Atypical Atypical Antipsychotic Drugs Research Articles

A functional HTR1A polymorphism, rs6295, predicts short-term response to lurasidone: confirmation with meta-analysis of other antipsychotic drugs.

Stimulation of the serotonin (5-HT)1A receptor (HTR1A) has been shown to contribute to the mechanism of action of some atypical antipsychotic drugs (APDs), including clozapine and lurasidone. A meta-analysis of rs6295, a functional polymorphism located at the promoter region of HTR1A, showed association with clinical response in schizophrenic patients treated with atypical APD. We have now tested whether other SNPs related to rs6295 predict response to lurasidone. We first evaluated whether rs358532 and rs6449693, tag SNPs for rs6295, predicted response to lurasidone, using data from two clinical trials of acutely psychotic schizophrenia patients with European (EUR, n = 171) or African (AFR, n = 131) ancestry; we then determined if those findings could be replicated in a third trial of lurasidone of similar design. Weekly changes (up to 6 weeks) in the Positive and Negative Syndrome Scale (PANSS) Total score and its five subscales were used to assess response. In EUR, a significant association, or trends for association, were observed for PANSS Total (p = 0.035), positive (p = 0.039), negative (p = 0.004), and disorganization (p = 0.0087) subscales, at week 1-6. There was a trend for replication with PANNS Total (p = 0.036) in the third trial. No significant association was observed in AFR or the placebo group. Meta-analysis of five studies, including the three with lurasidone, showed that rs6295 was associated with improvement in positive (p = 0.023) and negative (p ≤ 0.0001) symptoms in EUR patients with schizophrenia. This is the first study to show a significant association between functional HTR1A polymorphisms and treatment response to lurasidone. The meta-analysis provides additional evidence that rs6295 could be a race-dependent biomarker for predicting treatment response to APDs in schizophrenic patients with European Ancestry.

Serotonin 5-HT1A, 5-HT2A and dopamine D2 receptors strongly influence prefronto-hippocampal neural networks in alert mice: Contribution to the actions of risperidone

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT2AR and dopamine receptors D2R and stimulate 5-HT1AR directly or indirectly. However, the exact cellular mechanisms mediating their therapeutic actions remain unresolved. We recorded neural activity in the prefrontal cortex (PFC) and hippocampus (HPC) of freely-moving mice before and after acute administration of 5-HT1AR, 5-HT2AR and D2R selective agonists and antagonists and atypical APD risperidone. We then investigated the contribution of the three receptors to the actions of risperidone on brain activity via statistical modeling and pharmacological reversal (risperidone + 5-HT1AR antagonist WAY-100635, risperidone + 5-HT2A/2CR agonist DOI, risperidone + D2R agonist quinpirole). Risperidone, 5-HT1AR agonism with 8-OH-DPAT, 5-HT2AR antagonism with M100907, and D2R antagonism with haloperidol reduced locomotor activity of mice that correlated with a suppression of neural spiking, power of theta and gamma oscillations in PFC and HPC, and reduction of PFC-HPC theta phase synchronization. By contrast, activation of 5-HT2AR with DOI enhanced high-gamma oscillations in PFC and PFC-HPC high gamma functional connectivity, likely related to its hallucinogenic effects. Together, power changes, regression modeling and pharmacological reversals suggest an important role of 5-HT1AR agonism and 5-HT2AR antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D2R antagonism may contribute to risperidone-mediated changes in delta oscillations. This study provides novel insight into the neural mechanisms for widely prescribed psychiatric medication targeting the serotonin and dopamine systems in two regions involved in the pathophysiology of schizophrenia.

The role of dopamine D3 receptors in the mechanism of action of cariprazine.

Cariprazine is a new atypical antipsychotic drug (APD) with a unique pharmacodynamic profile, different from both typical and atypical APDs. Specifically, cariprazine acts as a partial agonist at the dopamine (DA) D2 and D3 receptors and serotonin 5-HT1A receptors, and as an antagonist at the 5-HT2B receptors. Moreover, it shows moderate affinities for adrenergic, histaminergic, and cholinergic receptors that are involved in mediating the side effects characteristic of typical APDs. In this review, we discuss the contribution of DA D3 receptors (D3Rs) in the etiology and pathophysiology of schizophrenia and the potential benefits that may be associated with a more selective targeting of D3R by APDs, as compared to other dopaminergic and non-dopaminergic receptor subtypes. Cariprazine, by acting on D3Rs, ameliorates anhedonia and cognitive deficits in animal models based on environmental or pharmacological manipulation. The reviewed results support the potential benefits of cariprazine in treating negative symptoms and cognitive deficits of schizophrenia, and therefore representing a promising approach in addressing the unmet clinical needs for the improved treatment of this serious neuropsychiatric disorder.

