Paliperidone palmitate for schizophrenia.

BACKGROUND: Paliperidone palmitate, a long-acting, intramuscular formulation of paliperidone, is now available for clinical use. Paliperidone is an active metabolite of risperidone and it is also available in an oral formulation for daily use. OBJECTIVES: To compare the effects of paliperidone palmitate with any other treatment for people with schizophrenia and schizophrenia-like illnesses. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Register (November 2009) and inspected references of identified studies for further trials. We contacted the manufacturers of paliperidone palmitate, the Food and Drug Administration, and authors of relevant trials for additional material. SELECTION CRITERIA: We included randomised controlled trials (RCTs). DATA COLLECTION AND ANALYSIS: We independently selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate, we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to benefit/harm statistic (NNB/H). We calculated mean differences (MD) for continuous data. MAIN RESULTS: Five studies with 2215 participants compared paliperidone palmitate with placebo. Fewer people left studies early if they were randomised to paliperidone palmitate (n = 2183, 5 RCTs, RR 0.76 CI 0.70 to 0.84, NNTB 9 CI 7 to 14) and those receiving any dose of paliperidone palmitate were significantly less likely to show no improvement in global state (n = 1696, 4 RCTs, RR 0.79 CI 0.74 to 0.85, NNTB 7 CI 5 to 9). People randomised to paliperidone palmitate were less likely to experience a recurrence of psychosis (n = 312, 1 RCT, RR 0.28 CI 0.17 to 0.48, NNTB 5 CI 4 to 6) than those allocated to placebo in a single trial specifically designed to study recurrence. In the other studies where recurrence was recorded only as an adverse event, we found that people who received paliperidone palmitate were also less likely to experience a recurrence of psychotic symptoms (n = 1837, 4 RCTs, RR 0.55 CI 0.44 to 0.68, NNTB 10 CI 8 to 14).  Paliperidone palmitate was associated with fewer reports of agitation or aggression (n = 2180, 5 RCTs, RR 0.65 CI 0.46 to 0.91, NNTB 39 CI 25 to 150) and of using anxiolytic medications (n = 2170, 5 RCTs, RR 0.89 CI 0.83 to 0.96, NNTB 16 CI 11 to 44). A consistent, significant elevation in serum prolactin (ng/mL) was found for both men and women receiving paliperidone palmitate, but the data were too heterogenous to sum. We found no evidence of sexual dysfunction in these short-term trials. People receiving paliperidone palmitate had a significantly greater increase in weight (n = 2052, 5 RCTs, MD 1.34 CI 0.97 to 1.70) in comparison with people who received placebo.Two studies with 1969 participants compared flexibly-dosed paliperidone palmitate with flexibly-dosed risperidone long-acting injection. The mean doses of paliperidone palmitate in these trials were 73.3 and 104.6 mg every four weeks compared with risperidone long-acting injection at mean doses, respectively, of 35.3 and 31.7 mg every two weeks. We found no differences between paliperidone palmitate and risperidone long-acting injection for leaving these studies early for any reason (n = 1969, 2 RCTs, RR 1.12 CI 1.00 to 1.25). Those receiving paliperidone palmitate were statistically no more likely to have a recurrence of psychotic symptoms than those receiving risperidone long-acting injection (n = 1961, 2 RCTs, RR 1.23 CI 0.98 to 1.53). While we found no significant difference in the occurrences of deaths in the pooled trials (n = 1967, 2 RCTs, RR 3.62 CI 0.60 to 21.89), we note that a total of six deaths occurred in these two trials, with five deaths among people who received paliperidone palmitate and one death among people who received risperidone long-acting injection. Although death is the most serious of adverse events, the small number of these events in these trials makes it unclear if this finding is meaningful. We found that participants randomised to paliperidone palmitate were significantly less likely to use anticholinergic medications in these trials (n = 1587, 2 RCTs, RR 0.67 CI 0.55 to 0.82, NNTB 13 CI 10 to 24). We found no data regarding paliperidone palmitate relating to services use, quality of life, behaviour, patient satisfaction, cognitive functioning or cost. AUTHORS' CONCLUSIONS: In short-term studies, paliperidone palmitate is an antipsychotic drug that is more efficacious than placebo. We found its adverse effects to be similar to those of its related compounds, paliperidone and risperidone, with extrapyramidal movement disorders, weight gain, and tachycardia all more common with paliperidone palmitate than placebo. While no difference was found in the incidence of reported adverse sexual outcomes, paliperidone palmitate is associated with substantial increases in serum prolactin. When flexibly dosed with a mean doses of approximately 70 to 110 mg every four weeks, paliperidone palmitate appears comparable in efficacy and tolerability to risperidone long-acting injection flexibly dosed with mean doses of approximately 35 mg every two weeks.  

Genome-wide association study of antipsychotic-induced QTc interval prolongation.

