Five potential therapeutic agents as antidepressants: a brief review and future directions

Abstract

Despite the availability of numerous antidepressants, many patients with depression do not show adequate response. The therapeutic lag between drug administration and onset of clinical improvement observed with conventional antidepressants has led to a need for antidepressants with a novel mechanism of action. Recently, five such agents, including acetyl-L-carnitine, scopolamine, ω-3 polyunsaturated fatty acids, ketamine, and selective 5-HT₇ serotonin receptor antagonists, have gained interest as potential antidepressants with enhanced symptom control, improved tolerability, and faster onset of action compared to conventional antidepressants. This review provides an update and critical examination of these five novel therapeutic agents as potential antidepressants.

Keywords:

• acetyl-L-carnitine
• depression
• ketamine
• novel mechanism
• ω-3 polyunsaturated fatty acids
• scopolamine
• selective 5-HT₇ serotonin receptor antagonist

Financial & competing interests disclosure

This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI12C0003). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Inadequate treatment efficacy and the therapeutic lag between drug administration and onset of symptom improvement observed in conventional antidepressants have created a need for agents with novel mechanisms of action. Many potential agents have been identified and investigated to meet this need.

• Acetyl-L-carnitine has been considered a potential antidepressant because of its diverse functions related to neuroplasticity, but its tolerability profile and pharmacokinetics/-dynamics have not been established.

• Scopolamine, a nonspecific competitive inhibitor of the muscarinic cholinergic receptor (mAChR), exerts its antidepressant effects via modification of tonic cholinergic inhibition, but its anticholinergic side effects limit its clinical application.

• The antidepressant effects of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) have long been supported in numerous preclinical animal studies, cellular models and clinical trials, yet the optimum ratio between eicosapentaenoic acid and docosahexaenoic acid must be elucidated.

• Countless studies have reported ketamine’s immediate antidepressant effects, but it can cause severe side effects, including severe sedation, dissociation, cognitive decline and psychosis. Moreover, the long-term adverse and antidepressant effects of ketamine remain unclear.

• In contrast to an ample amount of preclinical animal and cellular model studies, there is a dearth of RCTs, which have investigated the effect of selective 5-HT₇ receptor antagonists in the treatment of depression.