Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began in the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed for cognitive symptoms of ...Alzheimer's disease (AD), had unexpected antipsychotic activity. However, strategies to address tolerability concerns associated with activation of peripheral mAChRs were not available at that time. The discovery of specific targeted ligands and combination treatments to reduce peripheral mAChR engagement have advanced the potential of mAChR activators as effective treatments for psychotic disorders. This review provides perspectives on the background of the identification of mAChRs as potential antipsychotics, advances in the preclinical understanding of mAChRs as targets, and the current state of mAChR activators under active clinical development for schizophrenia.
Effective control of psychotic (positive) symptoms is key to successful drug development targets for schizophrenia.Central mAChR agonists have shown antipsychotic activity without any direct dopamine receptor antagonism.Early attempts at developing mAChR agonists targeting psychosis were thwarted by tolerability problems from unwanted peripheral mAChR receptor activation, but recent advances aim to reduce tolerability burden.M1 and M4 receptors are the subtypes most closely linked to antipsychotic activity targets and current mAChR agonists targeting psychosis include those with central M1, M4, or dual M1/M4 receptor agonist properties.Strategies to minimize peripheral muscarinic adverse events include (i) using orthosteric, allosteric, or bitopic functionality strategies, and (ii) using a cotreatment with a peripheral muscarinic antagonist.
To evaluate the effect of 1 oral and 2 distinct long-acting injectable (LAI) formulations of the same antipsychotic on times to relapse following medication discontinuation.
Data were drawn from 3 ...similarly designed, multicenter, double-blind, placebo-controlled, randomized-withdrawal studies of paliperidone in adults with a schizophrenia diagnosis (according to DSM-IV criteria for ≥ 1 year before screening): once-daily extended-release oral paliperidone (ORAL paliperidone), once-monthly paliperidone palmitate (PP1M), and once-every-3-months paliperidone palmitate (PP3M). In a post hoc analysis, we compared median time to relapse across the treatment-withdrawal arms of the 3 studies using final analysis datasets. Time to relapse in the withdrawal arm of each study was examined using log-rank tests and Cox proportional hazards models.
Four hundred forty-nine patients were withdrawn from 3 paliperidone formulations: 101 from ORAL paliperidone, 203 from PP1M, and 145 from PP3M. Postwithdrawal median (95% confidence interval CI) days to relapse were 58 days (42-114 days) for ORAL paliperidone, 172 days (134-222 days) for PP1M, and 395 days (274 days-not reached) for PP3M (P < .0001, pairwise comparisons). Relapse risk was significantly lower (P < .001) for patients who withdrew from either PP formulation relative to ORAL paliperidone and additionally for patients who withdrew from PP3M relative to PP1M.
Results demonstrate that 50% of patients who withdrew treatment from ORAL paliperidone, PP1M, or PP3M remained relapse free for approximately 2 months, 6 months, and 13 months, respectively. This may be relevant for risk mitigation strategies in schizophrenia, a condition in which interruptions in maintenance antipsychotic treatment are commonplace and unpredictable. LAI antipsychotic formulations may provide substantial delays over oral equivalents in times to relapse when patients discontinue therapy.
ClinicalTrials.gov identifiers: NCT00086320, NCT00111189, and NCT01529515.
To evaluate Positive and Negative Syndrome Scale (PANSS) categorical response rates, time course of response, and symptom subdomains of response with the combination oral agent KarXT ...(xanomeline-trospium) in the treatment of schizophrenia.
Post hoc analysis was conducted for EMERGENT-1 (NCT03697252), a 5-week, inpatient, placebo-controlled, phase 2 study of acute psychosis in patients who met
criteria for schizophrenia. The EMERGENT-1 study was conducted between September 2018 and August 2019. Categorical thresholds of response used were PANSS total score reductions of ≥ 20%, ≥ 30%, ≥ 40%, and ≥ 50% between baseline and study end. Number needed to treat (NNT) for each categorical threshold was calculated. The proportion of KarXT- and placebo-treated patients achieving each response threshold at weeks 2, 4, and 5 was assessed. Marder 5-factor analysis of PANSS assessed response with KarXT across symptom domains.
