Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist in late-stage clinical development for the treatment of schizophrenia, as well as for bipolar disorder (manic/mixed and depressive episodes), and as an adjunctive agent for the treatment of major depressive disorder. Four phase 2 or 3, 6-week, randomized controlled trials in acute schizophrenia have been completed and reported as poster presentations or in press releases by the manufacturer. Superiority over placebo on the Positive and Negative Syndrome Scale total score was evidenced for cariprazine in daily doses of 1.5, 3.0, 4.5, 6.0, 1.5-4.5, 3.0-6.0, and 6.0-9.0 mg. A randomized controlled trial for the prevention of relapse of schizophrenia is ongoing. In short-term, randomized controlled trials, cariprazine does not appear to adversely impact metabolic variables, prolactin, or the electrocardiogram (ECG) QT interval. In the fixed-dose study of cariprazine that tested 1.5, 3.0, and 4.5 mg/day, the most commonly encountered adverse events were insomnia, extrapyramidal disorder, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation. However, the differences in incidence versus placebo for these events were generally small. If approved by regulatory authorities, cariprazine would join aripiprazole as the second dopamine receptor partial agonist antipsychotic available for clinical use. Cariprazine differs from aripiprazole in terms of dopamine D3 receptor selectivity. Further studies would be helpful to discern the distinguishing features of cariprazine from other second-generation antipsychotics.

Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist in late-stage clinical development for the treatment of bipolar disorder (manic/mixed and depressive episodes), as well as for schizophrenia, and as an adjunctive agent for the treatment of major depressive disorder. Three phase 2 or 3, 3-week, randomized controlled trials in bipolar mania or mixed episodes have been completed and reported as poster presentations or in press releases by the manufacturer. Superiority over placebo on the Young Mania Rating Scale total score was evidenced for daily doses of cariprazine 3-12 mg/day. In short-term randomized controlled trials, cariprazine does not appear to adversely impact metabolic variables, prolactin, or the electrocardiogram (ECG) QT interval. The most commonly encountered adverse events in the mania trials were extrapyramidal disorder, akathisia, insomnia, vomiting, restlessness, sedation, vision blurred, and pain in extremity in the phase 2 trial where this was presented in a poster, and akathisia, extrapyramidal disorder, tremor, dyspepsia, vomiting, dizziness, diarrhea, somnolence, restlessness, and pyrexia for the phase 3 trial where this was presented in a poster. With the exception of akathisia and extrapyramidal disorder, the differences in incidence versus placebo for these events were generally small. If approved by regulatory authorities, cariprazine would join aripiprazole as the second dopamine receptor partial agonist antipsychotic available for clinical use in persons with bipolar mania or mixed episodes. Cariprazine differs from aripiprazole in terms of dopamine D3 receptor selectivity. Further studies would be helpful to discern the distinguishing features of cariprazine from other antimanic agents.

Rhabdomyolysis is a rare and potentially serious adverse drug reaction (ADR) to antipsychotic medicines. The aim of this study was to investigate the clinical circumstances surrounding the diagnosis of rhabdomyolysis in children and adolescents treated with antipsychotic medicines. We also critically reviewed individual case safety reports (ICSRs) of suspected ADRs to evaluate how clinically useful they can be in a case series analysis.This was a descriptive and an exploratory study. Published case reports and ICSRs from the World Health Organization (WHO) Global ICSR database, VigiBase, reported with rhabdomyolysis and antipsychotic medicines for patients ≤17 years years of age were described. Reporting patterns of ICSRs with rhabdomyolysis and antipsychotic medicines were explored in VigiBase for children and adolescents and for adults. The VigiBase ICSRs were also systematically evaluated regarding the report content.Of the 26 evaluated reports, 6 co-reported neuroleptic malignant syndrome (NMS) and 20 reports concerned rhabdomyolysis in the absence of NMS. The reported suspected antipsychotic medicines for these 20 reports were olanzapine, risperidone, haloperidol, paliperidone, quetiapine, clozapine, cyamemazine, and aripiprazole. In VigiBase, rhabdomyolysis (in the absence of NMS) was reported more frequently with olanzapine relative to all reports for children and adolescents with antipsychotic medicines. In the range of events that preceded rhabdomyolysis, muscle pains and abdominal pain were commonly recorded to have started during the week prior to the diagnosis. Other preceding symptoms were general weakness and dark urine. Onset of rhabdomyolysis for most patients occurred at any time within 2 months of starting antipsychotic treatment, in several cases triggered by changes to the patient's drug therapy or known risk factors of rhabdomyolysis. It was found that ICSRs can contribute with additional information, but that access to free text and narratives were crucial in order to capture clinically useful features of rhabdomyolysis.Monitoring of children and adolescents needs to be intensified during dose increases, or when a new, added, or switched antipsychotic medicine is introduced to their drug regimen, and during exposure to known risk factors for rhabdomyolysis. The development of seemingly nonserious events, such as abdominal pain, muscle pain, weakness, and dark urine, should be followed up during antipsychotic use, as they might be precursory events to rhabdomyolysis that eventually could develop into acute renal failure.

