piperidines and ziprasidone

The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses.. A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses.. Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice.. In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Topics: Acute Disease; Administration, Oral; Antipsychotic Agents; Aripiprazole; Clozapine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Haloperidol; Humans; Imidazoles; Indoles; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Thiophenes

To summarize and evaluate the existing literature regarding medications to treat Parkinson's disease (PD) psychosis.. MEDLINE (1946 to March 2017), EMBASE (1980 to March 2017), CINAHL (1982 to March 2017), and PsychInfo (1887 to March 2017) were searched using the following terms: Parkinson disease, Parkinson's disease, psychotic disorders, psychosis, delusions, and hallucinations.. The search was limited to randomized controlled trials (RCTs) reporting human outcomes. Data extracted included the following: study design, population, setting, intervention, control, outcomes related to psychosis and safety, and potential biases assessed using Cochrane Collaboration's Risk of Bias Assessment Tool.. After assessment, 16 of 235 studies were included; 11 articles reported comparisons between active drug and placebo, whereas 5 compared clozapine and an active comparator. Placebo-controlled trials demonstrated benefit for clozapine (n = 2) and pimavanserin (n = 2), with no firm benefits observed for quetiapine (n = 4) or olanzapine (n = 3). Comparative studies demonstrated improved efficacy in symptom scores when clozapine or comparator agent (n = 2, quetiapine; n = 1, olanzapine; n = 1, risperidone; and n = 1, ziprasidone) was assessed alone. However, no comparator data suggest that one agent is better than another, and none are yet available for pimavanserin. Overall risk of bias across all studies was moderate to high.. Despite lack of rigor in study designs, published data to date suggest that clozapine and pimavanserin should be considered drugs of choice to treat PD psychosis.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Evidence-Based Medicine; Humans; Olanzapine; Parkinson Disease; Piperazines; Piperidines; Practice Guidelines as Topic; Psychotic Disorders; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Thiazoles; Urea

Insufficient treatment of psychosis often manifests as violent and aggressive behaviors that are dangerous to the patient and others, and that warrant treatment strategies which are not considered first-line, evidence-based practices. Such treatment strategies include both antipsychotic polypharmacy (simultaneous use of 2 antipsychotics) and high-dose antipsychotic monotherapy. Here we discuss the hypothesized neurobiological substrates of various types of violence and aggression, as well as providing arguments for the use of antipsychotic polypharmacy and high-dose monotherapy to target dysfunctional neurocircuitry in the subpopulation of patients that is treatment-resistant, violent, and aggressive. In this review, we focus primarily on the data supporting the use of second-generation, atypical antipsychotics both at high doses and in combination with other antipsychotics.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Brain; Clozapine; Dibenzocycloheptenes; Drug Therapy, Combination; Heterocyclic Compounds, 4 or More Rings; Humans; Impulsive Behavior; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Polypharmacy; Psychotic Disorders; Quetiapine Fumarate; Receptors, Dopamine D2; Risperidone; Thiazoles; Violence

Akathisa is one of the most common and distressing neuroleptic-induced extrapyramidal side effects. Although it is well recognized in the context of conventional antipsychotic medications, there have been recent concerns raised by clinicians and researchers that this syndrome is overlooked in relation to second-generation or atypical antipsychotics. This review examines the recent literature relevant to second-generation antipsychotic (SGA)-induced akathisia.. Recent studies using large databases clearly indicate that extrapyramidal side effects, in particular akathisia, do occur with the SGAs, although the frequency is not as high as with the conventional antipsychotics. Risk factors include use of high doses, high potency SGAs, or combinations of SGAs with other psychotropic drugs, bipolar depression, palliative care settings, and comorbid substance abuse in psychosis. The dopamine hypothesis remains plausible for understanding the pathophysiology of akathisia. There is emerging evidence that mirtazapine may be useful in the treatment of acute akathisia.. Even though akathisia is less prevalent with SGAs than with the first-generation drugs, it remains clinically important and all clinicians should be conversant with its recognition and management.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Isoxazoles; Olanzapine; Piperazines; Piperidines; Prevalence; Psychomotor Agitation; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risk Factors; Risperidone; Sulpiride; Thiazoles

