The preclinical profile of asenapine: clinical relevance for the treatment of schizophrenia and bipolar mania

Introduction: Asenapine is a novel antipsychotic drug approved for the treatment of acute schizophrenia, manic, or mixed episodes associated with bipolar I disorder, as a maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Areas covered: This review focuses on the preclinical profile of asenapine. It analyzes the pharmacological, neurochemical, behavioral, and molecular mechanisms of asenapine and their contribution to the beneficial therapeutic advantages of the drug as reported in published preclinical and clinical studies, product labels, and poster presentations.

Expert opinion: Asenapine exhibits a broad pharmacological profile that targets a wide range of neurotransmitter receptors with variable affinities. The drug preferentially increases dopamine, norepinephrine, and acetylcholine levels in cortical and limbic brain areas. It also potentiates cortical glutamatergic neurotransmission, and is active in behavioral animal models predictive of antipsychotic, antidepressant, and pro-cognitive activities. Chronic administration of asenapine alters the abundance of dopamine, serotonin, glutamate, adrenergic, and cholinergic receptor subtypes in different brain regions. These action mechanisms of asenapine might contribute to its unique psychopharmacological properties in the improved treatment of schizophrenia and other psychotic disorders.     

Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia

Rationale Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder. Materials and methods The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-d-aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed. Results Asenapine (0.05–0.2 mg/kg, subcutaneous [s.c.]) induced a dose-dependent suppression of CAR (no escape failures recorded) and did not induce catalepsy. Asenapine (0.05–0.2 mg/kg, s.c.) increased dopamine efflux in both the mPFC and the NAc. Low-dose asenapine (0.01 mg/kg, intravenous [i.v.]) increased dopamine efflux preferentially in the shell compared to the core of NAc, whereas at a higher dose (0.05 mg/kg, i.v.), the difference disappeared. Finally, like clozapine (100 nM), but at a considerably lower concentration (5 nM), asenapine significantly potentiated the NMDA-induced responses in pyramidal cells of the mPFC. Conclusions These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.     

Paliperidone extended-release: a review of efficacy and tolerability in schizophrenia,schizoaffective disorder and bipolar mania

Importance of the field: Paliperidone extended-release (ER), a once-daily, oral, atypical antipsychotic, has been available in the USA and the EU for the treatment of schizophrenia for more than 2 years and was recently (July 2009) approved in the USA for treatment of schizoaffective disorder. Additional data on its efficacy and safety, including that for additional indications, is emerging.

Areas covered in this review: This review provides a background on the compound and summarizes recent data available on treatment of schizophrenia, including comparative data with other antipsychotics, and efficacy and safety data from clinical trials in schizoaffective and bipolar disorders.

What the reader will gain: The reader will gain knowledge of the compound and the existing clinical data so far for paliperidone ER.

Take home message: Paliperidone ER is effective for the treatment of schizophrenia and is at present the only antipsychotic approved in the USA for treatment of schizoaffective disorder. Its efficacy and tolerability profile in treating patients with schizophrenia or schizoaffective disorder indicates that paliperidone ER offers an important treatment option among atypical antipsychotic therapy for these patients.     

Iloperidone,asenapine and lurasidone: a primer on their current status

Introduction: Three newer atypical antipsychotic drugs were FDA-approved in 2009 and 2010 in the following order: iloperidone, asenapine and lurasidone. The three drugs are indicated for the treatment of acute schizophrenia. Asenapine is also approved for treatment of manic or mixed episodes associated with bipolar I disorder, for the maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Areas covered: This review compares and contrasts the current preclinical, clinical, safety and tolerability profiles of the three newer drugs, as reported in published preclinical and clinical studies, product labels, poster presentations and press releases.

Expert opinion: Preclinical studies have reported that the three drugs have variable affinities for a wide range of neurotransmitter receptors, and are active in animal models predictive of antipsychotic activity. Asenapine is the first antipsychotic to be administered sublingually, whereas iloperidone requires titration to minimize orthostatic hypotension. Asenapine and lurasidone are associated with dose-related akathisia, whereas iloperidone is not. The three drugs appear to have relatively benign metabolic profiles. The availability of the three novel antipsychotics should provide additional options for improved treatment of schizophrenia and other psychotic disorders.     