To compare longer-term safety and effectiveness of the 4 most commonly used atypical antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone) in 332 patients, aged > 40 years, having psychosis associated with schizophrenia, mood disorders, posttraumatic stress disorder, or dementia, diagnosed using DSM-IV-TR criteria.We used equipoise-stratified randomization (a hybrid of complete randomization and clinician's choice methods) that allowed patients or their treating psychiatrists to exclude 1 or 2 of the study atypical antipsychotics due to past experience or anticipated risk. Patients were followed for up to 2 years, with assessments at baseline, 6 weeks, 12 weeks, and every 12 weeks thereafter. Medications were administered employing open-label design and flexible dosages, but with blind raters. The study was conducted from October 2005 to October 2010.Primary metabolic markers (body mass index, blood pressure, fasting blood glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), percentage of patients who stay on the randomly assigned atypical antipsychotic for at least 6 months, psychopathology, percentage of patients who develop metabolic syndrome, and percentage of patients who develop serious and nonserious adverse events.Because of a high incidence of serious adverse events, quetiapine was discontinued midway through the trial. There were significant differences among patients willing to be randomized to different atypical antipsychotics (P < .01), suggesting that treating clinicians tended to exclude olanzapine and prefer aripiprazole as one of the possible choices in patients with metabolic problems. Yet, the atypical antipsychotic groups did not differ in longitudinal changes in metabolic parameters or on most other outcome measures. Overall results suggested a high discontinuation rate (median duration 26 weeks prior to discontinuation), lack of significant improvement in psychopathology, and high cumulative incidence of metabolic syndrome (36.5% in 1 year) and of serious (23.7%) and nonserious (50.8%) adverse events for all atypical antipsychotics in the study.Employing a study design that closely mimicked clinical practice, we found a lack of effectiveness and a high incidence of side effects with 4 commonly prescribed atypical antipsychotics across diagnostic groups in patients over age 40, with relatively few differences among the drugs. Caution in the use of these drugs is warranted in middle-aged and older patients.ClinicalTrials.gov identifier: NCT00245206.