The role of lithium carbonate in the maintenance treatment of bipolar disorder is well established. Unfortunately, many patients fail to respond adequately to this agent or are unable to tolerate its adverse effects. Divalproex has become a commonly used alternative to lithium, but it also is ineffective or poorly tolerated in many patients. This article attempts to review the available data on maintenance therapy in bipolar disorder with a variety of anticonvulsants and antipsychotics (both conventional and novel), with reference to relevant studies in acute mania and bipolar depression as well.. Evidence on maintenance therapy and relevant acute-phase data were collected using MEDLINE database searches.. Data on maintenance therapy with agents other than lithium and divalproex are sparse, and often derived from open, uncontrolled studies. Implications and flaws of available data are discussed.. Other than lithium, there are few robust double-blind data to support the use of a variety of agents in the maintenance phase. However, uncontrolled data suggest that a number of agents merit further study.

Topics: Acetates; Amines; Anticonvulsants; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Calcium Channel Blockers; Carbamazepine; Clozapine; Cyclohexanecarboxylic Acids; Dibenzothiazepines; Donepezil; Fatty Acids, Omega-3; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Indans; Lamotrigine; Lithium Carbonate; Olanzapine; Piperazines; Piperidines; Pirenzepine; Quetiapine Fumarate; Risperidone; Thiazoles; Topiramate; Treatment Outcome; Triazines; Valproic Acid

Innovation in atypical antipsychotic agents continues with new preparations of available drugs as well as novel agents. In this article, we provide an update on these novel products by reviewing information from a computerised literature search, recent abstracts and discussions with industry representatives. A generic formulation of clozapine is now available. It may be less well absorbed and/or less effective than Clozaril, although evidence is conflicting. A fatty acid amide derivative of clozapine is in early development. A liquid formulation of risperidone is currently available, which may be a useful treatment for psychotic agitation as well as a preferable alternative to tablets for some patients. A depot formulation is in development for the long-term management of psychosis. An orally disintegrating tablet formulation of olanzepine is a useful alternative to standard tablets. A short-acting injectable formulation of the drug is in development for psychotic agitation. Sachets and slow-release formulations of quetiapine are in development. Ziprasidone, a recently launched agent, is available in tablet form for schizophrenia/schizoaffective disorder, psychotic depression and mania. A short-acting injectable formulation is in development for psychotic agitation. Aripiprazole (tablets) and iloperidone (tablets and depot injection) are two antipsychotics in development for schizophrenia/schizoaffective disorder (available information regarding iloperidone is very limited). These new formulations and agents should broaden options for the treatment of psychosis.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dosage Forms; Humans; Isoxazoles; Olanzapine; Piperazines; Piperidines; Pirenzepine; Quinolones; Risperidone; Schizophrenia; Thiazoles

