| 1 | Ann Clin Psychiatry 2000 Mar 12: 51-4 |
|---|---|
| PMID | 10798826 |
| Title | Neuroleptic malignant syndrome and severe thrombocytopenia: case report and literature review. |
| Abstract | We report an unusual case of thrombocytopenia associated with neuroleptic malignant syndrome (NMS). A 31-year-old Black male with a history of hypertension, partial seizures, and schizophrenia developed acute rigidity closely followed by severe hyperpyrexia (temperature 102 degree F), tachypnea, and tachycardia. His home medications at the time of presentation included propanolol 10 mg tid, haloperidol 10 mg BID, sodium valproate 500 mg BID, benztropine 1 mg BID, and haloperidol decanoate 100 mg i.m. every 3 weeks, from another psychiatric facility. Despite vigorous therapy for the hyperthermia, he rapidly developed significant hypoxia requiring mechanical ventilation. A diagnosis of neuroleptic malignant syndrome was made and the patient continued to receive aggressive supportive care. On hospital day 2 his platelet count dropped to 47,000/microl and bottomed out at 36,000/microl by day 3 with other blood cell counts remaining within normal limits. Over the next few days he showed rapid clinical improvement with normalization of his blood chemistries and he was discharged home after 5 days of hospitalization in good condition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Clin Ther 2002 Feb 24: 209-22 |
| PMID | 11911552 |
| Title | Dosing and switching strategies for quetiapine fumarate. |
| Abstract | The atypical antipsychotic agent quetiapine fumarate has demonstrated efficacy and tolerability in clinical trials in patients with chronic or subchronic exacerbations of schizophrenic symptoms. This review summarizes clinical trial data and other practical information regarding the initiation and routine administration of quetiapine. Appropriate strategies for switching from other antipsychotic agents to quetiapine are also discussed. Quetiapine is an appropriate initial treatment for psychotic disturbances in patients with schizophrenia of any stage and for those in whom a therapeutic switch is indicated for clinical reasons, such as inability to tolerate the side effects of treatment. Titration to 400 mg/d is recommended using the following schedule, administered BID in divided doses: day 1, 50 mg; day 2, 100 mg: day 3, 200 mg; day 4, 300 mg; and day 5, 400 mg. In patients who respond to quetiapine, therapy should be continued at the optimal dose that maintains remission, within the range of 150 to 750 mg/d. When a change in therapy is indicated, several strategies for switching from one antipsychotic agent to another may be applied to switching to quetiapine. Whereas studies have shown that an abrupt switch to or withdrawal from quetiapine does not produce significant clinical consequences, in practice the switch should be carefully individualized to minimize the potential for psychotic relapse or development of withdrawal symptoms. Quetiapine has antipsychotic effects and good tolerability at doses from 150 to 750 mg/d. Patients can be switched to quetiapine and their treatment individualized to achieve the optimal therapeutic effect with a minimum of dose-limiting side effects. There are several strategies for switching to quetiapine from another antipsychotic agent that do not appear to cause significant exacerbation of psychosis or withdrawal reactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Clin Ther 2002 Feb 24: 209-22 |
| PMID | 11911552 |
| Title | Dosing and switching strategies for quetiapine fumarate. |
| Abstract | The atypical antipsychotic agent quetiapine fumarate has demonstrated efficacy and tolerability in clinical trials in patients with chronic or subchronic exacerbations of schizophrenic symptoms. This review summarizes clinical trial data and other practical information regarding the initiation and routine administration of quetiapine. Appropriate strategies for switching from other antipsychotic agents to quetiapine are also discussed. Quetiapine is an appropriate initial treatment for psychotic disturbances in patients with schizophrenia of any stage and for those in whom a therapeutic switch is indicated for clinical reasons, such as inability to tolerate the side effects of treatment. Titration to 400 mg/d is recommended using the following schedule, administered BID in divided doses: day 1, 50 mg; day 2, 100 mg: day 3, 200 mg; day 4, 300 mg; and day 5, 400 mg. In patients who respond to quetiapine, therapy should be continued at the optimal dose that maintains remission, within the range of 150 to 750 mg/d. When a change in therapy is indicated, several strategies for switching from one antipsychotic agent to another may be applied to switching to quetiapine. Whereas studies have shown that an abrupt switch to or withdrawal from quetiapine does not produce significant clinical consequences, in practice the switch should be carefully individualized to minimize the potential for psychotic relapse or development of withdrawal symptoms. Quetiapine has antipsychotic effects and good tolerability at doses from 150 to 750 mg/d. Patients can be switched to quetiapine and their treatment individualized to achieve the optimal therapeutic effect with a minimum of dose-limiting side effects. There are several strategies for switching to quetiapine from another antipsychotic agent that do not appear to cause significant exacerbation of psychosis or withdrawal reactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | J Clin Psychopharmacol 2002 Apr 22: 121-30 |
| PMID | 11910256 |
| Title | The safety and pharmacokinetics of quetiapine when coadministered with haloperidol, risperidone, or thioridazine. |
