Simplified Guide to 21 Common Antidepressants – Mechanisms of Action, Side effects and Indications

Posted on:March 26, 2018
Last Updated: August 4, 2023
Time to read: 7 minutes

The recent Cipriani et al. systematic review and network meta-analysis is the largest and most comprehensive examination of antidepressant efficacy and tolerability. The network meta-analysis (NMA) covered an extensive list of 21 antidepressants and placebo which included a total of 116477 patients in 522 double-blind, parallel RCT’s. [1]

This article aims to provide a reader with a summary of the antidepressants featured in the NMA that should help with the individualised choice of antidepressant therapy by taking into account clinical features and tolerability.

The antidepressants have been divided into first and second line based on the recent RANZCP guidelines. [2]

It is important to recognise that according to the guidelines there is some flexibility regarding 1st, 2nd, and 3rd treatment, based on patient’s symptoms. e.g Duloxetine may be a 1st line in a patient with depression and pain. SNRIs have been positioned as the 2nd line only because of more significant toxicity in overdose.

SNRIs and TCAs are more effective than SSRIs in treating severe depressive symptoms (HAM-D > 25) and melancholic depression and hence may be prescribed first line in these situations.

The antidepressants have been arranged in alphabetical order.

1. AGOMELATINE

Need to know:

2. AMITRYPTILINE

Need to know:

  • Effective antidepressant but limited by its tolerability profile.
  • Anti-H1 action leads to weight gain; Anticholinergic action leads to dry mouth, constipation, blurred vision and urinary retention; Alpha-1 antagonism leads to orthostatic hypotension and dizziness; Voltage-sensitive sodium channel (VSSC) blockade leads to arrhythmias, coma and seizures in overdose.
  • Dose – 50-200 mg nocte
  • Effective at low doses 25-50 mg nocte for neuropathic pain.
  • Risk of serotonin syndrome when combined with SSRIs or SNRIs.
  • Half life- 18-96 hours.

3. BUPROPION

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4. CITALOPRAM

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5. CLOMIPRAMINE

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  • Tricyclic with selective serotonin reuptake inhibition and noradrenergic activity. It is from a pharmacological perspective best considered as a SNRI. Clomipramine ration of NA/ 5HT∼2:1
  • Dose- 25-250 mg/day
  • Second line after SSRIs in OCD
  • Half-life is 12-26 hours
  • Side effects are similar to amitryptiline due to its H1, Alpha1 and VSSC antagonism.

6. DESVENLAFAXINE

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7. DULOXETINE

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  • Specifically indicated in pain with depression. Can improve diabetic peripheral neuropathic pain, fibromyalgia and chronic musculoskeletal pain
  • Milder withdrawal reaction and lower incidence of hypertension as compared to Venlafaxine
  • Dose – 60-120 mg /day. Can be administered twice a day
  • Half-life is 12 hours
  • Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) – Mechanism of Action

8. ESCITALOPRAM

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9. FLUOXETINE

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  • SSRI with 5HT2C antagonism. (More discussion about 5HT2C antagonism in the article on agomelatine)
  • 5HT2C antagonism increases prefrontal dopamine which may be activating for some patients; however, may benefit patients with lack of motivation and anhedonia
  • Dose – 20-60mg/day
  • Inhibits CYP2D6 and CYP3A4. (can increase levels of risperidone, diazepam)
  • Long half-life (2-3 days) with its active metabolite having a half-life of 7-14 days
  • Update on the Mechanism of Action of Selective Serotonin Reuptake Inhibitors (SSRIs)

10. FLUVOXAMINE

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  • SSRI with sigma(σ)1 binding properties which may contribute to anti-anxiety and antipsychotic properties
  • Dose – 100-300 mg /day (The higher doses are used in OCD)
  • CYP1A2/CYP2C19/CYP3A4 inhibitor- can increase levels of olanzapine and clozapine (CYP1A2), methadone, benzodiazepines and carbamazepine (CYP3A4)
  • Half life – 24-72 hours
  • Update on the Mechanism of Action of Selective Serotonin Reuptake Inhibitors (SSRIs)