The potential for iloperidone, a D2/5-HT2A antipsychotic, to affect the heart rate-corrected QT interval (QTc) was assessed in the absence and presence of metabolic inhibitors in a randomized, open-label, multicenter study. QT interval prolongation by medications, including both conventional and atypical antipsychotic drugs, can predispose patients to cardiac arrhythmias and result in sudden death. Adults with schizophrenia or schizoaffective disorder and normal electrocardiograms at baseline (N = 188) were randomized 1:1:1:1:1 to iloperidone, 8 mg twice daily (BID), 12 mg BID, 24 mg once daily (QD); quetiapine, 375 mg BID; or ziprasidone, 80 mg BID during period 1 (no metabolic inhibitors present). Iloperidone BID produced mean changes in QTc Fridericia correction (QTcF) interval (8.5-9.0 milliseconds [ms]) similar to those produced by ziprasidone (9.6 ms) and higher than those produced by quetiapine (1.3 ms). Iloperidone, 24 mg QD, produced a mean QTcF change of 15.4 ms. Coadministration of metabolic inhibitors with iloperidone during periods 2 (paroxetine) and 3 (paroxetine and ketoconazole) resulted in greater increases in the QTc interval. Increased QTc was observed in individuals with specific cytochrome P450 2D6 polymorphisms. Up to 10% of patients on iloperidone experienced QTc intervals of 60 ms or longer in the presence of metabolic inhibition and QD dosing. However, no patients experienced QTc changes of clinical concern (QTc ≥ 500 ms). The most common adverse events with iloperidone were headache, anxiety, and dyspepsia. The only cardiovascular adverse events with iloperidone were non-concentration-dependent tachycardia that was mild in most patients and did not lead to further sequelae. Pharmacogenetics and recommendations are discussed.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dibenzothiazepines; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Electrocardiography; Enzyme Inhibitors; Female; Genotype; Heart Rate; Humans; Isoxazoles; Ketoconazole; Linear Models; Long QT Syndrome; Male; Middle Aged; Paroxetine; Pharmacogenetics; Phenotype; Piperazines; Piperidines; Quetiapine Fumarate; Thiazoles; United States; Young Adult

Long-term use of the atypical antipsychotic iloperidone has not been investigated at doses above 16 mg/d. This article describes safety and tolerability results from the 25-week open-label extension of a 4-week placebo- and ziprasidone-controlled clinical trial of iloperidone.. Patients received a dose of 24 mg/d (given as 12 mg twice daily; mean dose = 21.6 mg) that could be reduced to 12 mg/d (given once daily at bedtime) any time after day 35 at the investigator's discretion.. A total of 72/173 patients (41.6%) completed the open-label extension. Treatment-emergent adverse events (TEAEs), most mild to moderate in severity, included headache (13.9%), weight increase (9.2%), dizziness (6.9%), nausea (6.4%), sedation (6.4%), and insomnia (5.2%). The only notable dose-related TEAEs were increased weight and headache. Levels of serum glucose, lipids, and prolactin were essentially unchanged or decreased during treatment. In general, akathisia and extrapyramidal symptoms (EPS) improved or were unchanged during treatment. There was no signal of worsening of efficacy based on changes from baseline in the Positive and Negative Syndrome Scale-Total.. This study further supports the long-term safety and tolerability of iloperidone for the treatment of schizophrenia, including iloperidone's favorable effect on metabolic laboratory parameters and low propensity to cause akathisia or EPS.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Substitution; Female; Humans; India; Isoxazoles; Longitudinal Studies; Male; Middle Aged; Piperazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Thiazoles; Time Factors; Treatment Outcome; United States; Young Adult