Atypical but not typical antipsychotic drugs ameliorate phencyclidine-induced emotional memory impairments in mice

Schizophrenia is associated with cognitive impairments related to hypofunction in glutamatergic N-methyl-D-aspartate receptor (NMDAR) transmission. Phencyclidine (PCP), a non-competitive NMDAR antagonist, models schizophrenia-like behavioral symptoms including cognitive deficits in rodents. This study examined the effects of PCP on emotional memory function examined in the passive avoidance (PA) task in mice and the ability of typical and atypical antipsychotic drugs (APDs) to rectify the PCP-mediated impairment. Pre-training administration of PCP (0.5, 1, 2 or 3 mg/kg) dose-dependently interfered with memory consolidation in the PA task. In contrast, PCP was ineffective when administered after training, and immediately before the retention test indicating that NMDAR blockade interferes with memory encoding mechanisms. The typical APD haloperidol and the dopamine D2/3 receptor antagonist raclopride failed to block the PCP-induced PA impairment suggesting a negligible role of D2 receptors in the PCP impairment. In contrast, the memory impairment was blocked by the atypical APDs clozapine and olanzapine in a dose-dependent manner while risperidone was effective only at the highest dose tested (1 mg/kg). The PCP-induced impairment involves 5-HT1A receptor mechanisms since the antagonist NAD-299 blocked the memory impairment caused by PCP and the ability of clozapine to attenuate the impairment by PCP. These results indicate that atypical but not typical APDs can ameliorate NMDAR-mediated memory impairments and support the view that atypical APDs such as clozapine can modulate glutamatergic memory dysfunctions through 5-HT1A receptor mechanisms. These findings suggest that atypical APDs may improve cognitive impairments related to glutamatergic dysfunction relevant for emotional memories in schizophrenia.

Antipsychotic Treatment Associated With Increased Mortality Risk in Patients With Dementia. A Registry-Based Observational Cohort Study

ObjectiveTo assess all-cause mortality patients with dementia treated with typical and atypical antipsychotic drugs (APDs). DesignRegistry-based cohort study. Setting and participantsA total of 58,412 patients diagnosed with dementia and registered in the Swedish Dementia Registry were included in the study. Of the study sample, 2526 of the patients were prescribed APDs. Of these, 602 patients were prescribed typical APDs and 1833 patients were prescribed atypical APDs. Ninety-one patients were prescribed both typical and atypical APDs. MeasurementsAll-cause mortality based on Swedish Cause of Death Register. Adjusted hazard ratios of mortality were calculated according to class of APDs (typical or atypical) prescribed. Final models were adjusted for age at dementia diagnosis, sex, Charlson comorbidity index, living arrangement, and Mini-Mental State Examination. ResultsIn the adjusted models, use of APDs at the time of dementia diagnosis was associated with increased mortality risk in the total cohort (hazard ratio = 1.4; 95% confidence interval 1.3–1.5). After stratifying for dementia types, increased mortality risks associated with APDs were found in patients with Alzheimer's disease, mixed dementia, unspecified dementia, and vascular dementia. Higher risk for mortality was found with typical APDs in patients with mixed and vascular dementia and with atypical APDs in patients with Alzheimer's disease, mixed, unspecified, and vascular dementia. Furthermore, in patients with Alzheimer's disease who had typical APDs, use lower risk of death emerged in comparison with patients with atypical APDs. Conclusions/ImplicationsBoth the use of atypical and typical APDs increased the risk of death in patients with dementia even after adjusting for differences in basic characteristics between groups. Although we cannot rule out the influence of residual confounding, these results would seem to add to studies suggesting caution in APD prescription for patients with dementia.

Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors

Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D2 receptor. However, support for this hypothesis is limited to a relatively small number of observations made across several decades and under different experimental conditions. Here we show that association rates, but not dissociation rates, correlate with EPS. We measured the kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay, and correlated these properties with their EPS and prolactin-elevating liabilities at therapeutic doses. EPS are robustly predicted by a rebinding model that considers the microenvironment of postsynaptic D2 receptors and integrates association and dissociation rates to calculate the net rate of reversal of receptor blockade. Thus, optimizing binding kinetics at the D2 receptor may result in APDs with improved therapeutic profile.

Neurochemical arguments for the use of dopamine D4 receptor stimulation to improve cognitive impairment associated with schizophrenia

BackgroundDopamine (DA) D4 receptors have been implicated in schizophrenia and the ability of some atypical antipsychotic drugs (APDs) to improve the cognitive impairment associated with schizophrenia (CIAS). Systemic administration of a D4 agonist, PD168077, at a sub-effective dose, together with a sub-effective dose of lurasidone, an atypical APD which is a weak D4 receptor antagonist, reversed the deficit in novel object recognition (NOR) in rats treated subchronically with phencyclidine (PCP), a rodent model of CIAS. Atypical APDs potentially stimulate D4Rs via their ability to enhance DA release in key brain areas related to cognition. However, some atypical APDs are relatively potent D4 antagonists at clinical dosages, including clozapine, and risperidone. The D4 antagonist, L745870, blocked the ability of clozapine, but not lurasidone, to reverse the NOR deficit in rats. MethodsThe purpose of this study was to determine the effects of a selective D4 agonist and antagonist, alone, and as pretreatment with lurasidone, on neurotransmitter efflux in mouse medial prefrontal cortex (mPFC) and dorsal striatum (dSTR), using in vivo microdialysis. Results and discussionPD168077 alone, and in combination with sub-effective dose lurasidone, increased DA and acetylcholine (ACh) efflux in mPFC, but only DA efflux in dSTR. L745870 had no effect on neurotransmitter efflux on its own or on the ability of lurasidone to increase cortical or striatal neurotransmitter efflux. These results indicate D4 receptor agonism alone is sufficient to increase cortical DA and ACh efflux without interfering with the effects of lurasidone and possibly other atypical APDs on extracellular cortical DA and ACh levels. A D4 agonist may be useful for treating CIAS, especially as augmentation of those atypical APDs which are not potent D4 antagonists.

Atypical antipsychotic therapy in Parkinson's disease psychosis: A retrospective study.

ObjectiveParkinson's disease psychosis (PDP) is a frequent complication of idiopathic Parkinson's disease (iPD) with significant impact on quality of life and association with poorer outcomes. Atypical antipsychotic drugs (APDs) are often used for the treatment of PDP; however, their use is often complicated by adverse drug reactions (ADRs). In this study, we present patients with PDP who were treated with the most commonly used atypical antipsychotic agents and review their respective ADRs.MethodsA retrospective study was carried out to include a total of 45 patients with iPD who visited a movement disorders clinic between 2006 and 2015. All PDP patients treated with atypical APDs were included in the analysis for their specific ADRs.ResultsForty‐five iPD patients (mean age of onset: 62.67 ± 9.86 years) were included, of those 10 patients had psychosis (mean age of onset: 76.80 ± 4.61 years). Of the 45 patients, 22.2% were found to have psychotic symptoms, of whom 70% had hallucinations, 20% had delusions, and 10% illusions. Seventy percent of psychotic symptoms occurred after ten or more years from diagnosis of iPD. PDP patients were treated with quetiapine, olanzapine, and risperidone separately or in combination, all of which were found to have certain ADRs.LimitationsThis study was limited by its retrospective study design and small sample size and with likely selection bias.ConclusionsThe prevalence of PDP is relatively high in older patients with iPD. The uses of the currently available atypical APDs in this patient population are often complicated by ADRs. The selective 5‐HT 2A inverse agonist, pimavanserin, could be a better alternative in the treatment of PDP.

Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement

Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS.