| Abstract | The effects of haloperidol, risperidone, and thioridazine on the pharmacokinetics and side-effect profile of quetiapine were investigated in 36 patients with schizophrenia, schizoaffective disorder, or bipolar disorder in a single-center, two-period, multiple-dose, open-label, randomized trial. Over a one-to two-week period, quetiapine doses were escalated to 300 mg twice daily (BID). Patients were then treated for at least 7 days at the target quetiapine dose and subsequently entered into the combination therapy period, receiving haloperidol (7.5 mg, BID), risperidone (3 mg, BID), or thioridazine (200 mg, BID) for 8.5 days (after 3 days of dose escalation). Key assessments included the pharmacokinetics of quetiapine at steady state (area under the curve within a dosing interval [AUCtSS], maximum [CmaxSS], and minimum [CminSS] observed plasma concentrations, and oral clearance [Cl/f]), as well as the UKU Side Effect Rating Scale scores and safety evaluations. Neither risperidone nor haloperidol had significant effects on quetiapine pharmacokinetics. However, thioridazine produced statistically significant changes, decreasing the least squares means values of the AUCtSS, CmaxSS, and CminSS by 40%, 47%, and 31%, respectively, and increasing Cl/f by 68%. Increases in the following adverse events were noted during coadministration: somnolence (risperidone), insomnia and dry mouth (all three coadministered therapies), and dizziness (thioridazine). UKU side effect items that became worse in >or= 25% of patients during each coadministration period included sedation and increased sleep duration. Results of laboratory tests, electrocardiograms, and vital sign measurements revealed few clinically important changes. Clinical stability can be maintained with good tolerability during the transition from quetiapine monotherapy to periods of coadministration with haloperidol, risperidone, or thioridazine. Coadministration of either haloperidol or risperidone did not have any important effects on the steady-state pharmacokinetics of quetiapine. Thioridazine significantly increased the oral clearance of quetiapine. Increased doses of quetiapine may be necessary to control psychotic symptoms when thioridazine is coadministered with quetiapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Int. J. Neuropsychopharmacol. 2003 Jun 6: 103-9 |
| PMID | 12890302 |
| Title | Lack of effect of amisulpride on the pharmacokinetics and safety of lithium. |
| Abstract | Lithium may be used as adjuvant therapy in schizophrenic patients and antipsychotics can be employed during the early phases of lithium therapy in patients with bipolar disorder. The issue of interactions between lithium and antipsychotics is therefore important. This study investigates the potential influence of repeated administration of amisulpride, an atypical antipsychotic, on the pharmacokinetics of lithium at steady state. Twenty-four healthy male volunteers (aged 1833 yr) received lithium carbonate (500 mg b.i.d.) for 14 d. All subjects were shown to have stable lithium serum concentrations after 57 d and were then randomized to receive double-blind administration of amisulpride (100 mg b.i.d.) or placebo BID from day 8 of lithium administration. Complete pharmacokinetic profiles were obtained on days 7 and 14 for lithium and trough plasma concentrations on days 10, 12 and 14 for amisulpride. Co-administration of amisulpride appeared to exert no effect on the pharmacokinetics of lithium. All treatments were well tolerated and safety assessment revealed no differences between the lithium+placebo and lithium+amisulpride groups. This finding permits the flexible use of amisulpride in patients already receiving lithium therapy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Hum. Mutat. 2004 Jul 24: 35-42 |
| PMID | 15221787 |
| Title | Functional analysis of polymorphisms in the promoter regions of genes on 22q11. |
| Abstract | Segmental aneusomy, which includes chromosome 22 deletion syndrome (del(22)(q11.2q11.2)), has been associated with DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face (CAF) syndrome, cat-eye syndrome (CES), der(22) syndrome, and duplication of the del(22)(q11.2q11.2) syndrome's typically deleted region. Adults with del(22)(q11.2q11.2) may develop psychiatric illnesses, including schizophrenia, schizoaffective disorder, and bipolar disorder, suggesting that lower gene dosage leads to a predisposition to these illnesses. In a BID to identify important regulatory polymorphisms (SNPs) that may emulate changes in gene dosage of the genes within the common deletion, we have analyzed the promoter region of 47 genes (44 of which encode a protein with known function) encoding proteins in and around 22q11 for sequence variants. A total of 33 of the promoters contained polymorphisms. Of those, 25 were cloned into a reporter gene vector, pGL3. The relative ability of each promoter haplotype to promote transcription of the luciferase gene was tested in each of two human cell lines (HEK293t and TE671), using a cotransfected CMV-SPAP plasmid as an internal control. Five genes (PRODH, DGCR14, GSTT2, SERPIND1, and a gene tentatively called DKFZP434P211) showed activity differences between haplotypes of greater than 1.5-fold. Of those, PRODH, which encodes proline dehydrogenase, has previously been highlighted in relation to schizophrenia, and the functional promoter polymorphism reported here may be involved in pathogenic mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Biol. Psychiatry 2005 Apr 57: 711-5 |
| PMID | 15820227 |
| Title | Differential changes in apolipoprotein E in schizophrenia and bipolar I disorder. |
