FDA Approvals, Highlights, and Summaries: Psychiatry

February 27, 2020

Wakix (pitolisant)

Pitolisant is a nonscheduled, first-in-class histamine 3 (H3) receptor antagonist/inverse agonist indicated for excessive daytime sleepiness in adults with narcolepsy. The efficacy of pitolisant was evaluated in 2 multicenter, randomized, double-blind, placebo-controlled studies in patients (n=261) with narcolepsy with or without cataplexy. In both studies, pitolisant demonstrated a statistically significant improvement in the Epworth Sleepiness Scale score. Lancet Neurology. 2017 Mar;16(3):200-207

Wakix prescribing information

Dayvigo (lemborexant)

Lemborexant is an orexin antagonist indicated for insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Orexins are neuropeptides that regulate the sleep-wake cycle by promoting wakefulness when bound to G-protein–coupled receptors OX1R and OX2R.

Approval of lemborexant was based on results from the phase 3 studies SUNRISE 1 and SUNRISE 2, which included nearly 2000 patients. Sleep onset and maintenance were improved compared with placebo. Middle-of-the-night safety (including awakening to sound) and next-day postural stability and memory studies over 12 months were also conducted. There were no meaningful differences between lemborexant 5 mg, 10 mg, or placebo with ability to wake to sound in the middle of the night; however, balance impairment at 4 hours postdose was evident with lemborexant compared with placebo.

JAMA Netw Open. 2019; 2(12):e1918254

Caplyta (lumateperone)

Lumateperone is indicated for schizophrenia. The mechanism of action of lumateperone in the treatment of schizophrenia is unknown; however, efficacy could be mediated through a combination of antagonist activity at central serotonin 5-HT2A receptors and postsynaptic antagonist activity at central dopamine D2 receptors.

In 2 placebo-controlled trials including nearly 800 patients, treatment with lumateperone (42 mg once daily) showed a statistically significant separation from placebo on the Positive and Negative Syndrome Scale total score (primary endpoint).

Caplyta prescribing Information

Zulresso (brexanolone)

Brexanolone is the first drug to be approved by the FDA for the treatment of postpartum depression (PPD). The mechanism by which brexanolone works for PDD is not fully understood, but it is believed to be related to positive allosteric modulation of both synaptic and extrasynaptic GABA-A receptors.

The drug is available only through a restricted program called the Zulresso Risk Evaluation and Mitigation Strategy (REMS) Program that requires the drug be administered by a healthcare provider in a certified healthcare facility. The REMS requires that patients be enrolled in the program prior to administration of the drug. Brexanolone is administered as a continuous intravenous infusion over a total of 60 hours (2.5 days). Because of the risk of serious harm resulting from the sudden loss of consciousness, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring.

Approval was based on 2 randomized, placebo-controlled phase 3 clinical trials that investigated the efficacy and safety of brexanolone injection in 246 women with moderate-to-severe PPD at 30 US centers.

In study 1, Hamilton Rating Scale for Depression (HAM-D) total scores decreased to a significantly greater extent at the end of the 60-hour infusion in the group receiving brexanolone 60 mcg/kg/hour (mean reduction, 19.5 points; P=.0013) and in the group on brexanolone 90 mcg/kg/hour (17.7 points; P=.0252) than in the placebo group (14 points). Similarly, in study 2, HAM-D scores improved significantly more in the higher-dose group (mean, 14.6 points; P=.016) as compared to the placebo group (12.1 points).

Lancet. 2018 Sep 22;392(10152):1058-1070

Depression scores had not returned to baseline by day 30 in any of the brexanolone groups and remained significantly lower in both treatment groups as compared to the placebo group of study 1 at day 30.

Data from a lactation study in 12 women indicate that brexanolone is transferred to breastmilk in nursing mothers; however, the relative infant dose is low, 1-2% of the maternal weight-adjusted dosage. Available data do not suggest a significant risk of adverse reactions to breastfed infants from exposure.

Zulresso prescribing information

Spravato (esketamine intranasal)

Esketamine intranasal is indicated in conjunction with an oral antidepressant for treatment-resistant depression (TRD). It is administered in a physician’s office, and the patient must be carefully monitored for at least 2 hours because of the risk of sedation, dissociation, and elevated blood pressure following the dose. Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (NMDA is an ionotropic glutamate receptor). The mechanism by which esketamine exerts its antidepressant effect is not fully understood.

Efficacy of esketamine was evaluated in 3 short-term (4-week) clinical trials and 1 longer-term maintenance-of-effect trial. In the short-term studies, patients were randomized to receive esketamine intranasal or a placebo nasal spray. Because of the serious nature of TRD and the need for patients to receive some form of treatment, all patients started a new oral antidepressant at the time of randomization, and the new antidepressant was continued throughout the trials. Primary efficacy was measured by the change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) used to assess the severity of depressive symptoms. In one of the short-term studies, esketamine nasal spray demonstrated statistically significant effect compared with placebo on the severity of depression, and some effect was seen within 2 days. The 2 other short-term trials did not meet the prespecified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with esketamine intranasal plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant.

Am J Psychiatry. 2018 Jul 1;175(7):620-630

JAMA Psychiatry. 2018 Feb 1;75(2):139-148

Other 2019 Psychiatry approval

Vraylar (cariprazine) has gained an expanded indication for bipolar 1 disorder that includes depressive episodes, in addition to its previously approved indication for manic or mixed episodes.


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