Although not indicated for attention-deficit/hyperactivity disorder (ADHD), atypical antipsychotics (AAPs) are commonly prescribed for children with ADHD. The treatment patterns, resource utilization, and costs associated with AAPs relative to non-antipsychotic medications have not been evaluated for children with ADHD. To compare treatment patterns, resource utilization, and costs to U.S. third party payers between stimulant-treated ADHD children who switch to or augment their stimulant treatment with AAPs (risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, paliperidone, and clozapine) compared with non-antipsychotic medications (atomoxetine, clonidine immediate-release (IR), guanfacine IR, dexmethylphenidate, mixed amphetamine salts, methylphenidate, lisdexamfetamine, and dextroamphetamine).Patients with at least one ADHD diagnosis (ICD-9-CM codes 314.00 or 314.01) and at least one stimulant medication claim between January 1, 2005 and December 31, 2009, were identified from a large U.S. commercial medical/pharmacy claims database. Patients were classified into the AAP cohort if they had a claim for an AAP following a stimulant fill or into the non-antipsychotic cohort if they had a claim for a non-antipsychotic medication after a stimulant fill and no AAP claims. The index date was defined as the date of the first fill of the AAP or a randomly selected eligible non-antipsychotic medication. Patients were eligible for inclusion if they were aged 6-12 as of the index date and had at least 18 months of continuous eligibility. Patients were excluded if they had a psychiatric diagnosis for which AAPs were approved by the U.S. Food and Drug Administration (FDA) or commonly used. Patients in the non-antipsychotic group were matched 1:1 to patients in the AAP group using a propensity score generated from a logistic regression that included demographics, treatments, resource utilization, and comorbidities during the 6 months prior to the index date. All outcomes were measured during the 12 months following the index date. Treatment patterns were compared using Kaplan-Meier (KM) estimates and Cox proportional hazards models. Annual resource utilization was compared using McNemar's test and Poisson regression. Costs were estimated from the perspective of U.S. third-party payers and were adjusted to 2010 dollars using the medical component of the Consumer Price Index. Both all-cause and mental health-related costs were examined and compared using Wilcoxon signed-rank tests. Of the 22,622 patients with ADHD identified to have used AAPs after a stimulant, 15,664 (69%) patients did not have a psychiatric diagnosis for which AAPs were FDA-indicated or commonly used. Among the 84,558 patients using non-antipsychotics after a stimulant, 81,397 (96%) did not have such psychiatric diagnoses. A total of 2,127 children in the AAP cohort and 16,508 children in the non-antipsychotic cohort met all of the study inclusion criteria. After propensity score matching, 1,857 children (358 switchers and 1,499 augmenters) were included in each of the matched cohorts. The baseline characteristics were well balanced between the matched cohorts. In the 12 months post-index date, children treated with AAPs were more likely to experience switching (KM: 17.2% vs. 10.4% at 12 months; HR = 1.75) and augmentation (KM: 43.4% vs. 22.4% at 12 months; HR = 2.62) than the non-antipsychotic group (both P  less than  0.001). Rates of discontinuation were similar between groups (KM: 71.8% vs. 71.7% at 12 months; HR = 0.98, P = 0.600). The AAP cohort also had higher mean numbers of hospitalizations, emergency room visits, and outpatient visits (0.08 vs. 0.03, 0.34 vs. 0.25, 14.1 vs. 12.7 per patient, respectively; event rate ratios = 2.61, 1.33, and 1.11, respectively; all P  less than  0.001). The AAP group also incurred higher all-cause mean medical, prescription drug, and total health care costs compared with the non-antipsychotic group ($3,090 vs. $2,238; $3,844 vs. $2,509; $6,934 vs. $4,748, respectively; all P  less than  0.001). Patients in the AAP group also incurred higher mean total, medical, and drug costs related to mental health ($5,057 vs. $2,859; $1,555 vs. $964; $3,502 vs. $1,895, respectively; all P  less than  0.001).Stimulant-treated children with ADHD who switched to or augmented with AAPs versus non-antipsychotics had significantly greater rates of subsequent augmentation and health care resource utilization as well as higher total health care costs. Further research and/or drug utilization reviews may be warranted to fully evaluate the clinical and economic outcomes of pediatric ADHD patients who are receiving AAPs.

Several studies in rodent models have shown that glycogen synthase kinase 3 β (GSK3β) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3β through a β-arrestin2/protein kinase B (PKB or Akt)/protein phosphatase 2A (PP2A) signaling complex regulates dopamine (DA)- and lithium-sensitive behaviors and is required to mediate endophenotypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antagonize DA D2 receptor (D2R)/β-arrestin2 interactions more efficaciously than G-protein-dependent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3β in regulating DA- or lithium-sensitive behaviors, we generated conditional knockouts of GSK3β, where GSK3β was deleted in either DA D1- or D2-receptor-expressing neurons. We analyzed these mice for behaviors commonly used to test antipsychotic efficacy or behaviors that are sensitive to lithium treatment. Mice with deletion of GSK3β in D2 (D2GSK3β(-/-)) but not D1 (D1GSK3β(-/-)) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3β(-/-) or D1GSK3β(-/-) mice compared with control mice. Interestingly, genetic stabilization of β-catenin, a downstream target of GSK3β, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3β(-/-) or D1GSK3β(-/-) mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be β-arrestin2- and GSK3β-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3β but not stabilization of β-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.

