Geriatric depression: A pilot study has compared the safety and effectiveness of vilazodone and paroxetine in 56 older adults with major depression (Lavretsky et al. APA 2016; abstract 72). Vilazodone (Viibryd) is an SSRI/5HT-1A partial agonist that received FDA approval in 2011. Subjects were randomized to vilazodone 40 mg/day or paroxetine (10-30 mg/day) for 12 weeks. There were no significant differences between the active therapy groups with respect to change from baseline in HAM-D scores, although there were trends to greater improvement in mood (HAM-D) and quality of life (SF-36) with vilazodone. There was greater improvement with paroxetine with respect to attention and executive function.
Treatment-resistant depression: Oral ketamine produces a rapid improvement in patients with treatment-resistant depression, according to the results of a small placebo-controlled trial (Sharon et al. APA 2016; abstract 67). A total of 27 outpatients were randomized to placebo or ketamine, an NMDA receptor antagonist, for 21 days. There was a significant reduction in MADRS score of 13.4 points with oral ketamine versus 2.9 points with placebo at day 21. Four of 12 completers on ketamine achieved remission, defined as MADRS score < 10. No serious adverse effects were reported. A prior proof-of-concept open-label study of oral ketamine (0.5 mg/kg) for 28 days reported significant improvements in depression by day 14 and in anxiety by day 3 in patients receiving hospice care (Irwin et al. J Palliat Med 2013;16:958-965).
Panic disorder: An open-label study of clonazepam or paroxetine has found that long-term treatment does not prevent relapse once the medication is withdrawn (Nardi et al. APA 2016; abstract 93). A total of 120 subjects were randomized to clonazepam 2 mg/day or paroxetine 40 mg/day for three years. Poor responders at 8 weeks were switched to combined clonazepam/paroxetine. All subjects underwent tapered withdrawal after three years. The proportion of patients off therapy was 80% and 55% with clonazepam and paroxetine, respectively, after 2 months of taper; and 89% and 64% after 6 months. No serious withdrawal symptoms were seen. All subjects were free of panic attacks for at least one year prior to withdrawal. The cumulative relapse rate after drug withdrawal was 41% at 1 year, 77% at 4 years, and 94% at 6 years. Risk of panic attacks was non-significantly lower with clonazepam versus paroxetine. Re-initiation of treatment was generally successful in patients who relapsed.
Phase II and III results: ITI-007 is a novel compound in development for schizophrenia. The agent is a 5HT-2A receptor antagonist, a dopamine D2 receptor modulator (pre-synaptic partial agonist, post-synaptic antagonist), a 5HT reuptake inhibitor and a glutamate GluN2B receptor modulator (Davis et al. Expert Rev Neurother 2016;16:601-614). In phase II testing, subjects received one of two doses of ITI-007 (60 or 120 mg/day), risperidone 4 mg, or placebo for four weeks (Davis et al. APA 2016; abstract 147). At endpoint, ITI-007 60 mg showed a significant improvement from baseline in PANSS total score versus placebo at day 28. In phase III testing, significant efficacy (PANSS total score, PANSS positive symptom subscale) was demonstrated as early as week 1. In both studies, ITI-007 was generally well-tolerated; there were no clinically significant changes in akathisia, extrapyramidal symptoms, prolactin, glucose levels, insulin or lipids (Mates et al. APA 2016; abstract 148).
Tardive dyskinesia: Valbenazine (NBI-98854), the parent drug of tetrabenazine, is a vesicular monoamine transporter-2 inhibitor in development for the management of TD (Muller T. Expert Opin Investig Drugs 2015; 24:737-742). According to the unpublished results of a phase IIb trial, KINECT 2, valbenazine (25 mg/day titrated to 50 or 75 mg) significantly improved scores on the Abnormal Involuntary Movement Scale (AIMS) at week 6. The rate of response, defined as >50% improvement from baseline, was 49% with valbenazine versus 18% with placebo. A subsequent analysis reported improvement in TD with valbenazine regardless of the antipsychotic used. Results of a phase III trial, KINECT 3, have also been recently reported (Hauser et al. AAN 2016; abstract PL02.003). In that study, valbenazine 40 mg and 80 mg resulted in a significant improvement in AIMS score versus placebo (least-squares mean change from baseline: 40 mg -1.9 vs. -0.1; 80 mg -3.2 vs. -0.1). The most common adverse effect was somnolence; 3-4% of patients discontinued due to adverse effects.