New compounds and novel applications for established products were evaluated in many of the clinical trials reported at the recent 49th annual NIMH-sponsored New Clinical Drugs Evaluation Unit meeting.
A phase 2 trial with a dopamine D3/D2 receptor antagonist caripra-zine (RGH-188, Forest Laboratories) yielded encouraging results in patients with bipolar disorder. The trial with 118 participants was a flexible-dose study, using the Young Mania Rating Scale (YMRS) as the primary efficacy measure. Mary Ann Knesevich, MD, University Hills Clinical Research, Irving, Tex, indicated that drug effects were observed “on a broad range of symptoms.” There was significantly greater change from baseline at 3 weeks in each YMRS item than occurred with placebo. The principal adverse effects with cariprazine were extrapyramidal reactions and headache.
A serotonergic agent, Lu AA21004 (H. Lundbeck A/S), which has serotonin 5-HT3 antagonist and 5-HT1 agonist effects, was also found in preclinical studies to increase levels of noradrenaline, dopamine, and acetylcholine. Enric lvarez, MD, PhD, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, described a phase 2 controlled trial of the compound in approximately 400 patients with major depression.
The participants were randomized to 6 weeks of treatment with 1 of 2 doses of the investigational agent, placebo, or venlafaxine (Effexor) titrated to 150 mg a day as an active reference. lvarez reported that both doses of the new agent were superior to placebo and comparable to venlafaxine for symptoms of both anxiety and depression. The most common adverse effects with the investigational agent were nausea, headache, hyperhidrosis, and dry mouth.
Another serotonergic drug, vilazo-done (PGxHealth), a partial 5-HT1a serotonin agonist with selective serotonin reuptake inhibition, was assessed in phase 2 clinical trials for depression. Arif Khan, MD, Northwest Clinical Research Center, Bellevue, Wash, reported finding vilazodone superior to placebo in improving depression symptoms using the Montgomery-sberg Depression Rating Scale in a 9-week controlled trial in 63 patients.
Lurasidone (Dainippon Sumitomo Pharma) is being investigated in phase 2 and phase 3 trials in the treatment of patients hospitalized with acute exacerbations of schizophrenia. The agent has a high affinity for dopamine D2 and serotonin 5-HT2a receptors, as well as several receptors the investigators indicate are “implicated in the enhancement of cognition, mood, and negative symptoms,” including serotonin 5-HT7 and 5-HT1a.
Josephine Cucchiaro, PhD, Dainippon Sumitomo Pharma, presented results from 3 trials of lurasidone using daily doses of 40 to120 mg. Higher dosages were associated with greater therapeutic effects, measured on the Positive and Negative Syndrome Scale and the Brief Psychiatric Rating Scale–derived. The agent was “generally well tolerated,” Cucchiaro indicated, “with few discontinuations due to adverse effects, and minimal effects on weight, lipids, and glucose.”
Maurizio Fava, MD, Massachusetts General Hospital, Boston, described a proof-of-concept study in which buspirone and melatonin in a proprietary combination, BCI-952, were employed for treatment of depression. Although the individual components are not associated with antidepressant effects, the combination was found in preclinical assessment to enhance hippocampal neurogenesis, a property that researchers at Brain Cells Inc, San Diego, have associated with the action of antidepressants.
In this preliminary study of 142 patients with depression, those who received BCI-952 achieved statistically significantly greater improvement on the Clinical Global Impression scales for severity and im-provement (CGI-S and CGI-I) than those who received placebo. Fava characterized the study as “the first demonstration that rational drug discovery utilizing a preclinical neurogenesis platform can be applied to the treatment of [major depressive disorder].”