The introduction of second-generation antipsychotics (SGAs), heralded by clozapine in 1990, represented an important advance in the pharmacologic treatment of schizophrenia. However, several recent comparative effectiveness trials found that non-clozapine SGAs provided little or no advantage in efficacy over first-generation antipsychotics, and all agents had substantial safety and tolerability concerns. Clearly, there remains a great unmet need for more effective and better-tolerated antipsychotics. Relatively potent antagonism of serotonin 5-HT2A receptors coupled with relatively weaker antagonism of dopamine D2 receptors is the central pharmacological characteristic shared by most SGAs. This profile continues to be a favored model for developing new SGAs, commonly defined as serotonin/dopamine antagonists. In the past ten years, aripiprazole, paliperidone, asenapine, iloperidone, and lurasidone have been introduced. Studies suggest that the newer agents have similar short-term efficacy to earlier serotonin/dopamine antagonists, and several demonstrate at least modest improvements in safety and tolerability profiles, particularly metabolic measures. However, as a group, the newer serotonin/dopamine antagonists are pharmacologically heterogeneous, and their side-effect burden can still be considerable. Moreover, their putative clinical advantages have not yet been well demonstrated via direct comparative studies. The absence of such evidence adds to the challenges in defining their place among more established treatment choices, or in providing clinicians with clear indications to guide treatment choices for individual patients. Long-term, head-to-head comparative studies are required to clarify the risk/benefit profiles of the newer antipsychotics and their roles in the treatment of schizophrenia.

This study examined the prescribing patterns of several first- (FGAs) and second-generation antipsychotic (SGAs) medications administered to older Asian patients with schizophrenia during the period between 2001 and 2009.Information on hospitalized patients with schizophrenia aged 65 or older was extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) study (2001-2009). There were no older patients in Thailand, therefore data on 467 patients in eight Asian countries and territories including China, Hong Kong SAR, India, Japan, Korea, Malaysia, Singapore, and Taiwan were analysed. Cross-sectional socio-demographic data, clinical characteristics and antipsychotic prescriptions were assessed using a standardized protocol and data collection procedure.Of the 467 patients, 192 patients (41.1%) received FGAs only, 166 (35.5%) received SGAs only and 109 (23.3%) received a combination of FGAs and SGAs. Of the FGAs, haloperidol was the most commonly used (31.3%; mean 9.4 ± 6.7 mg/day), followed by chlorpromazine (15.4%; mean 126.4 ± 156.4 mg/day) and sulpiride (6.6%; mean 375.0 ± 287.0 mg/day). Of the SGAs, risperidone was the most commonly used (31.5%; mean 4.5 ± 2.7 mg/day), followed by olanzapine (13.1%; mean 13.6 ± 6.5 mg/day), quetiapine (7.3%; mean 325.0 ± 237.3 mg/day) and aripiprazole (1.9%; mean 17.6 ± 7.7 mg/day).FGAs and higher doses of certain SGAs (risperidone, olanzapine and quetiapine) were still commonly dispensed to older Asian patients with schizophrenia. Considering older patients' reduced tolerability of potentially severe side effects associated with FGAs and higher doses of certain SGAs, continuing education and training addressing the rational use of antipsychotics in this population is clearly needed.

Tremendous progress has taken place in the last 8 years since the publication of our review on «Therapy of Tic Disorders» in the Zeitschrift für Kinder- und Jugendpsychiatrie. Several steps in treatment have been specified. For example, consensus-based indications for treatment have been published, and a detailed manual for a so-called habit-reversal training program has been developed and evaluated. In addition, new treatment options such as aripiprazole and deep-brain stimulation have been implemented. Increasing attention is being given to the disabling consequences of the commonly co-occurring psychiatric conditions known as ADHD or OCD. Nevertheless, there is still much to be learned about the treatment of tic disorders; standardized and sufficiently large drug trials in patients with tic disorders fulfilling evidence-based medicine standards are still scarce. The same is true for direct comparisons of different agents as well as of medication versus behavioral treatment. Finally, the question of how to predict the individual course of tics and how best to deal with the problems of waxing and waning of tics in this context still limits evidence base for treatment decisions. Large clinical experience is still a pre-requisite for making optimal decisions for the treatment of individual patients suffering from a tic disorder.

Lycanthropy is an unusual belief or delusion that one has been transformed into an animal, or behaviors or feelings suggestive of such a belief. We report a case of lycanthropic delusions of becoming a snake in a 47-year-old woman who suffered from a major depressive disorder with psychotic features. We also present a literature review of articles published on the subject in English or French since 1975 identified via a MedLine search using the terms "lycanthropy" or "werewolf." Many case reports have described lycanthropy as a delusional disorder occurring acutely in patients who think they suffer from a demonic possession as a punishment for their acts. In these cases, symptoms are generally rapidly reversible. Lycanthropy seems to be a nonspecific manifestation of many psychiatric diseases, most commonly major depressive disorder with psychotic features. It is largely influenced by the cultural environment of the patient so that the animal species frequently represents the patient's delusional representation of evil. Lycanthropy could be considered a culture-bound syndrome that occurs in association with Axis I, DSM-IV psychiatric pathology.