Raise the dose, augment, or switch? A new study suggests we may need to give antidepressants more time to be effective.
Raise the dose, augment, or switch? A new study suggests we may need to give antidepressants more time in treatment resistant depression.
While higher doses of antidepressants may bring additional benefits in obsessive compulsive disorder and anxiety disorders, they generally don’t help in depression. Whether one looks at all-comers or non-responders, going beyond the standard dose for depression has failed to bring greater response rates in half a dozen meta-analyses.1-4
There are three exceptions to that rule, however:
1. Some antidepressants do have a dose-dependent response: Tricyclics, MAOIs, venlafaxine, and vortioxetine.
2. There is a slight increase in response as one moves toward the maximum dose in the PDR, it’s just too small to qualify for the categorical definitions in these studies and is probably not clinically meaningful.4
3. There are always patients who prove exceptions to the rule, such as those with genetic variations in their metabolic enzymes.
Some of these adverse effects are depressogenic in themselves. This data is from a meta-analysis of 33 randomized controlled trials with SSRIs and SNRIs.5
Switching antidepressants can work after the first failed trial, although augmentation is a better strategy after two failed trials.6
In the past, 6-week trials were recommended for both the first and second trial of an antidepressant, but a recent analysis of the STAR-D trial calls that to question.7
Occasionally you will beat the odds with a good response on the third antidepressant trial, but meta-analyses suggest that kind of luck is likely due to the placebo or the natural course of illness.6 If you must switch, consider a tricyclic, MAOI, venlafaxine (Effexor), or vortioxetine (Trintillex). Isolated studies suggest possible benefit with those after 1-2 failed trials.
Although all the augmentation strategies on this slide have some evidence to work, the first-line ones are on the right. Their efficacy is more robust and has held up in multiple controlled trials and meta-analyses, while the ones on the left have failed in some large, well-designed trials.8,9
The psychotherapies that work in treatment resistant depression tend to have a strong behavioral component and more active involvement on the part of the therapist. They include cognitive behavioral therapy (CBT), mindfulness-based CBT, and intensive short-term psychodynamic therapy.9
The exact figures vary on this, but researchers consistently find high rates of undiagnosed bipolar disorder in patients with treatment-resistant depression (TRD). One study of 466 patients with TRD at 29 medical centers found that 57% endorsed past hypomanias on the hypomanic check list-32 (HCL-32), a screening instrument developed by one of the founders of the bipolar concept, Jules Angst.10 That scale is particularly good at picking up on hypomania, and I use it routinely in combination with the clinician-rated bipolarity index (both are available at www.moodtreatmentcenter.com/measurement).
There’s a scarcity of well-designed studies in treatment resistant depression. We’re not too far out of the cloud of unknowing that Hippocrates described so well: “Life is short, the art is long, opportunity fleeting, experiment perilous, and judgment difficult.”
1. Furukawa TA, Salanti G, Cowen PJ, Leucht S, Cipriani A. No benefit from flexible titration above minimum licensed dose in prescribing antidepressants for major depression: systematic review. Acta Psychiatr Scand. 2020;141(5):401-409.
2. Adli M, Baethge C, Heinz A, Langlitz N, Bauer M. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci. 2005;255(6):387-400.
3. Rink L, Braun C, Bschor T, Henssler J, Franklin J, Baethge C. Dose increase versus unchanged continuation of antidepressants after initial antidepressant treatment failure in patients with major depressive disorder: a systematic review and meta-analysis of randomized, double-blind trials. J Clin Psychiatry. 2018;79(3):17r11693.
4. Hansen RA, Moore CG, Dusetzina SB, Leinwand BI, Gartlehner G, Gaynes BN. Controlling for drug dose in systematic review and meta-analysis: a case study of the effect of antidepressant dose. Med Decis Making. 2009;29(1):91-103.
5. Safer DJ. Raising the minimum effective dose of serotonin reuptake inhibitor antidepressants: adverse drug events. J Clin Psychopharmacol. 2016;36(5):483-491.
6. Bschor T, Kern H, Henssler J, et al. Switching the antidepressant after nonresponse in adults with major depression: A systematic literature search and meta-analysis. J Clin Psychiatry, 2018;79(1).
7. Rush AJ, South C, Jha MK, Jain SB, Trivedi MH. What to expect when switching to a second antidepressant medication following an ineffective initial ssri: a report from the randomized clinical STAR*D study. J Clin Psychiatry. 2020;11;81(5):19m12949.
8. Zhou X, Ravindran AV, Qin B, et al. Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant depression: systematic review and network meta-analysis. J Clin Psychiatry, 2015;76(4):e487-498.
9. Strawbridge R, Carter B, Marwood L, et al. Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis. Br J Psychiatry. 2019;214(1):42-51.
10. Francesca MM, Efisia LM, Alessandra GM, et al. Misdiagnosed hypomanic symptoms in patients with treatment-resistant major depressive disorder in Italy: results from the improve study. Clin Pract Epidemiol Ment Health,2014;10:42-47.