A total of 83 patients in the KarXT group and 87 patients in the placebo group were included in the modified intent-to-treat analysis. Response rates with KarXT ranged from 59.0% for a ≥ 20% threshold to 15.7% for a ≥ 50% threshold. All response rates with KarXT were significantly higher than in the placebo arm (
< .05), with NNTs ranging from 3 (≥ 20% improvement) to 11 (≥ 50% improvement). KarXT was associated with a significantly higher response rate relative to placebo as early as 2 weeks for ≥ 20% (
= .0001) and ≥ 30% (
= .0022) thresholds and at 4 weeks for the ≥ 40% (
= .0049) and ≥ 50% (
= .0041) thresholds. Each of the Marder 5 factors showed significant differences favoring KarXT over placebo (
< .05) by 2 weeks and continuing through week 5 (endpoint Cohen
effect sizes, 0.48-0.66).
KarXT provided clinically meaningful responder rates on PANSS total score compared with placebo at each response threshold, providing further support of the successful primary and secondary endpoints. Response was demonstrated as early as 2 weeks relative to placebo. KarXT demonstrated improvements vs placebo in all 5 factors (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility, and anxiety/depression).
ClinicalTrials.gov identifier: NCT03697252.
OBJECTIVE: The purpose of this study was to estimate and compare the effects of antipsychotics-both the newer ones and the conventional ones-on body weight. METHOD: A comprehensive literature search ...identified 81 English- and non-English-language articles that included data on weight change in antipsychotic-treated patients. For each agent, a meta-analysis and random effects metaregression estimated the weight change after 10 weeks of treatment at a standard dose. A comprehensive narrative review was also conducted on all articles that did not yield quantitative information but did yield important qualitative information. RESULTS: Placebo was associated with a mean weight reduction of 0.74 kg. Among conventional agents, mean weight change ranged from a reduction of 0.39 kg with molindone to an increase of 3.19 kg with thioridazine. Among newer antipsychotic agents, mean increases were as follows: clozapine, 4.45 kg; olanzapine, 4.15 kg; sertindole, 2.92 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg. Insufficient data were available to evaluate quetiapine at 10 weeks. CONCLUSIONS: Both conventional and newer antipsychotics are associated with weight gain. Among the newer agents, clozapine appears to have the greatest potential to induce weight gain, and ziprasidone the least. The differences among newer agents may affect compliance with medication and health risk.
Objective: Weight gain is a common side effect of antipsychotic medications and is of particular concern with most of the newer “atypical” antipsychotics. It is, therefore, increasingly important to ...understand the impact of obesity and perceived weight problems on compliance with these medications.
Methods: A survey of treatment and health issues was mailed to local chapters of the National Alliance for the Mentally Ill (NAMI) and National Mental Health Association (NMHA), who distributed them to people with schizophrenia. Noncompliance was defined as a self-report of missing any antipsychotic medication in the previous month. The primary independent variables were (1) body mass index (BMI; weight kg/height m
2)—categorized as normal (<25,
n=73), overweight (25–30,
n=104), or obese (>30,
n=100)—and (2) subjective distress over weight gain. Other independent variables included demographics, medication attitudes, and treatment satisfaction.
Result: BMI status and subjective distress from weight gain were predictors of noncompliance. Obese individuals were more than twice as likely as those with a normal BMI to report missing their medication (OR=2.5; CI 1.1–5.5). A comprehensive model suggested that the primary mediator of noncompliance was distress over weight gain.
Conclusions: There appears to be a significant, positive association between obesity and subjective distress from weight gain and medication noncompliance, even when accounting for other possible confounding factors.