The efficacy and tolerability characteristics of an antipsychotic are difficult to determine from a single registration study. We thus conducted an analysis that assessed key efficacy and tolerability outcomes post hoc from four pooled short-term (4-6 weeks) phase III studies that evaluated iloperidone versus placebo in patients with schizophrenia or schizoaffective disorder.. Patient-level data were pooled from four prospective, randomized, double-blind, placebo-controlled and active-controlled, multicenter trials of iloperidone in patients with schizophrenia or schizoaffective disorder aged 18-65 years. Iloperidone 4-8, 10-16, and 20-24 mg/day (all dosed twice daily) were compared with placebo. Active controls used for assay sensitivity included risperidone 4-8 mg/day, haloperidol 15 mg/day, and ziprasidone 160 mg/day. Outcomes of interest were change from baseline to endpoint in the Brief Psychiatric Rating Scale (derived) (BPRSd), Positive and Negative Syndrome Scale (PANSS)-total (PANSS-T) score, and PANSS-positive (PANSS-P) and PANSS-negative (PANSS-N) subscale scores. An analysis of covariance (with treatment and study as factors, baseline as a covariate) was performed to compare changes between the iloperidone treatment groups versus placebo, on the basis of a last-observation-carried-forward approach for the intent-to-treat (ITT) populations. Tolerability outcomes were obtained from spontaneously reported adverse events (AEs), and number needed to harm was calculated for each antipsychotic versus placebo for the total population.. The ITT population included both schizoaffective and schizophrenia patients (N = 2401): n = 370, n = 494, and n = 424 for iloperidone 4-8, 10-16, and 20-24 mg/day, respectively; n = 294 for risperidone; n = 114 for haloperidol; n = 144 for ziprasidone; and n = 561 for placebo. Treatment with iloperidone 10-16 mg/day or 20-24 mg/day was associated with significantly improved BPRSd, PANSS-T, PANSS-P, and PANSS-N scores versus treatment with placebo. When only patients with schizophrenia were included (n = 1941), the pattern of results was essentially unchanged. The active controls confirmed assay sensitivity. Across all iloperidone dose groups, the incidences of extrapyramidal disorders and akathisia were similar to those observed with placebo. AEs for which the frequency was greater for iloperidone than placebo and for which the 95% confidence interval for number needed to harm did not contain infinity were dizziness, dry mouth, somnolence, nasal congestion, fatigue, sedation, and tachycardia; in general, for these AEs, frequency was higher with higher doses, resulting in a lower number needed to harm.. Consistent with product labeling, iloperidone 10-16 mg/day or 20-24 mg/day demonstrated significant improvement over placebo on BPRSd and PANSS-T scores, as well as on PANSS-P and PANSS-N subscale scores over 6 weeks of treatment in patients with schizophrenia and in the ITT population, which includes patients with schizoaffective disorder. Iloperidone did not differ from placebo in terms of extrapyramidal disorders and akathisia.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Labeling; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperazines; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Thiazoles; Treatment Outcome; Young Adult

Weight gain is a common side effect of antipsychotics, contributing to poor treatment adherence, and previously linked to the -759C/T polymorphism near the serotonin receptor 2C gene. The effect of this polymorphism was analyzed in schizophrenia patients treated with iloperidone for up to 7 months. No association was detected with the modest weight changes observed in these patients.

Topics: Analysis of Variance; Antipsychotic Agents; Female; Follow-Up Studies; Gene Frequency; Genotype; Humans; Isoxazoles; Male; Piperazines; Piperidines; Polymorphism, Genetic; Receptor, Serotonin, 5-HT2C; Schizophrenia; Thiazoles; Weight Gain

A whole genome association study was performed in a phase 3 clinical trial conducted to evaluate a novel antipsychotic, iloperidone, administered to treat patients with schizophrenia. Genotypes of 407 patients were analyzed for 334,563 single nucleotide polymorphisms (SNPs). SNPs associated with iloperidone efficacy were identified within the neuronal PAS domain protein 3 gene (NPAS3), close to a translocation breakpoint site previously observed in a family with schizophrenia. Five other loci were identified that include the XK, Kell blood group complex subunit-related family, member 4 gene (XKR4), the tenascin-R gene (TNR), the glutamate receptor, inotropic, AMPA 4 gene (GRIA4), the glial cell line-derived neurotrophic factor receptor-alpha2 gene (GFRA2), and the NUDT9P1 pseudogene located in the chromosomal region of the serotonin receptor 7 gene (HTR7). The study of these polymorphisms and genes may lead to a better understanding of the etiology of schizophrenia and of its treatment. These results provide new insight into response to iloperidone, developed with the ultimate goal of directing therapy to patients with the highest benefit-to-risk ratio.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Basic Helix-Loop-Helix Transcription Factors; Double-Blind Method; Female; Genome-Wide Association Study; Glial Cell Line-Derived Neurotrophic Factor Receptors; Humans; Isoxazoles; Male; Middle Aged; Nerve Tissue Proteins; Pharmacogenetics; Piperazines; Piperidines; Polymorphism, Single Nucleotide; Pseudogenes; Receptors, AMPA; Schizophrenia; Tenascin; Thiazoles; Transcription Factors; Young Adult

