Lorcaserin and pimavanserin: Emerging selectivity of serotonin receptor subtype-targeted drugs

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively

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. Neuropsychopharmacology advance online publication, 12 April 2017; doi:10.1038/npp.2017.52

Regulation of 5-HT Receptors and the Hypothalamic-Pituitary-Adrenal Axis

Disturbances in the serotonin (5-HT) system is the neurobiological abnormality most consistently associated with suicide. Hyperactivity of the hypothalmic-pituitary-adrenal (HPA) axis is also described in suicide victims. The HPA axis is the classical neuroendocrine system that responds to stress and whose final product, corticosteroids, targets components of the limbic system, particularly the hippocampus. We will review resulsts from animal studies that point to the possibility that many of the 5-HT receptor changes observed in suicide brains may be a result of, or may be worsened by, the HPA overactivity that may be present in some suicide victims. The results of these studies can be summarized as follows: (1) chronic unpredictable stress produces high corticosteroid levels in rats; (2) chronic stress also results in changes in specific 5-HT receptors (increases in cortical 5-HT2A and decreases in hipocampal 5-HT1A and 5-HT1B); (3) chronic antidepressant administration prevents many of the 5-HT receptor changes observed after stress; and (4) chronic antidepressant administration reverses the overactivity of the HPA axis. If indeed 5-HT receptors have a partial role in controlling affective states, then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73437/1/j.1749-6632.1997.tb52357.x.pd

Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis

BACKGROUND: The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response. METHODS: Searches using PubMed, Web of Science, and PsycInfo databases (03/01/2015) yielded 23 studies investigating COMT Val158Met variation and antipsychotic response in schizophrenia and schizo-affective disorder. Responders/nonresponders were defined using each study's original criteria. If no binary response definition was used, authors were asked to define response according to at least 30% Positive and Negative Syndrome Scale score reduction (or equivalent in other scales). Analysis was conducted under a fixed-effects model. RESULTS: Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (ntotal=1416). Met/Met individuals were significantly more likely to respond than Val-carriers (P=.039, ORMet/Met=1.37, 95% CI: 1.02-1.85). Met/Met patients also experienced significantly greater improvement in positive symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024-0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly more likely to respond relative to Val-carriers (P=.0098, ORMet/Met=1.54, 95% CI: 1.11-2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65). CONCLUSIONS: Our findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients. This effect may be more pronounced for atypical antipsychotics.C.C.Z. is supported by the Brain and Behavior Research Foundation, American Foundation for Suicide Prevention and Eli Lilly. D.F. is supported by the Vanier Canada Graduate Scholarship. D.J.M. has been or is supported by the Canadian Institute of Health Research (CIHR) Operating Grant: “Genetics of antipsychotic-induced metabolic syndrome,” Michael Smith New Investigator Salary Prize for Research in Schizophrenia, NARSAD Independent Investigator Award by the Brain & Behavior Research Foundation, and Early Researcher Award from Ministry of Research and Innovation of Ontario. E.H. is supported by the Canada Graduate Scholarship. H.Y.M. has grant support from Sumitomo Dainippon, Sunovion, Boehringer Ingelheim, Eli Lilly, Janssen, Reviva, Alkermes, Auspex, and FORUM. J.A.L. has received research funding from Alkermes, Biomarin, EnVivo/Forum, Genentech, and Novartis. J.L.K. is supported the CIHR grant “Strategies for gene discovery in schizophrenia: subphenotypes, deep sequencing and interaction.” J.R.B. is supported by NIH grant MH083888. A.K.T. is supported by a NARSAD Young Investigator Award. J.S. is supported by a Pfizer independent grant. P.M. receives salary from Clinica Universidad de Navarra and has received research grants from the Ministry of Education (Spain), the Government of Navarra (Spain), the Spanish Foundation of Psychiatry and Mental Health, and Astrazeneca. S.G. is supported by the Ningbo Medical Technology Project Fund (No. 2004050), the Natural Science Foundation of Ningbo (No. 2009A610186, No. 2013A610249), and the Zhejiang Provincial Medical and Health Project Fund (No. 2015127713). S.G.P. has received research support from Otsuka, Lundbeck, FORUM, and Alkermes

Factors affecting outcome in schizophrenia and their relevance for psychopharmacological treatment

A major focus of current treatment research in schizophrenia is the determinants of long-term outcome, including functional outcome and general medical well being, rather than just specific domains of psychopathology such as positive and negative symptoms, mood symptoms, and cognitive impairment. This focus does not negate the importance of the latter issues but sees them as factors contributing to long-term outcome to variable extents. A long-term treatment focus facilitates a more clinically relevant assessment of benefits versus risks of available treatments. For instance, atypical antipsychotic drugs as a group have clear advantages for several important domains of efficacy that may influence long-term outcome, but are also more expensive over the long term. Use of some agents may also result in deleterious physical health consequences as well as large additional costs over the long term owing to metabolic adverse effects. The present paper focuses on several key issues in schizophrenia which are important determinants of long-term outcome in schizophrenia, or influence choice of antipsychotic drugs, or both, including: (i) duration of untreated psychosis; (ii) impact of relapse on long-term outcome; (iii) limited efficacy for specific domains of psychopathology of current treatments; (iv) mortality owing to suicide; and (v) mortality owing to other causes (e.g. cardiovascular disease