This page is intended to be a document that will evolve – a place to store information about selection of antidepressants and comparative efficacy and dosing.
Antidepressant Selection – Symptom Clusters
A large study published in the prestigious journal, JAMA Psychiatry, suggests that, for patients with unipolar depression (not bipolar depression) a scientifically developed antidepressant selection survey may predict which antidepressant, or combination of antidepressants, is more likely to be effective.
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Antidepressant Selection – Inflammation and C Reactive Protein
Inflammation is often seen in people with depression. And there is evidence to suggest that it predicts treatment response.
The most widely accepted standard test to measure inflammation is the C-reactive protein, or CRP. This is a protein that is produced by the liver in inflammatory states. The American Heart Association and the Centers for Disease Control and Prevention consider a CRP greater than 3 mg/L to be a marker of high inflammation. In psychiatry, you need to order it as a high-sensitivity CRP because the regular-sensitivity CRP generally does not pick up the lower levels below 3 that can inform practice.
We don’t have a universally accepted cutoff in psychiatry. Some studies have used 1 mg/L. For example, a CRP above 1 mg/L predicts a more favorable response to bupropion than to an SSRI. Inflammation is on a spectrum, and the higher the CRP is, the more inflamed the patient tends to be (Jha MK et al, Psychoneuroendocrinology 2017;78:105–113).
There are other markers of inflammation, like interleukin-6 (IL6), but these tests are not as stable as CRP. They tend to fluctuate with circadian rhythms and acute stress, including the stress of a venous puncture when blood is drawn. CRP has a long half-life, so it stays more constant and is not as vulnerable to those perturbations.
Patients with inflammation may appear somewhat different than those without inflammation who are depressed; the typical patient with high inflammation would be expected to have anhedonia and low motivation (Miller AH and Raison CL, Nat Rev Immunol 2016;16(1):22–34). There’s a global lack of pleasure and enjoyment. They may also have prominent anxiety, fatigue, and psychomotor retardation.
An elevated CRP predicts a better response to dopaminergic or norepinephrine agents and a poorer response to SSRIs. The first study that looked at this compared nortriptyline to escitalopram (Lexapro) in 241 patients with depression. The patients with a high CRP > 3 mg/L did better on nortriptyline, while those with a low CRP below 1 mg/L did better on the escitalopram (Uher R et al, Am J Psychiatry 2014;171(12):1278–1286). More recently we have the CO-MED trial, which looked at bupropion augmentation of an SSRI (escitalopram) in 106 patients with major depression. When the results were first published in 2011, bupropion augmentation worked no better than a placebo. Later, the researchers parsed out the data by inflammatory markers. It turned out bupropion worked in the subset of patients with a mildly elevated CRP (> 1 mg/L), while the SSRI monotherapy worked better when the CRP was low (Jha MK et al, Psychoneuroendocrinology 2017;78:105–113).
SSRI’s may be less effective because inflammation activates the serotonin transporter, increasing both its expression and its function. The result is that serotonin is cleared more rapidly from the synapse. SSRIs target that transporter, and it’s harder for them to make an impact when there is a greater volume and number of those transporters
We do have some evidence, though, that omega-3s and L-methylfolate work better when inflammatory biomarkers are elevated. L-methylfolate is an essential cofactor in the production of dopamine, and inflammation hinders that particular pathway, so there’s reason to think that L-methylfolate would be especially useful in the context of inflammation (Shelton RC et al, J Clin Psychiatry 2016;76(12):1635–1641; Rapaport MH et al, Mol Psychiatry 2016;21(1):71–79). Other options would be to use pramipexole or even l-dopa to boost dopamine.
Antidepressant Comparative Efficacy
A large review of clinical trials found some significant differences. Some antidepressants differed both statistically and clinically. In terms of response, mirtazapine, escitalopram, venlafaxine, and sertraline were more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine. In terms of acceptability, escitalopram, sertraline, citalopram, and bupropion were better tolerated than other new-generation antidepressants. These results indicate that two of the most efficacious treatments (mirtazapine and venlafaxine) might not be the best for overall outcomes.
Note – since venlafaxine had increasing effectiveness the higher the dose and mirtazapine was less effective at higher doses, venlafaxine doses in these trials may have been too low to measure its true effectiveness.
Antidepressant Side Effects Table
A large meta-analysis of clinical trials of the most commonly prescribed antidepressants suggests that for all of them except venlafaxine there is a “sweet spot” for dosing where you get the best outcomes. Above that dose range side effects become more common and effectiveness does not increase and may actually, in the case of mirtazapine, decrease.
Venlafaxine seems to have increasing effectiveness all the way up to the top dose studied (375 mg).
They came up with a dose equivalence for the antidepressants and compared it with previous articles.
SSRI Dose vs Response and Adverse Effects
All of the SSRIs had a similar profile, once you adjusted for relative potency. Response peaked at a certain dose. Above that dose response did not increase, perhaps decreased somewhat, and adverse effects went up exponentially.
Mirtazapine Dose vs Response and Adverse Effects
Mirtazapine Response had a “U” shaped curve, it went up until you reached 30 mg and then fell relatively sharply.
Venlafaxine Dose vs Response and Adverse Effects
Venlafaxine response increased rapidly until 150 mg, and after that it increased more slowly but still kept increasing all the way to the top studied dose. Curiously, there was a reversed dose vs adverse effect graph. Adverse effects increased rapidly up to 150 mg and then went up very slowly. All of this suggests that higher dose venlafaxine may be worth considering in treatment resistant patients.
This chart summarizes optimal doses for the antidepressants reviewed.
Chekroud AM, Gueorguieva R, Krumholz HM, Trivedi MH, Krystal JH, McCarthy G. Reevaluating the Efficacy and Predictability of Antidepressant Treatments – A Symptom Clustering Approach. JAMA Psychiatry. Published online February 22, 2017. doi:10.1001/jamapsychiatry.2017.0025
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JPA, Geddes JR. 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. Lancet. 2018 Apr 7;391(10128):1357-1366. doi: 10.1016/S0140-6736(17)32802-7. Epub 2018 Feb 21. PMID: 29477251; PMCID: PMC5889788.
Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis. Lancet Psychiatry. 2019 Jul;6(7):601-609. doi: 10.1016/S2215-0366(19)30217-2. Epub 2019 Jun 6. PMID: 31178367; PMCID: PMC6586944.