Administration of certain drugs (for example, antiarrhythmics, antihistamines, antibiotics, antipsychotics) may occasionally affect myocardial repolarization and cause prolongation of the QT interval. We performed a whole genome association study of drug-induced QT prolongation after 14 days of treatment in a phase 3 clinical trial evaluating the efficacy, safety and tolerability of a novel atypical antipsychotic, iloperidone, in patients with schizophrenia. We identified DNA polymorphisms associated with QT prolongation in six loci, including the CERKL and SLCO3A1 genes. Each single nucleotide polymorphism (SNP) defined two genotype groups associated with a low mean QT change (ranging from -0.69 to 5.67 ms depending on the SNP) or a higher mean QT prolongation (ranging from 14.16 to 17.81 ms). The CERKL protein is thought to be part of the ceramide pathway, which regulates currents conducted by various potassium channels, including the hERG channel. It is well established that inhibition of the hERG channel can prolong the QT interval. SLCO3A1 is thought to play a role in the translocation of prostaglandins, which have known cardioprotective properties, including the prevention of torsades de pointes. Our findings also point to genes involved in myocardial infarction (PALLD), cardiac structure and function (BRUNOL4) and cardiac development (NRG3). Results of this pharmacogenomic study provide new insight into the clinical response to iloperidone, developed with the goal of directing therapy to those patients with the optimal benefit/risk ratio.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Carrier Proteins; CELF Proteins; Cytoskeletal Proteins; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Gene Frequency; Genome-Wide Association Study; Genotype; Humans; Intracellular Signaling Peptides and Proteins; Isoxazoles; Linear Models; Linkage Disequilibrium; Long QT Syndrome; Male; Middle Aged; Neuregulins; Organic Anion Transporters; Pharmacogenetics; Phosphoproteins; Phosphotransferases (Alcohol Group Acceptor); Piperazines; Piperidines; Polymorphism, Single Nucleotide; RNA-Binding Proteins; Schizophrenia; Thiazoles; Young Adult

To demonstrate how several polymorphisms previously associated with the efficacy of the novel antipsychotic iloperidone could be used together to predict clinical response and provide practical information for individualized treatment.. This inpatient randomized, double-blind, placebo- and ziprasidone-controlled, 28-day study of the efficacy of iloperidone was conducted from November 2005 to September 2006. Likelihood ratios, predicted probabilities of response, and number needed to treat were calculated for patients with schizophrenia (DSM-IV criteria) using 6 genetic markers of iloperidone response as measured by change in the Positive and Negative Syndrome Scale-Total (PANSS-T) score. Data analysis was performed on 409 patients of various ethnic origins.. The 6-marker genotype combinations defined 4 groups of patients with distinct probabilities of response. More than 75% of iloperidone-treated patients in the group with the optimal genotype combinations showed a 20% or greater improvement, compared with 37% for patients with other genotypes. These patients had a significant response by the first week of treatment, which was earlier than for patients with other genotype combinations. The odds of responding to iloperidone treatment with at least 20% improvement ranged from 2.4 to 3.6 for patients with 1 of the 6 favorable single-marker genotypes. The odds increased to 9.5 or greater for patients with the most favorable 6-marker combinations. The difference in PANSS-T score improvement observed between the genotype groups was also seen for the positive, negative, and general psychopathology PANSS subscales. The relationship between treatment efficacy and genotype combinations was not observed for patients treated with ziprasidone.. These results illustrate the combined use of genetic markers to predict enhanced response to iloperidone and support the application of pharmacogenetics to differentiate medication options and improve individualized treatments for schizophrenia.. (ClinicalTrials.gov) Identifier: NCT00254202.