Ketamine-like effects of a combination of olanzapine and fluoxetine on AMPA and NMDA receptor-mediated transmission in the medial prefrontal cortex of the rat

Preclinical studies indicate that the rapid antidepressant effect of ketamine is dependent on activation of AMPA receptors in the medial prefrontal cortex (mPFC) resulting in a prolonged enhancement of glutamatergic transmission in the mPFC. In similarity, addition of atypical antipsychotic drugs (APDs) to SSRIs has also been found to induce a rapid and potent antidepressant effect. Using intracellular recordings in layer V/VI pyramidal cells of the rat mPFC in vitro, we found that a combination of low, clinically relevant concentrations of the atypical APD olanzapine and the SSRI fluoxetine facilitated NMDA and AMPA-induced currents in pyramidal cells via activation of dopamine D1 receptors. A single ketamine injection (10mg/kg, 24h before the experiment) enhanced AMPA-and apparently to some extent also NMDA-induced currents. Our results propose that the rapid and potent antidepressant effects of both treatments may be related to a common mechanism of action, namely facilitation of glutamatergic, in particular AMPA receptor-mediated transmission, in the mPFC.

Psychopharmacology of atypical antipsychotic drugs: From the receptor binding profile to neuroprotection and neurogenesis.

The original definition of atypical antipsychotic drugs (APD) was drugs that are effective against positive symptoms in schizophrenia with no or little extrapyramidal symptoms (EPS). However, atypical APD have been reported to be more effective for cognitive dysfunction and negative symptoms in schizophrenia than typical APD, which expands the definition of 'atypicality'. This article provides a critical review of the pharmacology of atypical APD, especially from the viewpoint of receptor binding profiles and neurotransmitter regulations as well as neuroprotection and neurogenesis. A variety of serotonin (5-HT) receptors, such as 5-HT2A / 2C , 5-HT1A , 5-HT6 and 5-HT7 receptors, may contribute to the mechanisms of action of 'atypicality'. The dopaminergic modulations, including a low affinity for dopamine D2 receptors and a partial D2 receptor agonistic action, and glutamatergic regulations may also be involved in the pharmacological backgrounds of 'atypicality'. Atypical APD, but not typical APD, may facilitate cortical neuroprotection and hippocampal neurogenesis, which might be a part of the action mechanisms of atypical APD. The facilitation of cortical neuroprotection and hippocampal neurogenesis induced by atypical APD might be mediated by an increase in the Ser9 phosphorylation of glycogen synthase kinase-3β (GSK-3β). The stimulation of 5-HT1A receptors and/or the blockade of 5-HT2 receptors, which is characteristic of atypical APD, might increase Ser9 phosphorylation of GSK-3β. Moreover, atypical APD increase brain-derived neurotrophic factor (BDNF) levels. BDNF increases Ser9 phosphorylation of GSK-3β and has neuroprotective and neurogenic effects, as in the case of atypical APD. These findings suggest that GSK-3β might play a role in the action mechanisms of atypical APD, in both the 5-HT-dependent and BDNF-dependent mechanisms.

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.

Synaptic Proteins in the Postmortem Anterior Cingulate Cortex in Schizophrenia: Relationship to Treatment and Treatment Response

The anterior cingulate cortex (ACC) is one of several brain regions that are abnormal in schizophrenia (SZ). Here we compared markers of synapse and mitochondrial function using western blots of postmortem ACC in: 1) normal controls (NCs, n=13) vs subjects with SZ (n=25); NC, treatment-resistant SZ, and treatment-responsive SZ; and 3) NC and SZ treated with typical or atypical antipsychotic drugs (APDs). Protein levels of synaptophysin, mitofusin-2, vGLUT1, and calcineurin did not differ between the NC and SZ group as a whole, or the NCs vs the SZ group divided by treatment response or type of APDs. In several cases, the levels of vGLUT1 were minuscule or absent. The proportion of NCs lacking vGLUT1 was significantly less than that of the SZ groups. There were several positive correlations across all subjects between: 1) synaptophysin and vGLUT1; 2) synaptophysin and calcineurin; 3) synaptophysin and mitofusin; and 4) calcineurin and mitofusin. Synaptophysin and calcineurin were positively correlated in responders, and this correlation was significantly stronger than that in treatment-resistant SZ subjects or in NCs. Synaptophysin and calcineurin were positively correlated in SZ patients on atypical APDs; this correlation was significantly stronger than that in SZ patients on typical APDs or in NCs. Mitofusin-2 and calcineurin were positively correlated in SZ patients on atypical APDs and in NCs; this correlation was stronger in SZ patients on atypical rather than typical APDs or in NCs. The correlation between these proteins, which have roles in synaptic vesicle cycling, glutamate transmission, mitochondrial fusion, and calcium buffering, is complex and was differentially regulated among the groups.