QT prolongation is associated with increased risk of cardiac arrhythmias. Identifying the genetic variants that mediate antipsychotic-induced prolongation may help to minimize this risk, which might prevent the removal of efficacious drugs from the market. We performed candidate gene analysis and five drug-specific genome-wide association studies (GWASs) with 492K single-nucleotide polymorphisms to search for genetic variation mediating antipsychotic-induced QT prolongation in 738 schizophrenia patients from the Clinical Antipsychotic Trial of Intervention Effectiveness study. Our candidate gene study suggests the involvement of NOS1AP and NUBPL (P-values=1.45 × 10(-05) and 2.66 × 10(-13), respectively). Furthermore, our top GWAS hit achieving genome-wide significance, defined as a Q-value <0.10 (P-value=1.54 × 10(-7), Q-value=0.07), located in SLC22A23, mediated the effects of quetiapine on prolongation. SLC22A23 belongs to a family of organic ion transporters that shuttle a variety of compounds, including drugs, environmental toxins and endogenous metabolites, across the cell membrane. This gene is expressed in the heart and is integral in mouse heart development. The genes mediating antipsychotic-induced QT prolongation partially overlap with the genes affecting normal QT interval variation. However, some genes may also be unique for drug-induced prolongation. This study demonstrates the potential of GWAS to discover genes and pathways that mediate antipsychotic-induced QT prolongation.

Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs.

Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q=0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q=0.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.

Paliperidone for schizophrenia.

BACKGROUND: Paliperidone, risperidone's active metabolite, is now available in an oral formulation for daily use, and an intramuscular formulation for monthly administration may follow shortly. OBJECTIVES: To compare effects of oral paliperidone with any other treatment for people with schizophrenia and schizophrenia-like illnesses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (December 2006), and inspected references of identified studies for further trials. We contacted the manufacturers of paliperidone, the Food and Drug Administration, and authors of relevant trials for additional material. SELECTION CRITERIA: We included all relevant randomised trials. DATA COLLECTION AND ANALYSIS: We independently selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate, we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to treat (NNT). We calculated Weighted Mean Differences (WMD) for continuous data. MAIN RESULTS: Five studies compared paliperidone with placebo. Fewer people left the studies early if they were randomized to paliperidone (n=1647, 5 RCTs, RR 0.68 CI 0.61 to 0.76, NNT 7 CI 6 to 9) and those receiving any dose of paliperidone were significantly more likely to have an improvement in global state (n=1420, 4RCTs, RR 0.69 CI 0.63 to 0.75, NNT 5 CI 4 to 6). People randomised to paliperidone were less likely to experience a recurrence of psychosis (n=1638, 5 RCTs, RR 0.45 CI 0.31 to 0.66, NNT 16 CI 13 to 26) than those allocated to placebo. Adverse effect data were not well reported but paliperidone does seem to produce a greater incidence of tachycardia than placebo (n=1638, 5 RCTs, RR1.88 CI 1.28 to 2.76, NNH 21 CI 11 to 90) and a consistent, significant elevation in serum prolactin was found for both men (n=413, 3 RCTs, WMD 27.68 CI 23.66 to 31.69) and women (n=252, 3 RCTs, WMD 87.39 CI 74.27 to 100.51). People receiving paliperidone were more likely to experience extrapyramidal disorders (n=1638, 5 RCTs, RR 2.21 CI 1.26 to 3.88, NNH 28 CI 12 to 129) and weight gain (n=769, 4 RCTs, WMD 1.07 CI 0.65 to 1.49, I-squared 78%) compared with those allocated to placebo. When compared with 10 mg/day olanzapine we found no differences between paliperidone and olanzapine for leaving in the short term (n=1332, 3 RCTs, RR 1.04 CI 0.89 to 1.21; 40% in both groups left by six weeks). Those receiving any dose of paliperidone were no more likely to have a recurrence of psychotic symptoms than those receiving 10 mg/day olanzapine (n=1327, 3 RCTs, RR 0.1.07 CI 0.64 to 1.76). Data from all three studies found paliperidone was less likely to produce a weight change than olanzapine (n=660, 3 RCTs, WMD -0.88 CI -1.38 to -0.37). Results for various movement disorders all favoured olanzapine. There are no clear data relating to social functioning, services use, quality of life, satisfaction and cost. AUTHORS' CONCLUSIONS: In short-term studies, oral paliperidone is an antipsychotic that is more efficacious than placebo. We found its adverse effects to be similar to those of its parent compound, risperidone, with movement disorders, weight gain, and tachycardia all more common with paliperidone than placebo. In addition, paliperidone is associated with substantial increases in serum prolactin that may be associated with sexual dysfunction, although sexual functioning outcomes were not reported. At doses greater than 3 mg per day, oral paliperidone appears comparable in efficacy to oral olanzapine 10 mg per day. Regarding the critical comparison of oral paliperidone to risperidone, we have no information and are thus unable to determine if paliperidone has any advantages or disadvantages compared to its well-known parent compound.

Genomewide association for schizophrenia in the CATIE study: results of stage 1.