Topics: Adult; Alleles; Antipsychotic Agents; Double-Blind Method; Female; Genetic Markers; Genotype; Humans; Isoxazoles; Likelihood Functions; Male; Middle Aged; Odds Ratio; Pharmacogenetics; Piperazines; Piperidines; Polymorphism, Single Nucleotide; Probability; Psychiatric Status Rating Scales; Psychometrics; Schizophrenia; Thiazoles; Treatment Outcome

Iloperidone is a mixed D2/5-HT2 antagonist in development for treatment of schizophrenia. This trial aimed to evaluate the efficacy and safety of a fixed dose of iloperidone in patients with acute exacerbations of schizophrenia. This randomized, placebo-controlled, multicenter study comprised a 1-week titration period and a 3-week double-blind maintenance period. Eligible patients (n = 593) were randomized to iloperidone 24 mg/d, ziprasidone 160 mg/d as an active control, or placebo. Primary efficacy variable was change from baseline in the Positive and Negative Syndrome Scale Total (PANSS-T) score, using a mixed-effects model repeated measures analysis. Iloperidone demonstrated significant reduction versus placebo on the PANSS-T score (P< 0.01). Significant improvement versus placebo was also demonstrated with ziprasidone (P < 0.05). Compared with ziprasidone, iloperidone was associated with lower rates of many adverse events (AEs) that are particularly troublesome with antipsychotics, including sedation, somnolence, extrapyramidal symptoms, akathisia, agitation, and restlessness; iloperidone was associated with higher rates of weight gain, tachycardia, orthostatic hypotension, dizziness, and nasal congestion as reported as an AE. Most AEs were mild to moderate. A similar amount of QT prolongation was observed with both active treatments, although no patient had a treatment-emergent postbaseline corrected QT interval of 500 msec or greater. The incidence of clinically relevant changes in laboratory parameters was comparable between iloperidone and ziprasidone. Iloperidone was associated with a low incidence of extrapyramidal symptoms. Overall, there was improvement in akathisia with iloperidone treatment. Iloperidone treatment was effective, safe, and well tolerated in patients with acute exacerbation of schizophrenia.

Topics: Acute Disease; Adolescent; Adult; Aged; Antipsychotic Agents; Double-Blind Method; Drug Administration Schedule; Female; Humans; Isoxazoles; Male; Middle Aged; Piperazines; Piperidines; Prospective Studies; Schizophrenia; Thiazoles; Treatment Outcome

The concept of targeted therapies remains a holy grail for the pharmaceutical drug industry for identifying responder populations or new drug targets. Here we provide quantitative systems pharmacology as an alternative to the more traditional approach of retrospective responder pharmacogenomics analysis and applied this to the case of iloperidone in schizophrenia. This approach implements the actual neurophysiological effect of genotypes in a computer-based biophysically realistic model of human neuronal circuits, is parameterized with human imaging and pathology, and is calibrated by clinical data. We keep the drug pharmacology constant, but allowed the biological model coupling values to fluctuate in a restricted range around their calibrated values, thereby simulating random genetic mutations and representing variability in patient response. Using hypothesis-free Design of Experiments methods the dopamine D4 R-AMPA (receptor-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor coupling in cortical neurons was found to drive the beneficial effect of iloperidone, likely corresponding to the rs2513265 upstream of the GRIA4 gene identified in a traditional pharmacogenomics analysis. The serotonin 5-HT3 receptor-mediated effect on interneuron gamma-aminobutyric acid conductance was identified as the process that moderately drove the differentiation of iloperidone versus ziprasidone. This paper suggests that reverse-engineered quantitative systems pharmacology is a powerful alternative tool to characterize the underlying neurobiology of a responder population and possibly identifying new targets.

