PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?

PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia.

S77. ROLE OF DOPAMINE AND GLUTAMATE TRANSPORTERS IN GENERATION OF ANTIPSYCHOTIC EFFICACY

Background Antipsychotic drugs are the first line intervention to treat psychosis in schizophrenia and D2 receptor blockade is thought to be their primary mechanism of action. However, multiple lines of evidence from human and animal studies show that D2 receptor blockade is not always correlated with markers of antipsychotic efficacy. We previously demonstrated that reduced antipsychotic efficacy occurs after chronic antipsychotic administration in rodents despite stable D2 blockade, examined using PET imaging. Instead, we found that changes in expression of the dopamine transporter (DAT) were associated with decreases in endogenous dopamine and dopamine-mediated autoinhibition. These studies have led us to examine the DAT as a critical player in generation of an antipsychotic response. Methods Using antisense morpholino oligonucleotides, administered for 3 consecutive days using Long Evans rats, we selectively blocked translation of DAT or GLT-1 mRNA in the core of the nucleus accumbens, a brain region critical for motor outputs in response to salient stimuli. Baseline locomotion was monitored prior to and after an acute i.p. injection of haloperidol. Next, locomotion was monitored in response to a tail pinch or acute i.p. administration of cocaine. Transporter expression was quantified during acute or chronic haloperidol treatment using confocal microscopy. Results We found that DAT knockdown enhanced tail pinch-induced locomotion after acute haloperidol administration. Additionally, knockdown of the glutamate transporter GLT-1 strongly enhanced locomotion induced by tail pinch or cocaine injection after antipsychotic treatment. Confocal analysis of GLT-1 expression after acute or chronic haloperidol revealed significant GLT-1 up-regulation during a time period associated with antipsychotic efficacy. Discussion Our findings demonstrate a cause/effect relationship between reduced DAT and the behavioral response to an acute injection of antipsychotics in rodents. In all, our data point to the importance of both dopamine and glutamate uptake in the efficacy of antipsychotic drugs and argue against a D2-centric hypothesis of antipsychotic action.

26 A Phase 3 Study to Determine the Antipsychotic Efficacy and Safety of ALKS 3831 in Adult Patients with Acute Exacerbation of Schizophrenia

BackgroundALKS 3831, currently under development for the treatment of schizophrenia, is composed of olanzapine (OLZ) and a fixed dose of 10mg of samidorphan. In a Phase 2 study in stable patients with schizophrenia, ALKS 3831mitigated OLZ-associated weight gain while maintaining an antipsychotic efficacy profile similar to OLZ.Study objectiveTo assess the efficacy and safety of ALKS 3831 in patients with acute exacerbation of schizophrenia.MethodsThis was a Phase 3, 4-week, randomized, double-blind, active and placebo (PBO)-controlled study of ALKS 3831 in patients with acute exacerbation of schizophrenia (ClinicalTrials.gov: NCT02634346). Eligible patients (N=403) were randomized 1:1:1 to receive ALKS 3831, OLZ, or PBO. Patients were treated in an inpatient setting for the first 2weeks of the study and could be treated as inpatients or outpatients for the remaining 2weeks. Patients were excluded if they received OLZ within 6months prior to screening. Antipsychotic efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression–Severity (CGI-S) and CGI–Improvement (CGI-I) scales. Safety and tolerability were assessed as adverse events (AEs).ResultsOf 401 randomized patients who received ALKS 3831, OLZ, or PBO, 91%, 89%, and 83% of patients, respectively, completed treatment. The most common reason for discontinuation was withdrawal by patient (6% in both the ALKS 3831and PBO groups, and 7% in the OLZ group). Baseline characteristics were generally similar between groups; however, baseline mean body mass index was higher in the OLZ group than in the ALKS 3831 group. Baseline mean±standard deviation scores were 101.7±11.9 for PANSS total score and 5.1±0.7 for CGI-S scale score. The mean OLZ dose was 18.4mg/day in both active treatment arms. Least squares (LS) mean difference±standard error (SE) vs PBO from baseline to Week 4 in PANSS total score was –6.4±1.8 (P<.001) for the ALKS 3831 group and –5.3±1.8 (P=.004) for the OLZ group. LS mean difference±SE vs PBO from baseline to Week 4 in CGI-S scale score was −0.4±0.1 (P=.002) for the ALKS3831 group and −0.4±0.1 (P<.001) for the OLZ group. The percentage of patients with improvement in PANSS response (≥30% from baseline) at Week 4 was 60%, 54%, and 38% in the ALKS 3831, OLZ, and PBO groups, respectively. The percentage of patients with an improvement in CGI-I scale response (score of ≤2) at Week 4 was 58%, 51%, and 33% in the ALKS 3831, OLZ, and PBO groups, respectively. Discontinuation due to AEs was low in all groups. Common AEs (≥5% in any group) included weight gain, somnolence, dry mouth, anxiety, headache, and schizophrenia.DiscussionTreatment with ALKS 3831 was more effective than PBO, as measured by the PANSS and CGI-S scale, and its antipsychotic efficacy was similar to the active control OLZ. The safety profile of ALKS 3831 was similar toOLZ.Funding Acknowledgements: This study was funded by Alkermes, Inc.

