Nontraditional therapies for treatment-resistant depression

Many published studies and reviews have described ketamine’s role for treating MDD. Several studies have reported that low-dose (0.5 mg/kg) IV ketamine infusions can rapidly attenuate severe episodes of MDD as well as associated suicidality. For example, a meta-analysis of 9 RCTs (N = 368) comparing ketamine to placebo for acute treatment of unipolar and bipolar depression reported superior therapeutic effects with active treatment at 24 hours, 72 hours, and 7 days.⁶ The response and remission rates for ketamine were 52% and 21% at 24 hours; 48% and 24% at 72 hours; and 40% and 26% at 7 days, respectively.⁶

The most commonly reported AEs during the 4 hours after ketamine infusion included⁷:

• drowsiness, dizziness, poor coordination
• blurred vision, feeling strange or unreal
• hemodynamic changes (approximately 33%)
• small but significant (P < .05) increases in psychotomimetic and dissociative symptoms.

Because some individuals use ketamine recreationally, this agent also carries the risk of abuse.

Research is ongoing on strategies for long-term maintenance ketamine treatment, and the results of both short- and long-term trials will require careful scrutiny to better assess this agent’s safety and tolerability. Clinicians should first consider esketamine—the S-enantiomer of ketamine—because an intranasal formulation of this agent is FDA-approved for treating patients with TRD or MDD with suicidality when administered in a Risk Evaluation and Mitigation Strategy–certified setting.

Cholinergic strategies

Scopolamine is a potent muscarinic receptor antagonist used to prevent nausea and vomiting caused by motion sickness or medications used during surgery. Its use for MDD is based on the theory that muscarinic receptors may be hypersensitive in mood disorders.

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