Evidence-Based Reviews

Nontraditional therapies for treatment-resistant depression

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

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.

Endocrine strategies

Mifepristone (RU486). This anti-glucocorticoid receptor antagonist is used as an abortifacient. Based on the theory that hyperactivity of the hypothalamic-pituitary-adrenal axis is implicated in the pathophysiology of MDD with psychotic features (psychotic depression), this agent has been studied as a treatment for this indication.

An analysis of 5 double-blind RCTs (N = 1,460) found that 7 days of mifepristone, 1,200 mg/d, was superior to placebo (P < .004) in reducing psychotic symptoms of depression.¹¹ Plasma concentrations ≥1,600 ng/mL may be required to maximize benefit.¹¹

Overall, this agent demonstrated a good safety profile in clinical trials, with treatment-emergent AEs reported in 556 (66.7%) patients who received mifepristone vs 386 (61.6%) patients who received placebo.¹¹ Common AEs included gastrointestinal (GI) symptoms, headache, and dizziness. However, 3 deaths occurred: 2 patients who received mifepristone and 1 patient who received placebo. Given this potential for a fatal outcome, clinicians should first consider prescribing an adjunctive antipsychotic agent or electroconvulsive therapy.

Estrogens. These hormones are important for sexual and reproductive development and are used to treat various sexual/reproductive disorders, primarily in women. Their role in treating depression is based on the observation that perimenopause is accompanied by an increased risk of new and recurrent depression coincident with declining ovarian function.

Evidence supports the antidepressant efficacy of transdermal estradiol plus progesterone for perimenopausal depression, but not for postmenopausal depression.^12-14 However, estrogens carry significant risks that must be carefully considered in relationship to their potential benefits. These risks include:

vaginal bleeding, dysmenorrhea
fibroid enlargement
galactorrhea
ovarian cancer, endometrial cancer, breast cancer
deep vein thrombosis, pulmonary embolism
hypertension, chest pain, myocardial infarction, stroke.

Continue to: The use of estrogens...