Topics: Antipsychotic Agents; Computer Simulation; Genotype; Humans; Isoxazoles; Models, Biological; Molecular Targeted Therapy; Neurobiology; Pharmacogenetics; Piperazines; Piperidines; Schizophrenia; Thiazoles

Atypical antipsychotic drugs (AAPDs), such as olanzapine, are associated with weight gain and hyperphagia in both humans and rodents. This side effect, however, is absent or reduced for AAPD such as ziprasidone. The increased levels of appetite seen in rodents may be related to drug interactions with brain histamine systems involved in appetite control. We demonstrate a significant interaction of olanzapine treatment with histamine neurotransmission in a rat-feeding paradigm measuring the consumption of a palatable fat emulsion. This interaction was identified using the H3 receptor antagonist thioperamide, which by blocking autoreceptor control of histaminergic neurons enhances release of hypothalamic histamine, causing hypophagia. We challenged this effect of thioperamide with olanzapine, which among its pharmacological actions is a potent H1 receptor antagonist. Olanzapine pretreatment significantly attenuated thioperamide-induced hypophagia. Pretreatment of thioperamide with ziprasidone, an AAPD with negligible H1 receptor affinity, however, failed to have this effect. Although thioperamide may also increase levels of neurotransmitters other than histamine, the potent H1 antagonist property of olanzapine is likely to result in the suppression of thioperamide-induced hypophagia. We conclude that olanzapine may be directly modulating histaminergic neurotransmission associated with the regulation of feeding behaviour.

Topics: Animals; Antipsychotic Agents; Appetite; Benzodiazepines; Brain; Dose-Response Relationship, Drug; Eating; Fat Emulsions, Intravenous; Histamine; Histamine H1 Antagonists; Histamine H3 Antagonists; Hypothalamus; Male; Neurons; Olanzapine; Piperazines; Piperidines; Rats; Synaptic Transmission; Taste; Thiazoles

Excessive activation of non-NMDA receptors, AMPA and kainate, contributes to neuronal degeneration in acute and progressive pathologies, possibly including schizophrenia. Because 5-HT(1A) receptor agonists have neuroprotective properties (e.g., against NMDA-induced neurotoxicity), we compared the effects of the antipsychotics, clozapine, ziprasidone and aripiprazole, that are partial agonists at 5-HT(1A) receptor, with those of haloperidol, which is devoid of 5-HT(1A) agonist properties, on kainic acid (KA)-induced striatal lesion volumes, in C57Bl/6N mice. The involvement of 5-HT(1A) receptors was determined by antagonist studies with WAY100635, and data were compared with those obtained using the potent and high efficacy 5-HT(1A) receptor agonist, F13714. Intra-striatal KA lesioning and measurement of lesion volumes using cresyl violet staining were carried out at 48 h after surgery. F13714, antipsychotics or vehicle were administered ip twice, 30 min before and 3 1/2 h after KA injection. WAY100635 (0.63 mg/kg) or vehicle were given sc 30 min before each drug injection. Clozapine (2 x 10 mg/kg), ziprasidone (2 x 20 mg/kg) and aripiprazole (2 x 10 mg/kg) decreased lesion volume by 61%, 59% and 73%, respectively. WAY100635 antagonized the effect of ziprasidone and of aripiprazole but only slightly attenuated that of clozapine. In contrast, haloperidol (2 x 0.16 mg/kg) did not affect KA-induced lesion volume. F13714 dose-dependently decreased lesion volume. The 61% decrease of lesion volume obtained with F13714 (2 x 0.63 mg/kg) was antagonized by WAY100635. WAY100635 alone did not affect lesion volume. These results show that 5-HT(1A) receptor activation protects against KA-induced striatal lesions and indicate that some atypical antipsychotic agents with 5-HT(1A) agonist properties may protect against excitotoxic injury, in vivo.

