Rapid-acting antidepressants.

Conventional antidepressants (biogenic amine mechanisms) are not fully efficacious (e.g., symptoms remain after treatment, not all patients respond), produce effects only after weeks of daily dosing, and do not impact all disease symptoms. In contrast, a new class of antidepressants has been emerging since 2006 that has demonstrated rapid onset, large effect size, activity after only a single or few dose applications, and positive impact in treatment refractory patients and against some treatment-resistant symptoms (e.g., anhedonia). Rapid-acting antidepressant drug action has been demonstrated in controlled clinical studies for ketamine, a few other NMDA receptor antagonists, and scopolamine. Less clinical data are currently available for psychedelic drugs such as psilocybin, lysergic acid diethylamide, and ayahuasca. The mechanisms of action of rapid-acting antidepressants are not fully understood. However, a general triggering mechanism appears to involve the potentiation of AMPA receptor function. Although the durability of antidepressant effects of ketamine and scopolamine is limited, psychedelic drugs have been reported to produce effects for many months. The primary impediment to generating a medicine of this type for depressed patients is side effects and the lack of methods to ensure enduring antidepressant effects. Thus, further exploration of drug possibilities continues. Esketamine ((S)-ketamine) was recently FDA approved. Compounds currently in clinical development include the NMDA receptor antagonist (R)-ketamine, the NMDA receptor modulator, GLYX-13 (Rapastinel), and the AMPA receptor potentiator TAK-653. Additional pharmacological classes have produced effects in the preclinical laboratory to suggest their potential as rapid-acting agents. These include mGlu2/3 receptor antagonists, AMPA receptor potentiators, and negative allosteric modulators of GABAA(α5) receptors. In all cases, molecules exist that could be used to provide clinical proof of concept testing.

Negative allosteric modulation of alpha 5-containing GABAA receptors engenders antidepressant-like effects and selectively prevents age-associated hyperactivity in tau-depositing mice.

RATIONALE: Associated with frank neuropathology, patients with Alzheimer's disease suffer from a host of neuropsychiatric symptoms that include depression, apathy, agitation, and aggression. Negative allosteric modulators (NAMs) of α5-containing GABAA receptors have been suggested to be a novel target for antidepressant action. We hypothesized that pharmacological modulation of this target would engender increased motivation in stressful environments. METHODS: We utilized electrophysiological recordings from Xenopus oocytes and behavioral measures in mice to address this hypothesis. RESULTS: In the forced-swim assay in mice that detects antidepressant drugs, the α5ß3γ2 GABAΑ receptor NAM, RY-080 produced a marked antidepressant phenotype. Another compound, PWZ-029, was characterized as an α5ß3γ2 receptor NAM of lower intrinsic efficacy in electrophysiological studies in Xenopus oocytes. In contrast to RY-080, PWZ-029 was only moderately active in the forced-swim assay and the α5ß3γ2 receptor antagonist, Xli-093, was not active at all. The effects of RY-080 were prevented by the non-selective benzodiazepine receptor antagonist flumazenil as well as by the selective ligands, PWZ-029 and Xli-093. These findings demonstrate that this effect of RY-080 is driven by negative allosteric modulation of α5ßγ2 GABAA receptors. RY-080 was not active in the tail-suspension test. We also demonstrated a reduction in the age-dependent hyperactivity exhibited by transgenic mice that accumulate pathological tau (rTg4510 mice) by RY-080. The decrease in hyperactivity by RY-080 was selective for the hyperactivity of the rTg4510 mice since the locomotion of control strains of mice were not significantly affected by RY-080. CONCLUSIONS: α5ßγ2 GABAA receptor NAMs might function as a pharmacological treatment for mood, amotivational syndromes, and psychomotor agitation in patients with Alzheimer's and other neurodegenerative disorders.