Psychiatry Practice Changers 2014

Bret S. Stetka, MD; Cristoph U. Correll, MD


December 08, 2014

In This Article

Therapeutic Advances: Slow but Ongoing

Given that most severe mental disorders are chronic and recurrent and associated with serious suffering and functional disability, the field of psychiatry is longing for new therapeutic targets and agents that have new mechanisms of action. However, despite promising basic science findings and even phase 2 studies, novel mechanisms have been elusive and seem to be difficult to replicate in large phase 3 trials, as exemplified by two recent examples in the pharmacotherapy of schizophrenia. After the lack of success of Eli Lilly's program testing the efficacy and safety of pomaglumetad, a metabotropic 2/2 agonist for the treatment of schizophrenia, this year has seen another painful failure of a very large program attempting to modulate the glutamatergic system to improve currently unaddressed domains in schizophrenia.[15]

Based on promising phase 2A results,[16] bitopertin, a glycine-1 transporter inhibitor that enhances activity of endogenous glycine on the N-methyl-d-aspartate receptor, was tested by Roche and Genentech in a very large phase 3 clinical trial program. Unfortunately, one monotherapy study in acutely exacerbated patients with schizophrenia[17] and six augmentation studies, three in patients with persistent, predominant negative symptoms and three in patients with suboptimally controlled positive symptoms, did not show any benefit of multiple fixed doses of bitopertin compared with placebo.

Fortunately, other companies continue to examine the utility of compounds modulating dopamine D2, D3, and/or D4 receptors, the serotonin, glutamatergic, and muscarinergic/nicotinergic system, as well as phosphodiesterase, cannabinoid, and neuroprotective mechanisms, among others.[15]

Shifting gears, in the pharmacotherapy of insomnia, a new medication with a novel mechanism was approved by the US Food and Drug Administration this year. Suvorexant (Belsomra®), an orexin receptor antagonist, was approved for the treatment of difficulties with falling and staying asleep. Like other sleep medications, suvorexant is labeled as a schedule IV controlled substance because it can potentially be abused.

Finally, though many therapeutic investigations in psychiatry have been recently met with frustration, ongoing work like the human BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies) will hopefully allow us to better understand the roots of mental illness and lead to development of more effective treatments.


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