The alpha-7 nicotinic receptor partial agonist/5-HT3 antagonist RG3487 enhances cortical and hippocampal dopamine and acetylcholine release

Alpha-7 nicotinic acetylcholine receptor (nAChR) agonists may ameliorate cognitive deficits in schizophrenia, in part, because of their ability to enhance dopaminergic and cholinergic neurotransmission. In the current study, the effects of partial nAChR agonist and 5-HT3 receptor antagonist RG3487 (previously R3487/MEM3454) on dopamine (DA) and acetylcholine (ACh) effluxes in rat prefrontal cortex (mPFC) and hippocampus (HIP) were investigated in awake, freely moving rats. R3487/MEM3454, at doses of 0.1-10mg/kg, s.c., enhanced DA and ACh effluxes in rat mPFC and (HIP), with a peak effect at 0.3- to 0.6-mg/kg doses, producing a bell-shaped dose-response curve. Pretreatment with the selective nAChR antagonist, methyllycaconitine (1.0mg/kg), completely blocked RG3487-induced (0.45mg/kg) DA but not ACh efflux, while the selective 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (1.0mg/kg) partially inhibited cortical ACh but not DA efflux. RG3487 (0.45mg/kg) combined with atypical antipsychotic drug (APD) risperidone (0.1mg/kg), but not typical APD haloperidol (0.1mg/kg), induced a significantly greater increase in HIP ACh efflux. Their combined effect on DA efflux was additive. RG3487, combined with other atypical APDs, namely aripiprazole (0.3mg/kg), olanzapine (1.0mg/kg), and quetiapine (30mg/kg), also produced additive effects on DA efflux. These results suggest that RG3487 enhances DA efflux by nAChR stimulation, whereas ACh efflux is primarily mediated via 5-HT3 receptor antagonism, and that RG3487 alone or as augmentation may improve cognitive impairment in schizophrenia.

P.2.d.030 Treatment of bipolar mixed states: review of literature evidence and current guidelines

The main class of atypical antipsychotic drugs (APDs) in current use includes the protypical atypical APD, clozapine, as well as aripiprazole, asenapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone. At clinically effective doses, these agents produce extensive blockade of serotonin (5-HT)2A receptors, direct or indirect stimulation of 5-HT1A receptors, and to a lesser extent, reduction in dopamine (DA) D2 receptor-mediated neurotransmission. This contrasts with typical APDs, for example haloperidol and perphenazine, which are mainly DA D2/D3 receptor antagonists and have weaker, if any, potency as 5-HT2A receptor antagonists. Some, but not all, atypical APDs are also effective 5-HT2C receptor inverse agonists or neutral antagonists, 5-HT6 or 5-HT7 receptor antagonists. This diverse action on 5-HT receptors may contribute to significant differences in efficacy and tolerability among the atypical APDs. There is considerable preclinical and some clinical evidence that effects on 5-HT receptors contribute to the low risk of producing extrapyramidal side effects, which is the defining characteristic of an atypical APD, the lack of elevation in plasma prolactin levels (with risperidone and 9-hydroxyrisperidone being exceptions), antipsychotic action, and ability to improve some domains of cognition in patients with schizophrenia. The serotonergic actions of the atypical APDs, especially 5-HT2A receptor antagonism, are particularly important to the differential effects of typical and atypical APDs to overcome the effects of acute or subchronic administration of N-methyl-d-aspartate (NMDA) receptor antagonists, such as phencyclidine, ketamine, and dizocipline (MK-801). 5-HT1A receptor stimulation and 5-HT6 and 5-HT7 receptor antagonism may contribute to beneficial effects of these agents on cognition. In particular, 5-HT7 receptor antagonism may be the basis for the pro-cognitive effects of the atypical APD, amisulpride, a D2/D3 receptor antagonist, which has no effect on other 5-HT receptor. 5-HT2C receptor antagonism appears to contribute to the weight gain produced by some atypical APDs and may also affect cognition and psychosis via its influence on cortical and limbic dopaminergic activity.