The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses

Schizophrenia is the eighth leading cause of disability worldwide in people aged 15–44 years. Before antidopaminergic antipsychotics were introduced in the 1950s, no effective medications existed for the treatment of schizophrenia. This review summarizes key meta-analytic findings regarding antipsychotic efficacy in the acute treatment of schizophrenia, including clozapine in treatment-resistant patients. In the most comprehensive meta-analysis of randomized controlled trials conducted in multi-episode schizophrenia, antipsychotics outperformed placebo regarding total symptoms, positive symptoms, negative symptoms, depressive symptoms, quality of life and social functioning. Amongst these outcomes, the standardized mean difference for overall symptoms was largest, that is, 0.47 (95% credible interval = 0.42–0.51), approaching a medium effect size, being reduced to 0.38 when publication bias and small-trial effects were accounted for. A comparison of two meta-analyses indicated that first-episode patients, compared with multi-episode patients, were more likely to have at least minimal treatment response [⩾20% Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) score reduction: 81% versus 51%] and good response (⩾50% PANSS/BPRS score reduction: 52% versus 23%). In multi-episode schizophrenia, no response or worsening after 2 weeks of a therapeutic antipsychotic dose was highly predictive of not achieving a good response at endpoint (median treatment = 6 weeks: specificity = 86%; positive predictive value = 90%), suggesting a change in treatment should be considered in such cases. In first-episode psychosis, adequately dosed antipsychotic treatment trials for more than 2 weeks are recommended before using no response or worsening as a decision point for aborting a given antipsychotic. In clearly defined treatment-resistant schizophrenia, clozapine generally outperformed other antipsychotics, especially when dosed appropriately (target = 3–6 months’ duration; trough clozapine level ⩾350–400 μg/L) with a response rate (⩾20% PANSS/BPRS) of 33% by 3 months of treatment. High antipsychotic doses and psychotropic combinations are unlikely to be superior to standard doses of antipsychotic monotherapy. Acute antipsychotic efficacy in schizophrenia depends on the targeted symptom domain (greater efficacy: total and positive symptoms, lesser efficacy: negative symptoms, depressive symptoms, social functioning and quality of life). Greater antipsychotic efficacy is associated with higher total baseline symptom severity, treatment-naïveté/first-episode status, shorter illness duration, and trials that are nonindustry sponsored and that have a lower placebo effect. The heterogeneity of antipsychotic response across individuals and key symptom domains, the considerable degree of nonresponse/treatment resistance in multi-episode patients, and the adverse effect potential of antipsychotics are major limitations, underscoring the need to develop new medications for the treatment of schizophrenia. Drug development should include matching patient subgroups, which are identified by means of clinical and biomarker variables, to mechanisms of action of novel medications, targeting specific symptom domains, and investigating mechanisms of action other than dopaminergic blockade.