverse reactions similar to that of placebo.
  6. ^ a b c Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C (2009). "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis". Lancet. 373 (9665): 746–58. doi:10.1016/S0140-6736(09)60046-5. PMID 19185342.
  7. ^ a b c d e f g h i j k l Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  8. ^ a b White N, Litovitz T, Clancy C (2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". J Med Toxicol. 4 (4): 238–50. doi:10.1007/BF03161207. PMC 3550116. PMID 19031375.
  9. ^ a b c d e f g h Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  10. ^ a b van Moffaert M, de Wilde J, Vereecken A, Dierick M, Evrard JL, Wilmotte J, Mendlewicz J (March 1995). "Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalized patients with major depression". Int Clin Psychopharmacol. 10 (1): 3–9. doi:10.1097/00004850-199503000-00001. PMID 7622801.
  11. ^ a b c d e f g h i j k Voican, CS; Corruble, E; Naveau, S; Perlemuter, G (April 2014). "Antidepressant-induced liver injury: a review for clinicians". The American Journal of Psychiatry. 171 (4): 404–15. doi:10.1176/appi.ajp.2013.13050709. PMID 24362450.
  12. ^ "AMOXAPINE tablet [Watson Laboratories, Inc.]". DailyMed. Watson Laboratories, Inc. August 2010. Archived from the original on 2 November 2013. Retrieved 30 October 2013.
  13. ^ a b Walker, R; Whittlesea, C, eds. (2007) [1994]. Clinical Pharmacy and Therapeutics (4th ed.). Edinburgh: Churchill Livingstone Elsevier. ISBN 978-0-7020-4293-5. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  14. ^ Bruijn JA, Moleman P, Mulder PG, van den Broek WW, van Hulst AM, van der Mast RC, van de Wetering BJ (1996). "A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients" (PDF). Psychopharmacology. 127 (3): 231–7. doi:10.1007/BF02246131. PMID 8912401. Archived from the original (PDF) on 18 August 2017. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  15. ^ Bruijn JA, Moleman P, Mulder PG, van den Broek WW (1999). "Depressed in-patients respond differently to imipramine and mirtazapine". Pharmacopsychiatry. 32 (3): 87–92. doi:10.1055/s-2007-979200. PMID 10463374.
  16. ^ a b Fishback JA, Robson MJ, Xu YT, Matsumoto RR (2010). "Sigma receptors: potential targets for a new class of antidepressant drug". Pharmacol. Ther. 127 (3): 271–82. doi:10.1016/j.pharmthera.2010.04.003. PMC 3993947. PMID 20438757.
  17. ^ a b Kishimoto A, Todani A, Miura J, Kitagaki T, Hashimoto K (2010). "The opposite effects of fluvoxamine and sertraline in the treatment of psychotic major depression: a case report". Ann Gen Psychiatry. 9: 23. doi:10.1186/1744-859X-9-23. PMC 2881105. PMID 20492642.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ Borkowska A, Pilaczyńska E, Araszkiewicz A, Rybakowski J (2002). "[The effect of sertraline on cognitive functions in patients with obsessive-compulsive disorder]". Psychiatr. Pol. (in Polish). 36 (6 Suppl): 289–95. PMID 12647451.
  19. ^ Schmitt JA, Ramaekers JG, Kruizinga MJ, van Boxtel MP, Vuurman EF, Riedel WJ (2002). "Additional dopamine reuptake inhibition attenuates vigilance impairment induced by serotonin reuptake inhibition in man". J. Psychopharmacol. 16 (3): 207–14. doi:10.1177/026988110201600303. PMID 12236626.
  20. ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  21. ^ Goodwin GM (2009). "Clinical studies on the efficacy of agomelatine on depressive symptoms". CNS Drugs. 23 Suppl 2: 35–9. doi:10.2165/11318650-000000000-00000. PMID 19708724.
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