| Abstract | This study extends an initial finding of increased levels of apoE in Brodmann's area (BA) 9 from subjects with schizophrenia to determine if apoE is altered in other brain regions and in brains from subjects with bipolar I disorder (BID). ApoE was quantified apoE in BA 9, 10, 40, 46 and caudate putamen from control (n = 18), schizophrenic (n = 19) and BID (n = 8) subjects using Western blotting. In schizophrenia, there was increased apoE in BA9 (mean +/- SEM: schizophrenia 3.8 +/- .18 vs. control 3.2 +/- .19) and BA46 (schizophrenia 2.7 +/- .26 vs. control 1.6 +/- .20). In BID, increased levels of the apolipoprotein were detected in the caudate putamen (BID 3.3 +/- .44 vs. control 2.4 +/- .19) and BA9 (BID 4.0 +/- .27 vs. control 3.2 +/- .19) with a decrease in apoE being measured in BA10 (BID 1.6 +/- .16 vs. control 3.9 +/- .53). This study has shown disease specific, regionally discrete changes in levels of apoE in brain obtained post mortem from schizophrenic and BID subjects. Our data adds weight to the hypothesis that changes in the levels of apolipoproteins may be involved in the pathologies of schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Biol. Psychiatry 2005 Apr 57: 711-5 |
| PMID | 15820227 |
| Title | Differential changes in apolipoprotein E in schizophrenia and bipolar I disorder. |
| Abstract | This study extends an initial finding of increased levels of apoE in Brodmann's area (BA) 9 from subjects with schizophrenia to determine if apoE is altered in other brain regions and in brains from subjects with bipolar I disorder (BID). ApoE was quantified apoE in BA 9, 10, 40, 46 and caudate putamen from control (n = 18), schizophrenic (n = 19) and BID (n = 8) subjects using Western blotting. In schizophrenia, there was increased apoE in BA9 (mean +/- SEM: schizophrenia 3.8 +/- .18 vs. control 3.2 +/- .19) and BA46 (schizophrenia 2.7 +/- .26 vs. control 1.6 +/- .20). In BID, increased levels of the apolipoprotein were detected in the caudate putamen (BID 3.3 +/- .44 vs. control 2.4 +/- .19) and BA9 (BID 4.0 +/- .27 vs. control 3.2 +/- .19) with a decrease in apoE being measured in BA10 (BID 1.6 +/- .16 vs. control 3.9 +/- .53). This study has shown disease specific, regionally discrete changes in levels of apoE in brain obtained post mortem from schizophrenic and BID subjects. Our data adds weight to the hypothesis that changes in the levels of apolipoproteins may be involved in the pathologies of schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | BMC Psychiatry 2005 -1 5: 23 |
| PMID | 15892884 |
| Title | No evidence for association between polymorphisms in GRM3 and schizophrenia. |
| Abstract | Three studies have previously reported data that were interpreted by the authors as supportive of association between schizophrenia and polymorphisms in the gene encoding the metabotropic glutamate receptor GRM3. In a BID to examine this hypothesis, we examined seven SNPs spanning GRM3 in a UK case-control sample (schizophrenic cases n = 674, controls n = 716). These included all SNPs previously reported to be associated, alone or in haplotypes, with schizophrenia in European or European American samples. Our data showed no evidence for association with single markers, or 2, 3, 4 and 5 marker haplotypes, nor did any specific haplotypes show evidence for association according to previously observed patterns. Examination of our own data and those of other groups leads us to conclude that at present, GRM3 should not be viewed as a gene for which there is replicated evidence for association with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | BMC Psychiatry 2005 -1 5: 23 |
| PMID | 15892884 |
| Title | No evidence for association between polymorphisms in GRM3 and schizophrenia. |
| Abstract | Three studies have previously reported data that were interpreted by the authors as supportive of association between schizophrenia and polymorphisms in the gene encoding the metabotropic glutamate receptor GRM3. In a BID to examine this hypothesis, we examined seven SNPs spanning GRM3 in a UK case-control sample (schizophrenic cases n = 674, controls n = 716). These included all SNPs previously reported to be associated, alone or in haplotypes, with schizophrenia in European or European American samples. Our data showed no evidence for association with single markers, or 2, 3, 4 and 5 marker haplotypes, nor did any specific haplotypes show evidence for association according to previously observed patterns. Examination of our own data and those of other groups leads us to conclude that at present, GRM3 should not be viewed as a gene for which there is replicated evidence for association with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | J Clin Psychopharmacol 2005 Aug 25: 301-10 |
| PMID | 16012271 |
| Title | Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. |
| Abstract | In an earlier 21-day, placebo-controlled trial, ziprasidone was efficacious in improving symptoms of mania and was well tolerated. To confirm these results, a similarly designed 21-day trial was conducted. Inpatients with bipolar I disorder, manic or mixed, were randomized to ziprasidone (40 to 80 mg BID) or placebo. Efficacy rating scales were derived from the Schedule for Affective Disorders and schizophrenia-Change Bipolar Scale (SADS-CB). SADS-CB-derived Mania Rating Scale (MRS) total score was the primary efficacy parameter. Secondary SADS-CB-derived efficacy parameters included Manic Syndrome and Behavior and Ideation Subscales, Hamilton Depression Rating Scale (HAM-D), and the Montgomery Asberg Depression Rating Scale (MADRS). The Clinical Global Impression-Severity Scale (CGI-S), the Global Assessment of Functioning (GAF), and the Positive and Negative Syndrome Scale (PANSS) were also assessed. Sixty-five placebo and 137 ziprasidone patients were evaluable for efficacy. Baseline-to-endpoint mean changes in MRS scores were -11.1 for ziprasidone and -5.6 for placebo (all patients, last observation carried forward [LOCF]; P < 0.01). Ziprasidone produced significantly greater improvements in Manic Syndrome (P < or = 0.01) and Behavior and Ideation Subscales (P < or = 0.001), CGI-S score, (P < or = 0.001), PANSS Total (P < or = 0.01) and Positive Subscale (P < or = 0.001) scores, and GAF (P < or = 0.001). With ziprasidone, significant improvements were observed from Day 2 onward for MRS and CGI-S at all time points except Day 4 for MRS. Treatment-related discontinuations due to adverse events were 5.8% for ziprasidone and 1.5% for placebo (P = 0.20). Ziprasidone was well tolerated, rapidly efficacious, and superior to placebo in improving symptoms and global illness severity in these inpatients with acute bipolar mania, both manic and mixed episodes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Psychopharmacology (Berl.) 2005 Sep 181: 253-9 |