Asenapine: a new antipsychotic option

Asenapine is a new psychopharmacologic agent approved for the acute and maintenance treatment of schizophrenia and the acute and maintenance treatment of manic and mixed episodes associated with bipolar I disorder. The efficacy of asenapine in treating schizophrenia was evaluated in four 6-week studies in which placebo and active controls (risperidone, olanzapine, and haloperidol) were used. Two 3-week placebo-controlled trials examined the efficacy of asenapine and active control (olanzapine) in the treatment of bipolar I disorder. Asenapine demonstrated efficacy in relation to placebo for 2 of the acute schizophrenia trials and both trials examining the acute treatment of bipolar I disorder. Several factors should be examined when considering asenapine therapy in relation to other antipsychotics including efficacy, atypicality of receptor binding, obstacles to administration and compliance, and finally cost. No efficacy advantage is evident with asenapine over other antipsychotic agents. Barriers to achieving compliance with asenapine include the recommendations of twice daily dosing, the need to avoid food and liquids for at least 10 minutes postadministration, the need for patient cooperation with sublingual administration, and the low bioavailability of the tablet if swallowed. Finally, no cost advantage is evident for using asenapine in comparison to the already available generic risperidone or other soon-to-be generic atypical antipsychotics.     

Asenapine effects on cognitive and monoamine dysfunction elicited by subchronic phencyclidine administration

PurposeRepeated, intermittent administration of the psychotropic NMDA antagonist phencyclidine (PCP) to laboratory animals causes impairment in cognitive and executive functions, modeling important sequelae of schizophrenia; these effects are thought to be due to a dysregulation of neurotransmission within the prefrontal cortex. Atypical antipsychotic drugs have been reported to have measurable, if incomplete, effects on cognitive dysfunction in this model, and these effects may be due to their ability to normalize a subset of the physiological deficits occurring within the prefrontal cortex. Asenapine is an atypical antipsychotic approved in the US for the treatment of schizophrenia and for the treatment, as monotherapy or adjunctive therapy to lithium or valproate, of acute manic or mixed episodes associated bipolar I disorder. To understand its cognitive and neurochemical actions more fully, we explored the effects of short- and long-term dosing with asenapine on measures of cognitive and motor function in normal monkeys and in those previously exposed for 2 weeks to PCP; we further studied the impact of treatment with asenapine on dopamine and serotonin turnover in discrete brain regions from the same cohort.MethodsMonkeys were trained to perform reversal learning and object retrieval procedures before twice daily administration of PCP (0.3 mg/kg intra-muscular) or saline for 14 days. Tests confirmed cognitive deficits in PCP-exposed animals before beginning twice daily administration of saline (control) or asenapine (50, 100, or 150 μg/kg, intra-muscular). Dopamine and serotonin turnover were assessed in 15 specific brain regions by high-pressure liquid chromatography measures of the ratio of parent amine to its major metabolite.ResultsOn average, PCP-treated monkeys made twice as many errors in the reversal task as did control monkeys. Asenapine facilitated reversal learning performance in PCP-exposed monkeys, with improvements at trend level after 1 week of administration and reaching significance after 2–4 weeks of dosing. In week 4, the improvement with asenapine 150 μg/kg (p = 0.01) rendered the performance of PCP-exposed monkeys indistinguishable from that of normal monkeys without compromising fine motor function. Asenapine administration (150 μg/kg twice daily) produced an increase in dopamine and serotonin turnover in most brain regions of control monkeys and asenapine (50–150 μg/kg) increased dopamine and serotonin turnover in several brain regions of subchronic PCP-treated monkeys. No significant changes in the steady-state levels of dopamine or serotonin were observed in any brain region except for the central amygdala, in which a significant depletion of dopamine was observed in PCP-treated control monkeys; asenapine treatment reversed this dopamine depletion. A significant decrease in serotonin utilization was observed in the orbitofrontal cortex and nucleus accumbens in PCP monkeys, which may underlie poor reversal learning. In the same brain regions, dopamine utilization was not affected. Asenapine ameliorated this serotonin deficit in a dose-related manner that matched its efficacy for reversing the cognitive deficit.ConclusionsIn this model of cognitive dysfunction, asenapine produced substantial gains in executive functions that were maintained with long-term administration. The cognition-enhancing effects of asenapine and the neurochemical changes in serotonin and dopamine turnover seen in this study are hypothesized to be primarily related to its potent serotonergic and noradrenergic receptor binding properties, and support the potential for asenapine to reduce cognitive dysfunction in patients with schizophrenia and bipolar disorder.This article is part of a Special Issue entitled ‘Schizophrenia’.     

