The 5-HT2C receptor as a therapeutic target for alcohol and methamphetamine use disorders: A pilot study in treatment-seeking individuals.

Alcohol use disorder (AUD) and methamphetamine use disorder (MUD) are prevalent and have high adverse impacts on both the individual and society. Current treatment strategies for these disorders are ineffective at a population level. Lorcaserin, a 5-HT2C receptor agonist, has shown potential at reducing the symptoms of substance use disorder. This pilot study (initiated prior to market withdrawal) examined feasibility and safety of lorcaserin treatment in people undergoing residential detoxification and treatment for AUD and MUD. This was an open label pilot study of lorcaserin where participants (n = 10 AUD; n = 8 MUD) received 10-mg lorcaserin daily for 4 days then twice daily for 1 month. Primary outcome measures included recruitment and retention rate, incidence of treatment-emergent events, incidence of methamphetamine or alcohol withdrawal-related events, heart rate, and blood pressure. Secondary measures included pharmacokinetic data and self-reported alcohol or methamphetamine use, craving, and psychological distress. AUD participants were recruited faster and had a greater retention rate compared with MUD participants. Lorcaserin did not alter vital signs, was well tolerated, and had a similar pharmacokinetic profile to individuals with obesity. Lorcaserin reduced self-reported alcohol and amphetamine-type substance use and craving in AUD and MUD participants, respectively. Self-reported psychological health also improved over the treatment period for all participants. Despite the pilot nature of this study, our data support the notion of 5-HT2C receptors as a therapeutic target for drug and alcohol abuse.

Changing the treatment paradigm for Parkinson's disease psychosis with pimavanserin.

Introduction: Parkinson's disease psychosis (PDP) may affect up to 60% of patients with Parkinson's disease over the course of their disease, and is associated with poor prognosis, including increased risks of mortality and nursing home placement. PDP treatments have been limited to off-label use of atypical antipsychotics, most of which pose risks of worsened motor symptoms and other potential adverse events (AEs) due to their dopamine receptor blockade and additional off-target receptor affinities. Pimavanserin is a highly selective 5-HT2A inverse agonist and poses no known risks for worsening of parkinsonism or other off-target receptor AEs. Pimavanserin is the first and only medication approved for PDP treatment. Areas covered: This review covers estimated prevalence, clinical characteristics, diagnostic criteria, and risk factors for PDP; the hypothetical progression of PDP; management of PDP including use of antipsychotics; pharmacology and clinical trial data on pimavanserin; and expert opinion on PDP treatment. The NLM/PubMed database was searched for papers using the search terms of "PDP" AND "treatment" AND "pimavanserin" for the last 10 years. Expert opinion: The recent insights into PDP pathophysiology and approval of the only medication specifically to treat PDP are key advances that should improve the recognition, diagnosis, and management of PDP.

5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice.

All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D2 or serotonin (5-HT2A) receptors, or both; however, these medications are not universally effective, they may produce undesirable side effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests that additional drug targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT2C receptors may be a promising target for schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss-promoting capabilities. A difficulty in developing 5-HT2C agonists is that most ligands also possess 5-HT2B and/or 5-HT2A activities. We have developed selective 5-HT2C ligands and herein describe their preclinical effectiveness for treating schizophrenia-like behaviors. JJ-3-45, JJ-3-42, and JJ-5-34 reduced amphetamine-stimulated hyperlocomotion, restored amphetamine-disrupted prepulse inhibition, improved social behavior, and novel object recognition memory in NMDA receptor hypofunctioning NR1-knockdown mice, and were essentially devoid of catalepsy. However, they decreased motivation in a breakpoint assay and did not promote reversal learning in MK-801-treated mice. Somewhat similar effects were observed with lorcaserin, a 5-HT2C agonist with potent 5-HT2B and 5-HT2A agonist activities, which is approved for treating obesity. Microdialysis studies revealed that both JJ-3-42 and lorcaserin reduced dopamine efflux in the infralimbic cortex, while only JJ-3-42 decreased it in striatum. Collectively, these results provide additional evidence that 5-HT2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.

Pimavanserin: First Global Approval.

Pimavanserin (Nuplazid™) is a selective and potent serotonin 2A (5-HT2A) receptor inverse agonist and antagonist developed by ACADIA Pharmaceuticals that has been approved in the US as a treatment for patients with hallucinations and delusions associated with Parkinson's disease psychosis. Up to 60 % of patients with Parkinson's disease may develop Parkinson's disease psychosis, which is associated with increased morbidity and mortality and has few treatment options. This article summarizes the milestones in the development of pimavanserin leading to this first approval for the treatment of hallucinations and delusions in patients with Parkinson's disease psychosis.