| PMID | 15846482 |
| Title | 5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats. |
| Abstract | Performance on the Wisconsin Card Sorting Test (WCST), which requires patients to 'shift attention' between stimulus dimensions (sorting categories), is impaired in diseases such as schizophrenia. The rat attentional set shifting task is an analogue of the WCST. Given that 5-HT(6) receptor antagonists improve cognitive performance and influence cortical neurochemistry in rats, the present study investigated the effects of 5-HT(6) receptor antagonists upon attentional set shifting in rats. Rats were tested in this paradigm following sub-chronic SB-399885-T or SB-271046-A (both 10 mg kg(-1) BID, p.o. for 8 days prior to testing and either 4 or 2 h prior to testing on day 9, respectively). Rats were trained to dig in baited bowls for a food reward and to discriminate based on odour or digging media (Habituation, day 8). In a single session (day 9), rats performed a series of discriminations, including reversals (REV), intra-dimensional (ID) and extra-dimensional (ED) shifts. Neither compound altered performance during Habituation. On the test day, both SB-399885-T and SB-271046-A reduced the total trials to reach criterion and the total errors made when data were collapsed across all discriminations (P<0.05-0.01). Further, both compounds significantly reduced the trials to criterion for REV-1 (P<0.05-0.01) and abolished the ID/ED shift. SB-399885-T, but not SB-271046-A, reduced trials required to complete the ED shift (P<0.05) and the number of errors made during completion of the ID (P<0.05) and ED shifts (P<0.01). 5-HT(6) receptor antagonists improved performance in the attentional set shifting task and may have therapeutic potential in the treatment of disorders where cognitive deficits are a feature, including schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | J Pharm Pharm Sci 2005 -1 8: 47-53 |
| PMID | 15946597 |
| Title | Steady-state bioequivalence study of clozapine tablet in schizophrenic patients. |
| Abstract | To compare the bioavailability of two clozapine formulations (100 mg Clozaril tablet from Novartis Pharmaceuticals UK Ltd., UK, as a Reference formulation and 100 mg Cloril tablet from Atlantic Laboratories Corp., Ltd., Thailand, as a Test formulation). The present study was conducted under real-life conditions in schizophrenic patients using a steady-state, multiple-dose, randomized crossover design to avoid the risk of adverse effects in healthy volunteers and pharmacokinetic difference between single and multiple-dose of the drug. The subjects received 100 mg BID of either the Reference formulation or the Test formulation for 7 days. At day-7 of each study phase, blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h after drug administration. Plasma was separated and stored at -80 degrees C until assay. The plasma concentration of clozapine was determined by high performance liquid chromatography. Pharmacokinetic parameters were calculated from the observed plasma-concentration time profiles. The bioequivalence between the two formulations was assessed by calculating individual peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC(0-12 h)) ratios. All subjects well tolerated both clozapine formulations. No serious side effects were reported. The Tmax, terminal half-life and the total plasma clearance of clozapine (uncorrected for bioavailability) observed in the present study were comparable to those observed in other previous reports. All of the pharmacokinetic parameters investigated in the present study calculated from the subjects after administration of Test and Reference formulations were close. The 90% confident interval for the ratio of means for the lnCmax (0.9784-1.0622) and lnAUC(0-12h) (0.9559-1.0441) are within the guideline range of bioequivalence (0.80 to 1.25). The result demonstrated that the Test formulation was bioequivalent to the Reference formulation (Clozaril) when orally administered in schizophrenic patients, in terms of both the rate and extent of absorption. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Hum Psychopharmacol 2007 Oct 22: 469-76 |
| PMID | 17729385 |
| Title | Open-label steady-state pharmacokinetic drug interaction study on co-administered quetiapine fumarate and divalproex sodium in patients with schizophrenia, schizoaffective disorder, or bipolar disorder. |