Iloperidone for schizophrenia

Importance of the field: No existing antipsychotic adequately controls all symptoms associated with schizophrenia. Also, no antipsychotic adequately benefits most patients with this disorder. Finally, the safety and tolerability of each antipsychotic frequently dictate the choice of agent.

Areas covered in the review: The mechanism of action of iloperidone, its efficacy and its safety and tolerability when used to treat patients with schizophrenia.

What the reader will gain: An appreciation of the potential advantages and disadvantages of iloperidone when used for the treatment of schizophrenia.

Take home message: Iloperidone is a recent addition to the current group of second-generation antipsychotics. While it may share many qualities with other agents in this class, its unique neuroreceptor signature and adverse-effect profile may prove beneficial in clinical practice.     

Safety of olanzapine use in adolescents

Introduction: Olanzapine was the second first-line atypical antipsychotic medication approved by the Food and Drug Administration (FDA) for the treatment of adult schizophrenia and later approved for adolescent schizophrenia and bipolar disorder. Initial studies performed on adults demonstrated efficacy compared to placebo and a first-generation antipsychotic medication. Initial assessments in adolescents with schizophrenia demonstrated significant symptom reduction without movement disorder, but with weight gain. Later studies reported efficacy for bipolar disorder in teenagers, but with weight gain. The assessment of olanzapine safety in teenagers has shown substantial weight gain and metabolic measures. Because of equivalent efficacy to other atypical antipsychotic medications and the metabolic side-effects, olanzapine is often recommended as a second-use medication.

Areas covered: Studies of olanzapine use in adolescents with schizophrenia or bipolar disorder demonstrate significant reduction in symptoms while causing no movement disorder side-effects. There has been reduction in use of olanzapine with adolescents as newer atypical antipsychotics have emerged associated with less weight gain.

Expert opinion: Studies of olanzapine have demonstrated effectiveness in adolescents with a psychotic illness. Metabolic side-effects are a strong concern of the field and have led to the recommendation of using the medication in a secondary fashion.     

Asenapine elevates cortical dopamine,noradrenaline and serotonin release. Evidence for activation of cortical and subcortical dopamine systems by different mechanisms

Rationale  Asenapine, a psychopharmacologic agent developed for schizophrenia and bipolar disorder, has higher affinity for 5-HT_2A/C,6,7 and α₂ adrenergic receptors than for D₂ receptors. Asenapine exhibits potent antipsychotic-like effects without inducing catalepsy, increases cortical and subcortical dopamine release, and facilitates cortical glutamatergic transmission in rats. In this study, we further analyzed the effects of asenapine on dopaminergic, noradrenergic, and serotonergic systems in the rat brain. Materials and methods  We studied the effects of asenapine on (1) dopaminergic neurons in the ventral tegmental area (VTA) and noradrenergic neurons in the locus coeruleus using in vivo single cell recording, (2) release of dopamine and noradrenaline (medial prefrontal cortex), serotonin (frontal cortex), and dopamine (nucleus accumbens), using in vivo microdialysis. Results  Systemic asenapine increased dopaminergic (0.001–0.2 mg/kg, i.v.) and noradrenergic (0.025–0.05 mg/kg i.v.) neuronal firing, and asenapine (0.1–0.2 mg/kg, s.c) increased cortical noradrenaline and serotonin output. Local asenapine administration increased all three monoamines in the cortex but did not affect accumbal dopamine output. Intra-VTA tetrodotoxin perfusion blocked asenapine-induced accumbal but not cortical dopamine outflow. Conclusion  Asenapine at doses associated with antipsychotic activity enhanced cortical monoamine efflux. Whereas the asenapine-induced dopamine increase in nucleus accumbens is dependent on activation of dopaminergic neurons in the VTA, the increase of cortical dopamine outflow involves largely a local action at nerve terminals. Our data provide further insight on the pharmacologic characteristics of asenapine that may have bearing on its clinical efficacy in the treatment of schizophrenia and bipolar disorder.     

