Acetyl-L-carnitine and amisulpride
Acetyl-L-carnitine versus amisulpride (an atypical antipsychotic) has been studied in dysthymic disorder, and the results found that both were equally effective in relieving depression.[113]Zanardi R, Smeraldi E. A double-blind, randomised, controlled clinical trial of acetyl-L-carnitine vs. amisulpride in the treatment of dysthymia. Eur Neuropsychopharmacol. 2006 May;16(4):281-7.
http://www.ncbi.nlm.nih.gov/pubmed/16316746?tool=bestpractice.com
In elderly patients with dysthymia, acetyl-L-carnitine was as effective as fluoxetine, with possible benefits on subjective cognitive symptoms.[114]Bersani G, Meco G, Denaro A, et al. L-Acetylcarnitine in dysthymic disorder in elderly patients: a double-blind, multicenter, controlled randomized study vs. fluoxetine. Eur Neuropsychopharmacol. 2013 Oct;23(10):1219-25.
http://www.ncbi.nlm.nih.gov/pubmed/23428336?tool=bestpractice.com
Of note, neither of these studies included a placebo comparator, limiting conclusions that can be drawn about efficacy.
Dehydroepiandrosterone (DHEA)
DHEA, an adrenal androgen, has been evaluated in the treatment of patients with a midlife onset of dysthymia, and evidence has been found for the relief of depressive symptoms, suggesting that midlife-onset dysthymia may sometimes result from hormonal changes.[115]Bloch M, Schmidt PJ, Danaceau MA, et al. Dehydroepiandrosterone treatment of midlife dysthymia. Biol Psychiatry. 1999 Jun 15;45(12):1533-41.
http://www.ncbi.nlm.nih.gov/pubmed/10376113?tool=bestpractice.com
[116]Schmidt PJ, Daly RC, Bloch M, et al. Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch Gen Psychiatry. 2005 Feb;62(2):154-62.
http://archpsyc.ama-assn.org/cgi/content/full/62/2/154
http://www.ncbi.nlm.nih.gov/pubmed/15699292?tool=bestpractice.com
[117]Soares CN, Zitek B. Reproductive hormone sensitivity and risk for depression across the female life cycle: a continuum of vulnerability? J Psychiatry Neurosci. 2008 Jul;33(4):331-43.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440795/?tool=pubmed
http://www.ncbi.nlm.nih.gov/pubmed/18592034?tool=bestpractice.com
Ketamine
Ketamine is an emerging treatments for depression, in particular for treatment-resistant depression, a syndrome that likely includes many individuals with PDD.[118]Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry. 2019 Jun 1;176(6):428-38.
https://www.doi.org/10.1176/appi.ajp.2019.19020172
http://www.ncbi.nlm.nih.gov/pubmed/31109201?tool=bestpractice.com
[119]Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2019 Jun 5;:.
https://www.doi.org/10.1001/jamapsychiatry.2019.1189
http://www.ncbi.nlm.nih.gov/pubmed/31166571?tool=bestpractice.com
[120]Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct;170(10):1134-42.
https://www.doi.org/10.1176/appi.ajp.2013.13030392
http://www.ncbi.nlm.nih.gov/pubmed/23982301?tool=bestpractice.com
It has not been specifically studied for PDD, however. Ketamine is available as an intravenous formulation, which is sometimes used off-label for the treatment of depression. Ketamine is known to have significant addiction potential. It is also available as the active isomer esketamine, which is available in a nasal spray formulation. The Food and Drug Administration has approved esketamine nasal spray for treatment-resistant depression in adults. It is to be used in conjunction with an oral antidepressant and is only available under a restricted distribution system and Risk Evaluation and Mitigation Strategy. The category of treatment-resistant MDD, for which esketamine has received approval, likely includes many individuals with persistent depressive disorder; while esketamine’s relative efficacy compared to off-label use of racemic ketamine remains unclear, there is more rigorous long-term safety data for esketamine.[121]Swainson J, Thomas RK, Archer S, et al. Esketamine for treatment resistant depression. Expert Rev Neurother. 2019 Oct;19(10):899-911.
http://www.ncbi.nlm.nih.gov/pubmed/31282772?tool=bestpractice.com
Repetitive transcranial magnetic stimulation (rTMS)
Varying forms of transcranial magnetic stimulation have been studied for treatment of depression and treatment-resistant depression (TRD) but not specifically for persistent depressive disorder. A review of studies of rTMS vs. sham treatment for TRD showed a statistically significant effect favoring rTMS, with a 10% difference between rTMS and sham treatment for rates of remission or response, with a number needed to treat of 10; the effect was small and short-term; in addition rTMS was less effective in TRD than ECT.[122]Health Quality Ontario. Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Ont Health Technol Assess Ser. 2016;16(5):1-66.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808719
http://www.ncbi.nlm.nih.gov/pubmed/27099642?tool=bestpractice.com