| Abstract | To determine whether there is a pharmacokinetic drug interaction between quetiapine fumarate and divalproex sodium. The pharmacokinetics and short-term tolerability and safety of coadministered quetiapine and divalproex were examined in adults with schizophrenia/schizoaffective disorder (Cohort A) or bipolar disorder (Cohort B) in an open-label, parallel, 2-cohort drug-interaction study conducted at three centers in the United States. Cohort A was administered quetiapine (150 mg BID) prospectively for 13 days, with divalproex (500 mg BID) added on days 6-13. Cohort B was administered divalproex (500 mg BID) for 16 days, with quetiapine (150 mg BID) added on days 9-16. Quetiapine and valproic acid plasma concentration-time data over a 12-h steady-state dosing interval were used to determine C(max), T(max), C(min), area under the plasma concentration-time curve (AUC(tau)), and oral clearance (CL/F). In Cohort A (n = 18), addition of divalproex did increase the C(max) of quetiapine by 17% but did not change AUC(tau). In Cohort B (n = 15), addition of quetiapine decreased both total valproic acid C(max) and AUC(tau) by 11%. No differences were observed in adverse events (AEs) with either quetiapine or divalproex monotherapy or their combination. Combination therapy with quetiapine (150 mg BID) and divalproex (500 mg BID) resulted in small and statistically non-significant pharmacokinetic changes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Eur Child Adolesc Psychiatry 2007 Aug 16: 287-92 |
| PMID | 17473949 |
| Title | Prevalence of major depressive disorders and a validation of the Beck Depression Inventory among Nigerian adolescents. |
| Abstract | The aims of this study are to estimate the prevalence of major depressive disorder (MDD) in a representative sample of Nigerian adolescents, and to assess the validity of Beck Depression Inventory (BDI) in screening for depressive symptoms among adolescent population in Nigeria. A total of 1095 adolescents aged 13-18 years attending senior secondary schools completed the BDI. The presence of MDD in the adolescents was assessed using the Schedule for Affective Disorders and schizophrenia for School-Aged Children-Epidemiological Version 5 (K-SADS-E). The prevalence of MDD was 6.9%. (male = 5.5%, female = 8.9%). The difference between the rates for MDD in males and females was statistically significant (P = 0.028), but no age or age-gender-interaction difference was found. The BDI has good psychometric properties in screening for depression in adolescents. At a cut off score of 18 and above, the BID has a sensitivity of 0.91, specificity of 0.97, positive predictive value (PPV) of 0.88 and negative predictive value (NPV) of 0.98. The prevalence of MDD in Nigerian adolescents is comparable to those found in western culture and the BDI is a valid instrument for screening for MDD among Nigerian adolescents. Health policies in developing countries must integrate adolescents' depression as a disorder of public health significance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jul 144B: 701-3 |
| PMID | 17192893 |
| Title | Effect of 5-haplotype of dysbindin gene (DTNBP1) polymorphisms for the susceptibility to bipolar I disorder. |
| Abstract | We investigated a possible association between dysbindin gene (DTNBP1) variants and bipolar I disorder (BID). Five SNPs within DTNBP1 (rs3213207, rs1011313, rs2005976, rs760761, and rs2619522) were genotyped for 151 patients with BID and 478 controls. We observed a significant protective association of the haplotype A-C-G-T-A (all SNPs, P = 0.00016) and particularly G-T-A (the last three SNP, P = 0.00007) within DTNBP1 variants investigated. Single marker and subgroup (e.g., psychotic features, age at onset, family history, etc.) analyses showed no significant association. Although the association was due to a small number of subjects, specific DTNBP1 haplotypes, previously associated with schizophrenia, may be also associated with BID. Adequately powered studies from different ethnicities will be necessary to confirm our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Behav. Brain Res. 2007 Jan 176: 358-61 |
| PMID | 17101180 |
| Title | Enhanced anxiety follows withdrawal from subchronic exposure to phencyclidine in rats. |
| Abstract | Anxiety was assessed in rats treated with 5mg/kg of PCP BID for 7 days. One week after withdrawal, measures were collected in the light/dark apparatus and during exposure to a cat odor. PCP decreased time spent in the lit area and number of contacts with a cat collar. PCP thus amplified rats' fear of unprotected environments and predatory threats, which seems compatible with the distorted emotional experience in human schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Clin Ther 2007 Jul 29: 1476-86 |
| PMID | 17825699 |
| Title | Plasma pharmacokinetic characteristics of risperidone and their relationship to saliva concentrations in children with psychiatric or neurodevelopmental disorders. |
| Abstract | Risperidone is a second-generation antipsychotic agent widely used in the treatment of schizophrenia and other psychotic disorders in adults. Risperidone is probably the most frequently used atypical antipsychotic in the pediatric population. The goals of this study were to estimate the pharmacokinetic parameters of risperidone and its enantiomers in a pediatric population and explore relationships between saliva and plasma concentrations. Eligible patients, between 4 and 15 years of age, included those taking a stable dose of oral risperidone ranging from 0.01 to 0.07 mg/kg BID for > or =4 weeks to treat psychiatric or neurodevelopmental conditions. A trough blood level and predose saliva sample were collected at study initiation; the regular risperidone dose was administered; and paired samples of blood and saliva were collected at 1, 2, 4, and 7 hours postdose. Plasma/saliva concentrations of risperidone and enantiomers of its principal active metabolite, 9-hydroxyrisperidone (9-OH-risperidone), were measured using a chiral liquid chromatography-tandem mass spectrometry assay. Standard pharmacokinetic parameters were calculated. Cytochrome P450 2D6 genotypes of *3,*4,*5 deletion and duplication were determined. The study included 19 patients (age range, 4 years 2 months to 15 years 11 months). Mean (SD) values for C(max), t(1/2), and AUC 0 to 12 hours for risperidone in plasma were 15.9 (22.2) ng/mL, 3.0 (2.3) h, and 92.1 (200.6) ng x h/mL, respectively. Corresponding values in saliva were 12.0 (21.0) ng/mL, 3.4 (3.2) h, and 27.8 (38.7) ng