Abstract
Dear Sir,
No single neurotransmitter aberration could explain the heterogeneity of the schizophrenia syndrome, and hence, there is a pressing need to develop newer antipsychotics above and beyond dopamine (DA) antagonism. The following agents are promising and might usher in a new sparkle in the psychopharmacotherapy of schizophrenia.
Pimavanserin (Nuplazid®) is a 5-HT2A inverse agonist, and the United States Food and Drug Administration approved for Parkinson’s disease psychosis, largely devoid of D2 blockade. It is dosed at 34 mg once a day (OD) (10 mg OD if used concomitantly with a strong cytochrome P450 3A4 inhibitor), is metabolic friendly, and is non-sedating. Added to antipsychotics, pimavanserin resulted in greater improvement of negative symptoms. 1 A case series (n=10) of patients with schizophrenia, aged 21–77 years, with refractory hallucinations/delusions, received pimavanserin when clozapine or multiple antipsychotics failed. They were followed up for several months. All 10 patients showed marked response to pimavanserin 34 mg/day within 4–8 weeks, with continuation of the response for several months of follow-up. Improvements in negative symptoms and social functioning were also observed in several patients. 2
Ulotaront is an agonist at trace amine-associated receptor 1 (TAAR1) and 5-HT1A. TAAR1 is a G-protein-coupled receptor expressed in cortical, limbic, and midbrain monoaminergic regions that modulate dopaminergic, serotonergic, and glutamatergic activity. Ulotaront was effective for relapse of schizophrenia in a 4-week, double-blind, placebo-controlled study. This was followed by a 26-week open-label extension study evaluating the safety and effectiveness of ulotaront (25/50/75 mg/d). 3 Long-term treatment with ulotaront had a relatively high completion rate, sustained improvement in psychotic symptoms spanning different subscales on the Positive and Negative Symptom Scale (PANSS), improved depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale, an adverse event profile notable for the absence of extrapyramidal syndromes, a low liability for metabolic effects, and no effect on prolactin.
Xanomeline–Trospium: Xanomeline is a muscarinic receptor agonist with M1 and M4 preference. It has demonstrated antipsychotic properties in previous Alzheimer’s disease and schizophrenia trials. It is devoid of dopamine blockade but causes significant cholinergic adverse events. Trospium is a peripherally acting muscarinic receptor antagonist with no central nervous system penetrability that reduces peripheral cholinergic effects of xanomeline. Efficacy was demonstrated in a double-blind, phase 2 trial, in which 182 patients with schizophrenia were randomly assigned in a 1:1 ratio to receive twice-daily xanomeline–trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. 4 Xanomeline–trospium resulted in a greater decrease in the PANSS total score. The most common adverse events were gastrointestinal.
More studies are needed to further confirm the long-term efficacy and safety of these agents.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
