Nontraditional therapies for treatment-resistant depression

In these trials, pimavanserin was generally well-tolerated. The most common AEs were dry mouth, nausea, and headache. Pimavanserin has minimal activity at norepinephrine, dopamine, histamine, or acetylcholine receptors, thus avoiding AEs associated with these receptor interactions.

Given the mixed efficacy results of existing trials, further studies are needed to clarify this agent’s overall risk/benefit in the context of TRD.

Antihypertensive medications

Emerging data suggest that some beta-adrenergic blockers, angiotensin-inhibiting agents, and calcium antagonists are associated with a decreased incidence of depression. A large 2020 study (N = 3,747,190) used population-based Danish registries (2005 to 2015) to evaluate if any of the 41 most commonly prescribed antihypertensive medications were associated with the diagnosis of depressive disorder or use of antidepressants.⁴ These researchers found that enalapril, ramipril, amlodipine, propranolol, atenolol, bisoprolol, carvedilol (P < .001), and verapamil (P < .004) were strongly associated with a decreased risk of depression.⁴

Adverse effects across these different classes of antihypertensives are well characterized, can be substantial, and commonly are related to their impact on cardiovascular function (eg, hypotension). Clinically, these agents may be potential adjuncts for patients with TRD who need antihypertensive therapy. Their use and the choice of specific agent should only be determined in consultation with the patient’s primary care physician (PCP) or appropriate specialist.

Glutamatergic strategies

Ketamine is a dissociative anesthetic and analgesic. Its MOA for treating depression appears to occur primarily through antagonist activity at the N-methyl-D-aspartate ionotropic receptor of the glutamatergic system. There is preliminary evidence that its opioid receptor actions also may contribute to its antidepressant effect.⁵

Continue to: Many published studies...