x h/mL, respectively. Mean (SD) plasma enantiomer values for C(max) and AUC calculated up to the last observation were: (+)-9-OH-risperidone, 13.6 (10.0) ng/mL and 73.6 (52.3) ng x h/mL; (-)-9-OH-risperidone, 4.9 (3.1) ng/mL and 29.3 (19.1) ng x h/mL. Corresponding enantiomer values in saliva were: (+)-9-OH-risperidone, 5.2 (8.8) ng/mL and 15.6 (8.9) ng x h/mL; (-)-9-OH-risperidone, 5.0 (7.9) ng/mL and 15.6 (9.1) ng x h/mL, respectively. Large interindividual variability in risperidone and enantiomer concentrations was noted. A highly significant relationship between predose plasma and predose saliva risperidone concentrations was observed. The logarithmic regression model indicated that the log risperidone saliva concentration = -0.100 + 0.594 x log plasma concentration (R(2) = 0.93 [Spearman]). In this preliminary pharmacokinetic study of parameters for risperidone and the enantiomers of 9-OH-risperidone in a pediatric population, mean C(max) and t(1/2) of risperidone were generally similar to those previously described in adults. The highly significant relationship between predose plasma and predose saliva risperidone concentrations suggests that saliva measurements may be a viable alternative to plasma sampling in children. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2007 Oct 31: 1493-9 |
| PMID | 17688987 |
| Title | The impact of omega-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizophrenia patients treated with haloperidol: an open-label pilot study. |
| Abstract | Classical antipsychotics like haloperidol are suggested to increase oxidative stress and oxidative cell injury in the brain. Pro-oxidant effect of haloperidol may influence the course and treatment outcomes of schizophrenia. Dietary supplementation of either antioxidants or omega-3 fatty acids was found to improve symptoms of schizophrenia. Thus we decided to assess the impact of combining omega-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizophrenia patients treated with haloperidol. Ongoing haloperidol treatment of 17 schizophrenia patients was supplemented with 1000 mg capsule of omega-3 fatty acids (180 mg EPA+120 mg DHA) BID, vitamin E 400 IU BID and vitamin C 1000 mg/day. Patients were assessed with Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), Simpson Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS) over a 4 month period. Gluthatione peroxidase, superoxide dismutase, malondialdehyde, vitamin E and C levels were also evaluated at baseline and at the end of study. BPRS, SANS, SAS and BARS scores obtained at follow-up visits were significantly lower compared to baseline. Superoxide dismutase level was significantly lower at the end of study. No significant differences were detected in other laboratory parameters. Our results support the beneficial effect of the supplementation on positive and negative symptoms of schizophrenia as well as the severity of side effects induced by haloperidol. The effect of supplementation on akathisia is especially noteworthy and it has not been investigated in previous studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Prim Care Companion J Clin Psychiatry 2007 -1 9: 122-8 |
| PMID | 17607334 |
| Title | The 3-year clinical and functional course of schizophrenia among individuals with and without diabetes at study entry. |
| Abstract | This prospective observational study compared the 3-year clinical and functional course of schizophrenia among individuals with and without diabetes at study entry. Data were drawn from a large, 3-year, multisite, prospective, naturalistic study of treatment for schizophrenia-related disorders. The study was conducted in the United States between July 1997 and September 2003 and represented treatment practices in diverse systems of care. Participants were diagnosed with schizophrenia or schizoaffective or schizophreniform disorders based on DSM-IV criteria. Clinical and functional outcomes were assessed at study enrollment and at 12-month intervals using standard psychiatric measures, medical records, and a validated patient-reported questionnaire. Diabetes status was determined by participant interview at enrollment. Statistical analyses used mixed models with repeated measures. Of 594 participants queried about comorBID medical conditions at enrollment, 76 (12.8%) reported having diabetes. Other comor-BID conditions were reported by 79% of the diabetes group (N = 60) and 50% of the nondiabetes group (N = 259). Across the 3-year study, participants with diabetes differed significantly from participants without diabetes on 2 of 36 outcome measures: more contacts with nonpsychiatrist physicians (p < .001) and poorer physical health (p = .015). Groups did not differ significantly on mental health symptomatology, mental health resource utilization, legal and safety issues, substance use, productivity, activities and relationships, or quality of life. In this 3-year, prospective, naturalistic study, the course of schizophrenia did not differ significantly between participants with and without diabetes, although persons with diabetes did have poorer physical health and more contacts with nonpsychiatrist physicians. Findings highlight the need for better medical treatment for people with schizophrenia, both with and without comorBID diabetes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Psychopharmacology (Berl.) 2007 May 192: 27-38 |
| PMID | 17393142 |
| Title | Behavioral effects of orally administered glycine in socially housed monkeys chronically treated with phencyclidine. |