Topics: Aminopyridines; Animals; Antipsychotic Agents; Aripiprazole; Clozapine; Corpus Striatum; Disease Models, Animal; Excitatory Amino Acid Agonists; Haloperidol; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Piperazines; Piperidines; Pyridines; Quinolones; Receptor, Serotonin, 5-HT1A; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin Antagonists; Thiazoles

The noradrenergic system may play a role in antipsychotic modulation of schizophrenia symptoms. Therefore, the antagonistic potencies of the antipsychotics clozapine, chlorpromazine, risperidone, olanzapine, haloperidol, quetiapine, ziprasidone, iloperidone and aripiprazole were quantified using cell lines expressing the recombinant human alpha(2C)-adrenoceptor, alpha(2A)-adrenoceptor, or dopamine D(2L) receptor. The alpha(2)-adrenoceptor antagonists, yohimbine and idazoxan, were also tested. Alterations in cAMP were measured as changes in luminescence. In the alpha(2A)-adrenoceptor cell line, the agonist 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK14,304) induced a concentration-dependent increase in luminescence. In cell lines expressing alpha(2C) and D(2L) receptors, agonists induced a concentration-dependent reduction in luminescence. Yohimbine and idazoxan were the most potent alpha(2A)-adrenoceptor antagonists, yohimbine and iloperidone were the most potent alpha(2C)-adrenoceptor antagonists, and haloperidol and olanzapine were the most potent dopamine D(2) receptor antagonists. Clozapine had the highest alpha(2C)/D(2) selectivity, and iloperidone the highest alpha(2C)/alpha(2A) ratio. It is hypothesised that alpha(2C)-adrenoceptor blockade contributes to improvement of cognitive function.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Brimonidine Tartrate; Chlorpromazine; CHO Cells; Clozapine; Cricetinae; Cyclic AMP; Dibenzothiazepines; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Gene Expression; Haloperidol; Humans; Isoxazoles; Norepinephrine; Olanzapine; Piperazines; Piperidines; Pirenzepine; Quetiapine Fumarate; Quinolones; Quinoxalines; Receptors, Adrenergic, alpha-2; Receptors, Dopamine D2; Risperidone; Thiazoles; Transfection; Yohimbine

5-HT(1A) receptors are implicated in the aetiology of schizophrenia. Herein, the influence of 15 antipsychotics on the binding of the selective 'neutral' antagonist, [3H]WAY100,635 ([3H]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cyclo-hexanecarboxamide), was examined at human 5-HT(1A) receptors expressed in Chinese Hamster Ovary cells. In competition binding experiments, 5-HT displayed biphasic isotherms which were shifted to the right in the presence of the G-protein uncoupling agent, GTPgammaS (100 microM). In analogy, the isotherms of ziprasidone, quetiapine and S16924 (((R-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), were displaced to the right by GTPgammaS, consistent with agonist actions. Binding of several other antipsychotics, such as ocaperidone, olanzapine and risperidone, was little influenced by GTPgammaS. Isotherms of the neuroleptics, haloperidol, chlorpromazine and thioridazine were shifted to the left in the presence of GTPgammaS, suggesting inverse agonist properties. For most ligands, the magnitude of affinity changes induced by GTPgammaS (alteration in pK(i) values) correlated well with their previously determined efficacies in [35S]GTPgammaS binding studies [Eur. J. Pharmacol. 355 (1998) 245]. In contrast, the affinity of the 'atypical' antipsychotic agent, clozapine, which is a known partial agonist at 5-HT(1A) receptors, was less influenced by GTPgammaS. When the ratio of high-/low-affinity values was plotted against efficacy, hyperbolic isotherms were obtained, consistent with a modified ternary complex model which assumes that receptors can adopt active conformations in the absence of agonist. In conclusion, modulation of [3H]-WAY100,635 binding by GTPgammaS differentiated agonist vs. inverse agonist properties of antipsychotics at 5-HT(1A) receptors. These may contribute to differing profiles of antipsychotic activity.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Chlorpromazine; CHO Cells; Clozapine; Cricetinae; Dose-Response Relationship, Drug; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Haloperidol; Humans; Membranes; Piperazines; Piperidines; Pyridines; Pyrimidinones; Pyrrolidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Thiazoles; Thioridazine; Tritium