Sertindole for the treatment of schizophrenia

Importance of the field: Despite considerable progress in the pharmacological treatment of schizophrenia, unmet needs remain concerning refractory patients, as well as improvement of negative symptoms, cognition, quality of life, adherence and tolerability. Sertindole, a second-generation antipsychotic with high affinity for dopamine D₂, serotonin 5-HT_2A, 5-HT_2C, and α₁-adrenergic receptors, is the first phenylindole-derived antipsychotic agent.

Areas covered in this review: Pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of sertindole are covered based on a literature review (PubMed) from 1990 to 2010. Pivotal as well as supportive randomized controlled trials are reviewed along with observational and/or naturalistic safety studies.

What the reader will gain: This review of sertindole will allow the reader to determine the place for sertindole in the schizophrenia treatment landscape.

Take home message: Studies conducted so far suggest a beneficial effect of sertindole on positive and negative symptoms as well as on cognition, relapse prevention and quality of life. There is also some evidence for the treatment of refractory patients. Sertindole induces moderate weight gain, with few extrapyramidal symptoms and metabolic changes. More head-to-head comparisons with other second-generation antipsychotics are, however, still needed as well as further clarification on cardiac safety.     

Asenapine effects in animal models of psychosis and cognitive function

Rationale

Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, α-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties.

Objectives

The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone.

Materials and methods

Amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted prepulse inhibition (Apo-PPI; 0.5 mg/kg s.c.) were used as tests for antipsychotic activity. Delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks were used to assess short-term spatial memory and attention, respectively. Asenapine doses varied across tasks: Amp-LMA (0.01–0.3 mg/kg s.c.), Apo-PPI (0.001–0.3 mg/kg s.c.), DNMTP (0.01–0.1 mg/kg s.c.), and 5-CSR (0.003–0.3 mg/kg s.c.).

Results

Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P?<?0.01) reduced DNMTP accuracy at short delays; post hoc analyses revealed that only 0.1 mg/kg asenapine and 0.3 mg/kg risperidone differed from vehicle. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03–0.3 mg/kg; and risperidone, 0.01–0.1 mg/kg) significantly impaired 5-CSR accuracy (P?<?0.05).

Conclusions

Asenapine has potent antidopaminergic properties that are predictive of antipsychotic efficacy. Asenapine, like risperidone and olanzapine, did not improve cognition in normal rats. Rather, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone.     

Serotonin 2A receptor antagonists for treatment of schizophrenia

Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D₂) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia.

Areas covered: Preclinical, clinical and post-mortem studies of the serotonin 5-HT_2A system in schizophrenia are reviewed. The implications of a combined D₂ and 5-HT_2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT_2A receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT_2A receptor antagonists for the treatment of schizophrenia.

Expert opinion: 5-HT_2A receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT_2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT_2A receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia.     

Development of novel therapy of schizophrenia in children and adolescents

Introduction: Typical and atypical antipsychotics are efficacious treatments for early-onset schizophrenia (EOS) with very subtle differences in their efficacy. Therefore, when choosing an antipsychotic, the side-effect profile of the individual antipsychotic needs to be taken into account. There is a growing body of neurobiological and genetic evidence for early-onset patients, but these findings have not yet translated into the clinic.

Areas covered: The authors summarize the current treatment options for EOS and discuss the novel treatment options that are under evaluation. The authors focus specifically on Phase II and Phase III clinical trials.

Expert opinion: Currently, there are no truly groundbreaking pharmacological treatment options emerging in EOS. There are several newer antipsychotic agents (iloperidone, lurasidone, asenapine, blonanserin) that are currently in clinical trials. It is unclear whether therapeutic efficacy of any of these agents will be superior or even similar to the existing treatment and the main differentiating factor between individual drugs remains to be their side-effect profile. Beyond these antipsychotics, oxytocin and N-acetylcysteine are the only new pharmacological treatment options that are being evaluated in EOS. Therefore, a major change in the treatment development paradigm is necessary to identify novel and efficacious drugs.     