| Abstract | schizophrenia is a major mental disorder. Dissociative anesthetics such as phencyclidine (PCP) produce a syndrome in humans that is clinically indistinguishable from schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors in brain are modulated by the amino acid glycine (GLY), which reverses neurochemical and behavioral effects of PCP in rodents. The present study investigates GLY effects on PCP-induced behavior in primates. In primates, PCP induces characteristic behavioral symptoms that can be used to model positive and negative symptoms of schizophrenia. This study investigated the effects of GLY treatment in ten socially housed monkeys receiving chronically infused PCP. Ten monkeys received escalating then stable doses of continuously infused PCP through a series of subcutaneously implanted osmotic minipumps. During a segment of the highest PCP dose period, monkeys were concurrently treated with glycine (2 g kg(-1) day(-1) BID p.o.). Behavioral observations were recorded during baseline and treatment periods. Chronic PCP treatment was associated with a progressive decrease in stereotyped pacing and a progressive increase in scanning behavior. Eight of ten animals had one or more episodes of extreme motoric and physiological responses precipitated by stressful events. GLY treatment significantly reversed the effects of PCP on stereotyped pacing but had no effect on scanning. The results support GLY treatment as beneficial for negative symptoms of schizophrenia. Although further validation is needed, the results also indicate that chronic PCP in primates may be an appropriate model system for development of drugs targeting positive and negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Pharmacol. Biochem. Behav. 2007 Mar 86: 524-30 |
| PMID | 17320157 |
| Title | Differential effects of acute and subchronic clozapine and haloperidol on phencyclidine-induced decreases in voluntary sucrose consumption in rats. |
| Abstract | Prior exposure to the psychotomimetic drug phencyclidine (PCP) decreases voluntary sucrose consumption in rats. This may be indicative of reduced reward function, a phenomenon associated with negative schizophrenic symptomatology. Given that atypical antipsychotics have been shown to ameliorate negative symptoms of schizophrenia more effectively than typical neuroleptics, this effect should be reversed by clozapine but not haloperidol. PCP (15 mg/kg) or saline was administered 20 h prior to testing for voluntary sucrose consumption in non-deprived rats. In the acute experiments, rats were treated with clozapine (5 mg/kg), haloperidol (0.2 mg/kg), or vehicle 45 min prior to testing. In the subchronic experiments, rats were treated with clozapine (3 mg/kg, BID), haloperidol (0.5 mg/kg, BID), or vehicle for 10 days prior to PCP administration. Acute clozapine exacerbated the PCP-induced decrease in sucrose consumption without altering water consumption. Acute haloperidol produced an overall decrease in sucrose consumption in both PCP-pretreated and control groups. Subchronic treatment with clozapine, but not haloperidol, reversed PCP-induced decreases in sucrose consumption. The synergistic effect of acute clozapine and PCP may reflect a PCP-induced increase in the reward-reducing properties of CLZ, normally seen only at higher doses. The observation that subchronic clozapine, but not haloperidol, reversed PCP-induced decreases in sucrose consumption supports the hypothesis that this effect of PCP represents a plausible animal model for negative schizophrenic symptomatology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Pharmacol. Biochem. Behav. 2007 Mar 86: 524-30 |
| PMID | 17320157 |
| Title | Differential effects of acute and subchronic clozapine and haloperidol on phencyclidine-induced decreases in voluntary sucrose consumption in rats. |
| Abstract | Prior exposure to the psychotomimetic drug phencyclidine (PCP) decreases voluntary sucrose consumption in rats. This may be indicative of reduced reward function, a phenomenon associated with negative schizophrenic symptomatology. Given that atypical antipsychotics have been shown to ameliorate negative symptoms of schizophrenia more effectively than typical neuroleptics, this effect should be reversed by clozapine but not haloperidol. PCP (15 mg/kg) or saline was administered 20 h prior to testing for voluntary sucrose consumption in non-deprived rats. In the acute experiments, rats were treated with clozapine (5 mg/kg), haloperidol (0.2 mg/kg), or vehicle 45 min prior to testing. In the subchronic experiments, rats were treated with clozapine (3 mg/kg, BID), haloperidol (0.5 mg/kg, BID), or vehicle for 10 days prior to PCP administration. Acute clozapine exacerbated the PCP-induced decrease in sucrose consumption without altering water consumption. Acute haloperidol produced an overall decrease in sucrose consumption in both PCP-pretreated and control groups. Subchronic treatment with clozapine, but not haloperidol, reversed PCP-induced decreases in sucrose consumption. The synergistic effect of acute clozapine and PCP may reflect a PCP-induced increase in the reward-reducing properties of CLZ, normally seen only at higher doses. The observation that subchronic clozapine, but not haloperidol, reversed PCP-induced decreases in sucrose consumption supports the hypothesis that this effect of PCP represents a plausible animal model for negative schizophrenic symptomatology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Psychopharmacology (Berl.) 2007 Jun 192: 283-90 |
| PMID | 17265073 |
| Title | Repeated phencyclidine in monkeys results in loss of parvalbumin-containing axo-axonic projections in the prefrontal cortex. |