Little is known for certain about the genetics of schizophrenia. The advent of genomewide association has been widely anticipated as a promising means to identify reproducible DNA sequence variation associated with this important and debilitating disorder. A total of 738 cases with DSM-IV schizophrenia (all participants in the CATIE study) and 733 group-matched controls were genotyped for 492,900 single-nucleotide polymorphisms (SNPs) using the Affymetrix 500K two-chip genotyping platform plus a custom 164K fill-in chip. Following multiple quality control steps for both subjects and SNPs, logistic regression analyses were used to assess the evidence for association of all SNPs with schizophrenia. We identified a number of promising SNPs for follow-up studies, although no SNP or multimarker combination of SNPs achieved genomewide statistical significance. Although a few signals coincided with genomic regions previously implicated in schizophrenia, chance could not be excluded. These data do not provide evidence for the involvement of any genomic region with schizophrenia detectable with moderate sample size. However, a planned genomewide association study for response phenotypes and inclusion of individual phenotype and genotype data from this study in meta-analyses hold promise for eventual identification of susceptibility and protective variants.

Sexually dimorphic aging of dendritic morphology in CA1 of hippocampus.

During aging, rats of both sexes experience a decline in performance on hippocampal-dependent tasks. Investigations into the neuroanatomical correlates of this functional decline have been conducted almost exclusively in male subjects. In the present study, dendritic spine density in stratum radiatum and complexity of the entire apical dendritic tree were quantified using Golgi-Cox-stained tissue in young (3-5 months) and aged (19-22 months) rats of both sexes. Because both cognitive decline and hippocampal morphology may be influenced by ovarian hormonal state, young adult females were examined during either proestrus or estrus, and aged females were examined in one of two reproductively senescent states: persistent estrus or persistent diestrus. A sex difference in dendritic branching of CA1 pyramidal cells was found among young adults. However, this difference disappeared during aging, due to a reduction in branching with age for males but not for females. Spine density was not influenced by age or sex, nor did ovarian hormone status influence either measure. These results are consistent with our previous findings in the rat medial prefrontal cortex and primary motor cortex and with the human literature, which indicate that age-related atrophy of cognitive brain regions is more severe for males than females.

Correlates of family burden under medicaid managed mental health care.

This study examined predictors of family burden (assistance in daily living, supervision, and subjective concern) for family members of Medicaid recipients with severe mental illness in two regions of Virginia. In the Richmond area, mental health services were provided on a no-risk fee-for-service basis, while in Tidewater these services were provided through a risk-based capitated contract with a managed care organization. No differences in family burden were attributable to the risk-based payment system. Predictors of increased family burden were (a) more reported client symptoms and disruptive behaviors, (b) status as a parent, and (c) living with the client.

Causes of schizophrenia reported by patients' family members in China.

BACKGROUND: Better methods of assessing patients' and family members' causal models of illness are needed to improve adherence with biomedical interventions and to design services that meet the needs of consumers. AIMS: To develop a quantitative measure suitable for assessing the relationship of causal beliefs to expressed emotion, stigma, care-seeking and adherence. METHOD: The Causal Models Questionnaire for Schizophrenia, which includes 45 causes identified during in-depth interviews with family members, was administered to 245 family members of 135 patients with DSM-III-R schizophrenia in Suzhou and Siping, China at the time of admission to hospital. RESULTS: Respondents, who identified a mean of 2.5 causes (range 1-10, mode 2), attributed 84% of the cause of schizophrenia to social, interpersonal and psychological problems. Hence, their beliefs do not concur with Chinese professionals' ideas about the biomedical causes of schizophrenia. Multivariate analyses identified the socio-economic factors that influence family members' causal beliefs. CONCLUSIONS: Despite the complexity of causal models, measures can be developed that will help improve clinicians' communication with patients and understanding of help-seeking behaviours.

Comparative effectiveness of antipsychotic drugs in schizophrenia.

Chlorpromazine, which was discovered in 1952, has an exhaustively characterized efficacy/safety profile comprising serious limitations: effectiveness in the field failing to match efficacy in trials, residual symptoms in 50% of patients, a 20% relapse rate in compliant patients, and worrisome extrapyramidal side effects, including tardive dyskinesia in 5% per year. Second-generation "atypical" antipsychotics bypass these effects by having less affinity for the dopamine D(2) receptor and affinities for other neuroreceptors. Clozapine, the lead atypical antipsychotic, was followed in the mid 1990s by risperidone, olanzapine, and quetiapine, which now account for over half of new antipsychotic prescriptions in North America, The debate over their relative efficacy involves the potential well-being of millions of schizophrenics and billions of dollars. Atypical antipsychotics are considerably more expensive; evidence for their superiority is highly variable and often inadequate, largely confined to short-term regulatory studies. Their effects on long-term outcome (particularly negative symptoms), relapse prevention, social and vocational functioning, suicide prevention and quality of life, and family and caregiver burden are largely unknown. The National institute of Mental Health's Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project is a combined efficacy-effectiveness trial that aims to answer these questions in a broad range of patients with schizophrenia and Alzheimer's disease.