Blonanserin reverses the phencyclidine (PCP)-induced impairment in novel object recognition (NOR) in rats: Role of indirect 5-HT1A partial agonism

Blonanserin is an atypical antipsychotic drug (APD) which, compared to other atypical APDs, is a relatively selective serotonin (5-HT)2A and dopamine D2 antagonist. Comparing blonanserin with more broadly acting atypical APDs could be useful to test the contributions of actions at other monoamine receptors, e.g. 5-HT1A receptors, to the reversal of PCP-induced novel object recognition (NOR) deficit. In this study, we tested the effect of blonanserin alone, and in combination with 5-HT1A agents, on NOR deficit induced by subchronic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP; 2mg/kg), b.i.d., for 7 days. Blonanserin, 1mg/kg, but not 0.3mg/kg, improved the PCP-induced NOR deficit. However, at 1mg/kg, object exploration was diminished. Co-administration of sub-effective doses of blonanserin (0.3mg/kg) and the 5-HT1A partial agonist, tandospirone (0.2mg/kg), significantly reversed the NOR deficit without diminishing activity during the acquisition or retention periods. The combination of WAY100635 (0.6mg/kg), a 5-HT1A antagonist, and blonanserin (1mg/kg), also diminished object exploration which prevented assessment of the effect of this combination on NOR. WAY100635 (0.6mg/kg) blocked the ameliorating effect of risperidone (0.1mg/kg), another atypical APD with low affinity for 5-HT1A receptors, but did not impair exploration. These results suggest that blonansein and risperidone, atypical APDs which lack a direct action on 5-HT1A receptors require 5-HT1A receptor stimulation to reverse the subchronic PCP-induced NOR deficit and provide a support for clinical trial of blonanserin in combination with tandospirone to ameliorate cognitive impairment in schizophrenia and to have fewer side effects.

Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2 mg/day, but does not enhance efficacy of haloperidol, 2 mg/day: Comparison with reference dose risperidone, 6 mg/day

Most atypical antipsychotic drugs (APDs), e.g. risperidone (RIS), produce more extensive blockade of brain serotonin (5-HT)2A than dopamine (DA) D2 receptors. This distinguishes them from typical APDs, e.g. haloperidol (HAL). Our objective was to test the hypothesis that augmentation of low doses of RIS or HAL (2mg/day) with pimavanserin (PIM), a selective 5-HT2A inverse agonist, to enhance 5-HT2A receptor blockade, can achieve efficacy comparable to RIS, 6mg/day, but with lesser side effects. In a multi-center, randomized, double-blind, 6week trial, 423 patients with chronic schizophrenia experiencing a recent exacerbation of psychotic symptoms were randomized to RIS2mg+placebo (RIS2PBO), RIS2mg+PIM20mg (RIS2PIM), RIS6mg+PBO (RIS6PBO), HAL2mg+PBO (HAL2PBO), or HAL2mg+PIM20mg (HAL2PIM). Improvement in psychopathology was measured by the PANSS and CGI-S. The reduction in PANSS Total Score with RIS2PIM at endpoint was significantly greater than RIS2PBO: −23.0 vs. −16.3 (p=0.007), and not significantly different from the RIS6PBO group: −23.2 points. The percentage of patients with ≥20% improvement at day 15 in the RIS2PIM group was 62.3%, significantly greater than the RIS6PBO (42.1%; p=0.01) and the RIS2PBO groups (37.7%; p=0.002). Weight gain and hyperprolactinemia were greater in the RIS6PBO group than the RIS2PIM group but there was no difference in extrapyramidal side effects (EPS). HAL2PBO and HAL2PIM were not significantly different from each other in efficacy but HAL2PIM had less EPS at end point. Both HAL groups and RIS6PBO showed equal improvement in psychopathology at endpoint, indicating HAL 2mg/day is effective to treat an acute exacerbation in chronic schizophrenia patients. In conclusion, a sub-effective RIS dose combined with PIM to enhance 5-HT2A receptor blockade provided faster onset of action, and at endpoint, equal efficacy and better safety, compared to standard dose RIS. These results support the conclusion that 5-HT2A receptor blockade is a key component of the action of some atypical APDs and can reduce EPS due to a typical APD.

Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT1A Partial Agonist

Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT)(2A)/dopamine D(2) antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT(1A) partial agonist properties, tandospirone, a selective 5-HT(1A) partial agonist, haloperidol, a D(2) antagonist, and pimavanserin, a 5-HT(2A) inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1 mg/kg), tandospirone (5 mg/kg), pimavanserin (3 mg/kg), or haloperidol (1 mg/kg) b.i.d. 30 min before PCP (2 mg/kg, b.i.d.) for 7 days (day1-7), followed by a 7-day washout (day 8-14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT(1A) antagonists, further evidence for the importance of 5-HT(1A) receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.

The role of 5-HT1A receptors in phencyclidine (PCP)-induced novel object recognition (NOR) deficit in rats

Atypical antipsychotic drugs (APDs), many of which are direct or indirect serotonin (5-HT)(1A) agonists, and tandospirone, a 5-HT(1A) partial agonist, have been reported to improve cognition in schizophrenia. We tested the effect of 5-HT(1A) agonism, alone, and in combination with other psychotropic agents, including the atypical APD, lurasidone, in reversing the deficit in novel object recognition (NOR) induced by subchronic treatment with the non-competitive NMDA receptor antagonist, phencyclidine (PCP) (2mg/kg, b.i.d., for 7days). Subchronic treatment with PCP induced a persistent NOR deficit. Lurasidone (0.1mg/kg), a potent 5-HT(1A) partial agonist, 5-HT(2A) antagonist, and weaker D(2) antagonist, tandospirone (0.6mg/kg), and the selective post-synaptic 5-HT(1A) agonist, F15599 (0.16mg/kg), ameliorated the subchronic PCP-induced-NOR deficit. The 5-HT(1A) antagonist, WAY100635 (0.6mg/kg), blocked the ameliorating effects of tandospirone and lurasidone. The combination of sub-effective doses of tandospirone (0.2mg/kg) and lurasidone (0.03mg/kg) also reversed the PCP-induced NOR-deficit. Buspirone, a less potent partial 5-HT(1A) agonist than tandospirone, was less effective. Co-administration of tandospirone (0.2mg/kg) and pimavanserin (3mg/kg), a relatively selective 5-HT(2A) receptor inverse agonist, did not reverse the effect of sub-chronic PCP on NOR. The D(2) antagonist, haloperidol, blocked the ameliorating effect of tandospirone on the PCP-induced deficit in NOR. These results indicate that 5-HT(1A) agonism is adequate to ameliorate the PCP-induced impairment in NOR and suggest further study of utilizing the combination of a 5-HT(1A) agonist and an atypical APD to ameliorate some types of cognitive impairment in schizophrenia.

The Novel Antipsychotic Drug Lurasidone Enhances N-Methyl-d-aspartate Receptor-Mediated Synaptic Responses

N-Methyl-D-aspartate (NMDA) receptor (NMDAR) hypofunction has been postulated to contribute to the cognitive deficit of schizophrenia. In this study, we examined the effect of lurasidone (Latuda; Dainippon Sumitomo Pharma Co. Ltd., Tokyo, Japan), a newly approved atypical antipsychotic drug (APD), on NMDAR synaptic function in rat frontal cortical pyramidal neurons. In vivo administration of lurasidone produced a significant and selective enhancement of NMDAR-mediated synaptic responses and surface expression of NR2A and NR2B subunits. Lurasidone has high affinity for serotonin 5-HT(1A), 5-HT(2A), and 5-HT(7) receptors and dopamine D(2) receptors. In vivo administration of the 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2 -(2-(4-methyl-1-piperidinyl)ethyl)pyrrolidine (SB-269970) mimicked the enhancing effect of lurasidone on NMDAR responses, whereas the D(2) receptor antagonist haloperidol failed to do so. Previous studies have found that short-term administration of lurasidone reverses the cognitive impairment induced by subchronic administration of phencyclidine (PCP), an NMDAR noncompetitive antagonist. In this study, we found that lurasidone, as well as the prototypical atypical APD clozapine, restored NMDAR-mediated synaptic responses to normal levels in the PCP model of schizophrenia. These results suggest that NMDAR is the potential key molecular target of lurasidone, possibility via antagonizing 5-HT(7) receptors, which is consistent with evidence that 5-HT(7) receptor antagonism contributes to cognitive enhancement by atypical APDs in patients with schizophrenia.