Comparison of antidepressants' effectiveness and side effects - pharmacogenetics to assist in therapy selection
Reviewed by Alison Wong, RPh.
Patients suffering from depression, anxiety, post-traumatic stress disorder (PTSD) and other mental health conditions are frequently facing significant antidepressant side effects and often have a hard time finding the right dose or drug. When the medication is ineffective or the side effects become intolerable, patients have to switch to alternative medication. Analysis of drug claims data shows that, on average, claimants try 2.6 antidepressants before finding the correct one. Finding the right drug and dose by trial and error increases the risk of worsening depression, disability, hospital admission and suicide.
What do Canadian guidelines recommend?
The Canadian Network for Mood and Anxiety Treatments Clinical Guidelines (2023 update) for adult patients group medications based on the expected efficacy and tolerability though the choice of a specific antidepressant therapy depends on individual patient characteristics. Here below are examples of first, second and third line treatments that are recommended.
First-line antidepressants
Agomelatine*, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, mianserin*, milnacipran*, mirtazapine, paroxetine, sertraline, venlafaxine-XR, vilazodone and vortioxetine.
Second-line antidepressants
Amitriptyline, clomipramine and other tricyclic antidepressants (TCAs), dextromethorphan-bupropion*, moclobemide, nefazodone*, quetiapine, selegiline transdermal* and trazodone.
Third-line antidepressants
Phenelzine, tranylcypromine and reboxetine*.
*Not available in Canada when the guidelines were published.
Which antidepressants are most effective?
A recent large scale network meta-analysis published by Cipriani and colleagues in the Lancet provides a somewhat different rating of medications. The analyses ranked 21 antidepressants for efficacy (response rate) and acceptability (treatment discontinuations due to any cause). Acceptability of treatment is a complex outcome to evaluate as patients can discontinue treatment due to several causes including significant side effects (poor tolerability) or low perceived efficacy. Efficacy is also linked to patients’ adherence to treatment which can often be a challenge. In the meta-analysis, a comparison of the efficacy of 21 antidepressants showed that amitriptyline is one of the most effective medications.
Table: Antidepressant efficacy and acceptability comparison chart:
Why is amitriptyline a second-line treatment?
As shown in the meta-analysis, though amitriptyline is generally effective, its acceptability is only average. This may be due to tolerability issues. Amitriptyline and other TCAs are metabolized by both CYP2D6 and CYP2C19 enzymes. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for TCAs recommend avoiding the use of amitriptyline and similar medications in patients who are ultrarapid metabolizers of either CYP2C19 or CYP2D6 enzyme due to potential lack of efficacy. Patients who are poor metabolizers of either CYP2C19 or CYP2D6 enzyme should also avoid amitriptyline due to potential increased risk of side effects. Alternatively, a 50% dose reduction of the initial dose could be considered.
In rare cases where a patient is an ultrarapid metabolizer of one enzyme and a poor metabolizer of the other, it would be difficult to anticipate the clinical response of the patient. The clinician would have to monitor such a patient carefully.
How does CYP2C19 affect citalopram and escitalopram?
Citalopram and escitalopram are the most commonly prescribed SSRIs because of a better tolerability profile. Both these medications are metabolized by the CYP2C19 enzyme. However, up to 25% of people in North America carry the *17 allele of the CYP2C19, which leads to faster clearance of these medications. For people with two copies of *17 (ultrarapid metabolizers), the CPIC guidelines recommend considering an alternative antidepressant not predominantly metabolized by CYP2C19, such as paroxetine, fluvoxamine, vortioxetine, fluoxetine, duloxetine or venlafaxine. For people with one copy (rapid metabolizers), CPIC recommends starting with the usual dose and, if the response is inadequate, considering a higher dose or a switch to such an alternative. On the contrary, patients with significantly decreased CYP2C19 function have a much higher risk of side effects when treated at usual doses of citalopram and escitalopram. These patients may benefit from a lower starting dose of these medications or a change to an antidepressant that is not metabolized by CYP2C19. To learn why some people cannot tolerate SSRIs, and how this can lead to serotonin syndrome, read Wondering why you can't tolerate antidepressants?
Which antidepressants depend on CYP2D6?
Drugs that are metabolized by the CYP2D6 enzyme include paroxetine, fluvoxamine, vortioxetine, fluoxetine, duloxetine and venlafaxine. Similarly, patients who are ultrarapid metabolizers may have inadequate clinical response, whereas those who are poor metabolizers may have more side effects.
What if both CYP2D6 and CYP2C19 are altered?
For patients who have a significantly altered metabolism of both CYP2D6 and CYP2C19, there are few antidepressants that are not metabolized by either of these enzymes. For example, vilazodone, levomilnacipran and trazodone are metabolized primarily by the CYP3A4 liver enzyme and may be preferred treatment options in these scenarios. Very few antidepressants such as milnacipran and desvenlafaxine are a lot less dependent on CYP liver enzymes for their elimination and could also be treatment options.
Can pharmacogenetic testing help choose an antidepressant?
For patients suffering from antidepressant side effects or who present with treatment resistant depression or anxiety, pharmacogenetic testing can provide useful insights into a patient’s drug metabolism. Pharmacogenetic tests with a broad CYP enzyme profiling supported by medication review by expert clinical pharmacists could assist primary care physicians and psychiatrists to identify preferable treatment options for a specific patient and help reduce the number of drug trials.
Frequently asked questions
How many antidepressants do people try before finding the right one?
Analysis of drug claims data shows that, on average, people try 2.6 antidepressants before finding the right one.
Which antidepressant is the most effective?
In a Lancet meta-analysis of 21 antidepressants, amitriptyline was one of the most effective, but its acceptability was only average. That is why Canadian guidelines list it as a second-line treatment. The best choice depends on each patient.
Which genes affect how antidepressants work?
Mainly the genes for two liver enzymes, CYP2D6 and CYP2C19. Ultrarapid metabolizers may not get enough benefit from drugs these enzymes break down, while poor metabolizers may have more side effects.
Are there antidepressants that do not depend on CYP2D6 or CYP2C19?
Yes. Vilazodone, levomilnacipran and trazodone are metabolized mainly by the CYP3A4 enzyme, and milnacipran and desvenlafaxine depend much less on CYP liver enzymes.
Can a pharmacogenetic test help?
For people with antidepressant side effects, or with depression or anxiety that has not responded to treatment, a pharmacogenetic test with a medication review by a clinical pharmacist can help doctors identify suitable options and reduce the number of drug trials.
Selected references:
Lam RW, Kennedy SH, Adams C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults. Can J Psychiatry. 2024;69(9):641-687.
Cipriani A., Furukawa T.A., Salanti G., et al. 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 VOLUME 391, ISSUE 10128, P1357-1366, APRIL 07, 2018
Hicks, J.K. et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC®) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update (December 2016) Clin Pharmacol Ther. 2017 Jul; 102(1): 37–44
Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clin Pharmacol Ther. 2023;114(1):51-68.
Zhou Y., Ingelman-Sundberg M., Lauschke V.M. Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects. Clin Pharmacol Ther. 2017 Oct; 102(4): 688–700.