Modifying the risk of atypical antipsychotics in the treatment of juvenile-onset schizophrenia

Importance to the field: This review summarizes the evidence for use of typical and atypical antipsychotic medications for the treatment of juvenile-onset schizophrenia. We highlight the risks and benefits of antipsychotic agents for youth with this disorder, paying special attention to weight gain and metabolic effects, an area of specific concern within child and adolescent psychiatry.

Areas covered in this review: We describe the seriousness of juvenile-onset schizophrenia and its impact on long-term functioning, noting that pharmacological treatment remains the standard of care for this disorder. We focus on weight gain and metabolic effects associated with atypical agents and review strategies to modify risks associated with these agents.

What the reader will gain: We summarize strategies for attenuating the risk of weight gain for youth on atypical antipsychotics, including what is known about nutritional counseling and exercise programs as well as pharmacotherapy with adjunctive weight loss agents.

Take-home message: Given the negative consequences associated with untreated schizophrenia, it appears that the most effective way to improve the risk:benefit ratio in the treatment of adolescents with schizophrenia is to reduce the risks associated with pharmacological treatment.     

Iloperidone, asenapine and lurasidone: a primer on their current status

Introduction: Three newer atypical antipsychotic drugs were FDA-approved in 2009 and 2010 in the following order: iloperidone, asenapine and lurasidone. The three drugs are indicated for the treatment of acute schizophrenia. Asenapine is also approved for treatment of manic or mixed episodes associated with bipolar I disorder, for the maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. Areas covered: This review compares and contrasts the current preclinical, clinical, safety and tolerability profiles of the three newer drugs, as reported in published preclinical and clinical studies, product labels, poster presentations and press releases. Expert opinion: Preclinical studies have reported that the three drugs have variable affinities for a wide range of neurotransmitter receptors, and are active in animal models predictive of antipsychotic activity. Asenapine is the first antipsychotic to be administered sublingually, whereas iloperidone requires titration to minimize orthostatic hypotension. Asenapine and lurasidone are associated with dose-related akathisia, whereas iloperidone is not. The three drugs appear to have relatively benign metabolic profiles. The availability of the three novel antipsychotics should provide additional options for improved treatment of schizophrenia and other psychotic disorders.     

Brexpiprazole for the treatment of schizophrenia

Introduction: Limited efficacy on negative and cognitive symptoms and adverse effects of current antipsychotics raise the need of developing new antipsychotics. Brexpiprazole, a new antipsychotic drug approved by the U.S. Food and Drug Administration in July 2015 for the treatment of schizophrenia, is a novel serotonin-dopamine receptor modulator with partial agonist activity at serotonin 1A (5-HT_1A) and D_2/3 receptors.

Areas covered: We reviewed brexpiprazole related in vitro and in vivo studies, including phase II and phase III clinical trials in this article. Brexpiprazole showed significant improvement of psychotic symptoms for patients with schizophrenia in clinical trials. Most of the clinical trials demonstrated the antipsychotic effect of brexpiprazole using Positive and Negative Syndrome Scale (PANSS) in acute schizophrenia patients, and found that higher doses (2–4 mg daily) of brexpiprazole had better outcomes. In short-term trials, brexpiprazole did not show benefit for cognitive function in 6 weeks. Insomnia, akathisia, headache, and agitation were the most frequently recorded adverse events.

Expert commentary: Brexpiprazole showed better efficacy than placebo in acute phase of schizophrenia. Long-term studies are needed to investigate the efficacy of brexpiprazole for cognitive function as well as the strength and weakness of brexpiprazole among current antipsychotic drugs.     

Drug safety and efficacy evaluation of sertindole for schizophrenia

Introduction: Despite the progress in antipsychotic treatment, modern antipsychotic medication is still associated with side effects, reduced compliance, drug discontinuation and insufficient effects on negative and cognitive symptoms. Sertindole is an antipsychotic compound, with high affinity for dopamine D₂, serotonin 5-HT_2A, 5-HT_2C and α₁-adrenergic receptors, which has been reintroduced in the market after extended re-evaluation of its safety and risk–benefit profile.