Objective:Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine. This ...study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia.Methods:This was an international, multicenter, randomized phase 2 study of olanzapine plus samidorphan in patients with schizophrenia. The study had a 1-week open-label olanzapine lead-in period followed by a 12-week double-blind treatment phase in which patients were randomly assigned in a 1:1:1:1 ratio to receive olanzapine plus placebo (N=75) or olanzapine plus 5 mg (N=80), 10 mg (N=86), or 20 mg (N=68) of samidorphan. The primary aims were to confirm that the antipsychotic efficacy of olanzapine plus samidorphan was comparable to olanzapine plus placebo, to assess the effect of combining olanzapine with samidorphan on olanzapine-induced weight gain, and to assess the overall safety and tolerability of olanzapine plus samidorphan.Results:Antipsychotic efficacy, as assessed by total score on the Positive and Negative Syndrome Scale (PANSS), was equivalent across all treatment groups. Treatment with olanzapine plus samidorphan resulted in a statistically significant lower weight gain (37% lower weight gain compared with olanzapine plus placebo). The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% 2.1 kg for the 5 mg group, 2.1% 1.5 kg for the 10 mg group, and 2.9% 2.2 kg for the 20 mg group). Adverse events reported at a frequency ≥5% in any of the olanzapine plus samidorphan groups and occurring at a rate ≥2 times greater than in the olanzapine plus placebo group were somnolence, sedation, dizziness, and constipation. Other safety measures were comparable between the olanzapine plus samidorphan groups and the olanzapine plus placebo group.Conclusions:The antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo, and olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo. Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.
OBJECTIVE: The objective of this study was to evaluate the relationship between compliance with an antipsychotic medication regimen and risk of hospitalization in a cohort of California Medicaid ...patients with schizophrenia. METHODS: Compliance behavior was estimated by using a retrospective review of California Medicaid pharmacy refill and medical claims for 4,325 outpatients for whom antipsychotics were prescribed for treatment of schizophrenia from 1999 to 2001. Compliance behavior was estimated by using four different definitions: gaps in medication therapy, medication consistency and persistence, and a medication possession ratio. Patients were followed for one year and had an average of 19.1 dispensing events. Logistic regression models using each compliance estimate were used to determine the odds of hospitalization. RESULTS: Risk of hospitalization was significantly correlated with compliance. With all definitions, lower compliance was associated with a greater risk of hospitalization over and above any other risk factors for hospitalization. For example, the presence of any gap in medication coverage was associated with increased risk of hospitalization, including gaps as small as one to ten days (odds ratio OR=1.98). A gap of 11 to 30 days was associated with an OR of 2.81, and a gap of more than 30 days was associated with an OR of 3.96. CONCLUSIONS: This study showed a direct correlation between estimated partial compliance and hospitalization risk among patients with schizophrenia across a continuum of compliance behavior.
Medication adherence is as much of a problem today as it was 50 years ago. A major barrier to progress is that the definition emphasizes obedience to medication recommendations rather than shared ...outcome goals. As a result, schizophrenia patients are keenly aware of the social risks of disclosing nonadherence. Nondisclosure leads to misinformation, which in turn leads to serious errors in medication decisions. Another consequence is that adherence struggles may harm the therapeutic relationship. When nonadherence is inevitable, the strategy should shift to the use of harm reduction strategies that aim to preserve the therapeutic relationship while mitigating risks.
Olanzapine is a second-generation atypical antipsychotic with proven efficacy for the treatment of schizophrenia. Approved in 1996, olanzapine is one of the most studied antipsychotics, resulting in ...a considerable amount of clinical data across diverse patient populations. Despite the fact that olanzapine is associated with a known risk of metabolic side effects, including weight gain, many clinicians continue to prescribe olanzapine for the treatment of schizophrenia with the expectation of additional therapeutic antipsychotic efficacy relative to other first-line atypical antipsychotics. The goal of this narrative is to revisit the role of oral olanzapine in the management of patients with schizophrenia, including those with recently diagnosed schizophrenia ("first-episode"), those with an established schizophrenia diagnosis who experience acute exacerbations, those receiving long-term antipsychotic treatment as a maintenance intervention, and those with suboptimal response to antipsychotic treatment, including treatment resistance. Collectively, data from published literature support the favorable efficacy of olanzapine compared with other first- and second-generation antipsychotics, including lower rates of treatment discontinuation and clinically meaningful improvements in the symptoms of schizophrenia. The development of antipsychotic medications with the favorable efficacy of olanzapine, but with reduced weight gain, could address a major unmet need in the treatment of schizophrenia. Keywords: antipsychotic, efficacy, metabolic dysregulation, weight gain
PDF
