Evidence-Based Reviews

Nontraditional therapies for treatment-resistant depression

Current Psychiatry. 2021 September;20(9):38-43,49 | doi:10.12788/cp.0166

Mehmet E. Dokucu, MD, PhD

Philip G. Janicak, MD

FIRST OF 2 PARTS

Some off-label agents show promise, but carry risks.

PDF Download

References

1. Fava M, Dirks B, Freeman M, et al. A phase 2, randomized, double-blind, placebo-controlled study of adjunctive pimavanserin in patients with major depressive disorder and an inadequate response to therapy (CLARITY). J Clin Psychiatry. 2019;80(6):19m12928.

2. Jha MK, Fava M, Freeman MP, et al. Effect of adjunctive pimavanserin on sleep/wakefulness in patients with major depressive disorder: secondary analysis from CLARITY. J Clin Psychiatry. 2020;82(1):20m13425.

3. ACADIA Pharmaceuticals announces top-line results from the Phase 3 CLARITY study evaluating pimavanserin for the adjunctive treatment of major depressive disorder. News release. Acadia Pharmaceuticals Inc. Published July 20, 2020. https://ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-top-line-results-phase-3-0

4. Kessing LV, Rytgaard HC, Ekstrom CT, et al. Antihypertensive drugs and risk of depression: a nationwide population-based study. Hypertension. 2020;76(4):1263-1279.

5. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215.

6. Han Y, Chen J, Zou D, et al. Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatr Dis Treat. 2016;12:2859-2867.

7. Wan LB, Levitch CF, Perez AM, et al. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry. 2015;76(3):247-252.

8. Hasselmann, H. Scopolamine and depression: a role for muscarinic antagonism? CNS Neurol Disord Drug Targets. 2014;13(4):673-683.

9. Drevets WC, Zarate CA Jr, Furey ML. Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: a review. Biol Psychiatry. 2013;73(12):1156-1163.

10. Stearns TP, Shad MU, Guzman GC. Glabellar botulinum toxin injections in major depressive disorder: a critical review. Prim Care Companion CNS Disord. 2018;20(5): 18r02298.

11. Block TS, Kushner H, Kalin N, et al. Combined analysis of mifepristone for psychotic depression: plasma levels associated with clinical response. Biol Psychiatry. 2018;84(1):46-54.

12. Rubinow DR, Johnson SL, Schmidt PJ, et al. Efficacy of estradiol in perimenopausal depression: so much promise and so few answers. Depress Anxiety. 2015;32(8):539-549.

13. Schmidt PJ, Ben Dor R, Martinez PE, et al. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry. 2015;72(7):714-726.

14. Gordon JL, Rubinow DR, Eisenlohr-Moul TA, et al. Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):149-157.

15. Fava M, Thase ME, Trivedi MH, et al. Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies. Mol Psychiatry. 2020;25(7):1580-1591.

16. Fernandes BS, Dean OM, Dodd S, et al. N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis. J Clin Psychiatry. 2016;77(4):e457-466.

Presently, FDA-approved first-line treatments and standard adjunctive strategies (eg, lithium, thyroid supplementation, stimulants, second-generation antipsychotics) for major depressive disorder (MDD) often produce less-than-desired outcomes while carrying a potentially substantial safety and tolerability burden. The lack of clinically useful and individual-based biomarkers (eg, genetic, neurophysiological, imaging) is a major obstacle to enhancing treatment efficacy and/or decreasing associated adverse effects (AEs). While the discovery of such tools is being aggressively pursued and ultimately will facilitate a more precision-based choice of therapy, empirical strategies remain our primary approach.

In controlled trials, several nontraditional treatments used primarily as adjuncts to standard antidepressants have shown promise. These include “repurposed” (off-label) medications, herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

Importantly, some nontraditional treatments also demonstrate AEs (Table^1-16). With a careful consideration of the risk/benefit balance, this article reviews some of the better-studied treatment options for patients with treatment-resistant depression (TRD). In Part 1, we will examine off-label medications. In Part 2, we will review other nontraditional approaches to TRD, including herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

We believe this review will help clinicians who need to formulate a different approach after their patient with depression is not helped by traditional first-, second-, and third-line treatments. The potential options discussed in Part 1 of this article are categorized based on their putative mechanism of action (MOA) for depression.

Serotonergic and noradrenergic strategies

Pimavanserin is FDA-approved for treatment of Parkinson’s psychosis. Its potential MOA as an adjunctive strategy for MDD may involve 5-HT2A antagonist and inverse agonist receptor activity, as well as lesser effects at the 5-HT2Creceptor.

A 2-stage, 5-week randomized controlled trial (RCT) (CLARITY; N = 207) found adjunctive pimavanserin (34 mg/d) produced a robust antidepressant effect vs placebo in patients whose depression did not respond to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).¹ Furthermore, a secondary analysis of the data suggested that pimavanserin also improved sleepiness (P < .0003) and daily functioning (P < .014) at Week 5.²

Unfortunately, two 6-week, Phase III RCTs (CLARITY-2 and -3; N = 298) did not find a statistically significant difference between active treatment and placebo. This was based on change in the primary outcome measure (Hamilton Depression Rating Scale-17 score) when adjunctive pimavanserin (34 mg/d) was added to an SSRI or SNRI in patients with TRD.³ There was, however, a significant difference favoring active treatment over placebo based on the Clinical Global Impression–Severity score.

Continue to: In these trials...