Areas covered: Sertindole's pharmacological profile, pharmacokinetics, neuophysiological properties, efficacy on positive, negative and cognitive symptoms and safety issues are covered in this article, based on a literature review from 1990 to 2012.

Expert opinion: Based on five double-blind, randomized, placebo-, haloperidol- or risperidone-controlled studies in patients with schizophrenia, sertindole shows a comparable efficacy with haloperidol and risperidone on positive symptoms, while the effect on negative symptoms seems to be superior. Sertindole is generally well tolerated, but is associated with a dose-related QTc interval prolongation (+22 ms). Risk factors for drug-induced arrhythmia, such as cardiac diseases, congenital long QT syndrome, prolongated QTc at baseline, etc. and drug interactions should be considered before prescribing sertindole. To minimize cardiovascular risk, regular ECG recording is required. Sertindole can be an important second-line option for the treatment of schizophrenia for patients intolerant to at least one other antipsychotic. Further comparison with other SGAs and investigations on subgroups (e.g., children, elderly, first-episode, treatment-refractory patients, etc.) are still needed for a precise understanding of the therapeutic benefits and its role in schizophrenia therapy.     

Lurasidone in the treatment of schizophrenia: a critical evaluation

Introduction: Antipsychotic medications are the foundation of the pharmacological treatment of schizophrenia and lurasidone is the most recent of the 65 agents around the world to become available. In order to use it optimally, it is important to understand its pharmacological and clinical nature and its comparative effectiveness to other antipsychotic agents in the treatment of schizophrenia.

Areas covered: Following a comprehensive review of the literature, this article summarizes current information about the pharmacology of lurasidone, data about its short- and long-term efficacy and safety/tolerability in the treatment of schizophrenia, its comparative effectiveness to other antipsychotic agents, and guidance about its optimal use in the treatment of individuals with schizophrenia.

Expert opinion: Lurasidone is a benzoisothiazole with potent dopamine D₂ and serotonin 5HT_2A antagonist and serotonin 5HT_1A partial agonist properties (like other second-generation antipsychotic agents) with additional potent 5HT₇ and alpha_2C noradrenergic antagonism. It has little or no activity at the alpha₁ and alpha_2A noradrenergic, 5HT_2C serotonergic, histaminergic and cholinergic receptors. Available only in an oral formulation, it is effective in once-daily dosing (40 – 160 mg/day) and its absorption is affected by food. There is an extensive clinical trial database with short-term and long-term placebo- and antipsychotic-controlled clinical trials evaluating the efficacy and safety/tolerability of lurasidone in the treatment of schizophrenia. It has been found to be efficacious with comparable efficacy to other agents in the treatment of acute psychosis and prevention of relapse in individuals with schizophrenia. The greater antidepressant and cognitive benefits suggested by its receptor profile need substantiation in robust clinical trials. It is less likely to cause metabolic and cardiac adverse effects than most other second-generation agents and is associated with a modest risk of extrapyramidal side-effects, akathisia, and prolactin elevation.     

Olanzapine: review of safety 2008

Background: Olanzapine is a second-generation antipsychotic approved for the treatment of schizophrenia, bipolar mania and associated agitation. Objective: To assess the safety profile of olanzapine, including its propensity to be associated with weight gain, diabetes mellitus and dyslipidemias. Methods: Review of English-language reports located through PubMed and information available on regulatory agency websites. Results/conclusion: The use of olanzapine can pose a therapeutic dilemma in that on one hand, a number of large scale studies have found effectiveness advantages for olanzapine in comparison to other first-line second-generation medications. On the other hand, olanzapine is associated with substantial weight gain and the development of dyslipidemia. Regarding other important safety concerns, olanzapine has a favorable profile in terms of extra-pyramidal side effects and is also relatively prolactin-sparing. The effectiveness benefits may outweigh the risks, particularly in patients with low baseline risk for metabolic syndrome but monitoring for untoward metabolic effects is crucial. Switch-or-stay and other intervention decisions need to be made early before substantial weight gain has occurred.