11. MILNACIPRAN AND 12. LEVOMILNACIPRAN

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13. MIRTAZAPINE

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  • Mirtazapine works through α2 pre-synaptic antagonism and 5HT2A, 5HT2C, 5HT3 and H1 antagonism
  • Alpha 2 antagonism increases serotonin and noradrenaline release
  • Combined use with SNRIs is termed as California rocket fuel due to its significant NA and DA potentiating properties
  • Dose 15-60 mg/day
  • Lower doses have a sedating property due to greater antihistamine effects which is also responsible for weight gaining properties.
  • It is metabolised primarily in the liver by demethylation and hydroxylation via cytochrome P450 enzymes, CYP1A2, CYP2D6, CYP3A4. One of its major metabolites is desmethylmirtazapine.
  • Mirtazapine – Mechanism of Action and Psychopharmacology By Dr. Sanil Rege

14. PAROXETINE

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15. REBOXETINE

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  • Dose – 8-12 mg/day (administered twice a day)
  • Metabolised by CYP3A4 (avoid ketoconazole and erythromycin)
  • Half life -13 hours
  • Common side effects include insomnia, fatigue, nausea, dry mouth and constipation

16. SERTRALINE

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  • SSRI with DAT inhibition and sigma(σ)1 binding properties
  • DAT inhibition can be beneficial in patients with fatigue, poor concentration and amotivation but can result in activation
  • The sigma(σ)1 binding properties contribute to its anxiolytic and antipsychotic properties
  • Dose – 50-200 mg/day
  • Inhibits CYP2D6 – can increase levels of TCA’s and Risperidone
  • Half life-24-72 hours
  • Psychopharmacology of Selective Serotonin Re-uptake Inhibitors (SSRIs) – Mechanism of Action

17. TRAZODONE AND 18. NEFAZODONE

Need to know:

  • Nefazodone is not used due to rare liver toxicity
  • Trazodone at lower doses (25-150 mg) is used as a hypnotic due to its 5HT2A, α1 and H1 antagonism
  • Trazodone acts as an antidepressant at higher doses (150-600mg) due to 5HT2A/C antagonism and SERT inhibition
  • Trazodone has biphasic elimination, with a redistribution half-life of about one hour and an elimination half-life of 10-12 hours

19. VENLAFAXINE

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20. VILAZODONE

Need to know:

  • Serotonin 5HT1A partial agonist (like buspirone) and reuptake inhibitor
  • Results in greater serotonin elevation in the brain
  • Dose – 10-40 mg/day
  • Metabolised by CYP 3A4
  • Half-life is 25 hours
  • Highly protein bound, therefore, can displace other medications that are protein bound, e.g. warfarin

21.VORTIOXETINE

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OTHER ANTIDEPRESSANTS

In this article, we have focused on the commonly used antidepressants.

Other antidepressants include MAOIs and psychostimulants.

Monoamine Oxidase Inhibitors (MAOI) – Mechanism of Action | Psychopharmacology | Clinical Application

Modafinil and Armodafinil – Mechanism of Action | Psychopharmacology | Clinical Application

Dexamphetamine and Lisdexamfetamine- Mechanism of Action, Side Effects and Dosing

Methylphenidate – Mechanism of Action, Side Effects and Dosing

UPDATES ON MECHANISM OF ACTION OF ANTIDEPRESSANTS

The common underlying effect for many antidepressants (TCAs, SSRIs, and ketamine) may be linked to the binding of the BDNF receptor (the transmembrane domain of tyrosine kinase receptor 2 (TRKB)) facilitating increased expression and signalling of brain-derived neurotrophic factor (BDNF) which promotes neuronal plasticity and antidepressant responses. [Casarotto et al., 2021]

Besides these anti-inflammatory effects and astrocyte modulation have also been postulated.

Mechanism of Action of Selective Serotonin Reuptake Inhibitors (SSRIs) – The Latest

QUIZ


References

1. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis
Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., … & Egger, M. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet.
2. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders.
Malhi, G. S., Bassett, D., Boyce, P., Bryant, R., Fitzgerald, P. B., Fritz, K., … & Porter, R. (2015). Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Australian & New Zealand Journal of Psychiatry, 49(12), 1087-1206.
3. Stahl's essential psychopharmacology: neuroscientific basis and practical applications.
Stahl, S. M. (2013). Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. Cambridge university press.
Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. 

Casarotto, P.C., Girych, M., Fred, S.M., Kovaleva, V., Moliner, R., Enkavi, G., Biojone, C., Cannarozzo, C., Sahu, M.P., Kaurinkoski, K. and Brunello, C.A., 2021. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell.

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