| Abstract | Repeated exposure to the N-methyl-D-aspartate antagonist, phencyclidine, has been shown to result in biochemical and cognitive changes similar to aspects of schizophrenia. Recently, emerging evidence indicated that the symptoms of schizophrenia might result at least in part from dysfunction of local circuit neurons containing parvalbumin, including a loss of their axo-axonic projections to pyramidal neurons. In this report, we test if repeated exposure to phencyclidine in the primate shares this change to parvalbumin-containing cells and their axo-axonic structures. Eight adult male African green monkeys were treated with saline or phencyclidine (0.3 mg/kg BID x 14 days) and, after 8 days drug-free, perfused and fixed, and the principal sulcus was collected (Walker's area 46) for immunohistochemical analysis. Prior treatment with phencyclidine resulted in a 40% reduction in the density of parvalbumin-containing axo-axonic structures. There was no apparent change in the lengths or laminar location of the axo-axonic projections. Additionally, there was no change in the total density or laminar location of parvalbumin-containing or calretinin-containing cell bodies in area 46. These results indicate that repeated treatment with phencyclidine results in plastic changes in parvalbumin-containing local circuit neurons in the prefrontal cortex similar to that reported in schizophrenia and that these changes may contribute to the common cognitive disruption seen in both schizophrenic patients and the phencyclidine monkey model. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Psychopharmacology (Berl.) 2007 Jun 192: 283-90 |
| PMID | 17265073 |
| Title | Repeated phencyclidine in monkeys results in loss of parvalbumin-containing axo-axonic projections in the prefrontal cortex. |
| Abstract | Repeated exposure to the N-methyl-D-aspartate antagonist, phencyclidine, has been shown to result in biochemical and cognitive changes similar to aspects of schizophrenia. Recently, emerging evidence indicated that the symptoms of schizophrenia might result at least in part from dysfunction of local circuit neurons containing parvalbumin, including a loss of their axo-axonic projections to pyramidal neurons. In this report, we test if repeated exposure to phencyclidine in the primate shares this change to parvalbumin-containing cells and their axo-axonic structures. Eight adult male African green monkeys were treated with saline or phencyclidine (0.3 mg/kg BID x 14 days) and, after 8 days drug-free, perfused and fixed, and the principal sulcus was collected (Walker's area 46) for immunohistochemical analysis. Prior treatment with phencyclidine resulted in a 40% reduction in the density of parvalbumin-containing axo-axonic structures. There was no apparent change in the lengths or laminar location of the axo-axonic projections. Additionally, there was no change in the total density or laminar location of parvalbumin-containing or calretinin-containing cell bodies in area 46. These results indicate that repeated treatment with phencyclidine results in plastic changes in parvalbumin-containing local circuit neurons in the prefrontal cortex similar to that reported in schizophrenia and that these changes may contribute to the common cognitive disruption seen in both schizophrenic patients and the phencyclidine monkey model. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Schizophr. Res. 2007 Feb 90: 179-85 |
| PMID | 17208413 |
| Title | Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. |
| Abstract | Some evidence suggests that the pathophysiology of schizophrenia is associated with the abnormal immune system, and cytokines may be important in schizophrenia. Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib reduce the production of proinflammatory cytokines including Th1-like cytokines. Indeed, COX-2 inhibitors rebalance type-1 and type-2 immune response. The purpose of the present investigation was to assess the efficacy of celecoxib as an adjuvant agent in the treatment of chronic schizophrenia in an eight-week, double-blind and placebo-controlled trial. Eligible participants in this study were 60 patients with chronic schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV criteria for schizophrenia. Patients were allocated in a random fashion, 30 to risperidone 6 mg/day plus celecoxib 400 mg/day (200 mg BID) (morning and evening) and 30 to risperidone 6 mg/day plus placebo. Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and celecoxib showed a significant superiority over risperidone alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores. The means Extrapyramidal Symptoms Rating Scale for the placebo group were higher than in the celecoxib group over the trial. However, the differences were not significant. The results of this study suggest that celecoxib may be an effective adjuvant agent in the management of patients with chronic schizophrenia and anti-inflammatory therapies should be further investigated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Saudi Med J 2008 Aug 29: 1130-4 |
| PMID | 18690305 |
| Title | A randomized, double-blind, placebo-controlled trial of metformin treatment for weight gain associated with initiation of risperidone in children and adolescents. |
| Abstract | To evaluate the effect of metformin treatment on the risperidone-induced body weight gain in patients. In a 12-weeks, double-blind, placebo controlled, randomized trial between October 2006 and October 2007 which was conducted in the Child and Adolescent Psychiatric Consultation Center of Isfahan University of Medical Sciences, 49 patients were entered the study with schizophrenia diagnosis. Then metformin (500 mg BID) or placebo was administrated with risperidone (6 mg) for the patients. Weight, height, and body mass index BMI were measured at the beginning, at 4 weeks, and at 12 weeks of the study. Changes in weight and BMI were evaluated by using repeated measures analysis of variance. Seventeen patients were excluded from the study. Repeated measure analysis of variances showed a significant difference between weight and BMI in both metformin (p<0.001, p<0.015) and placebo group (p<0.013, p<0.005). Metformin treatment did not show a significant effect to control the body weight of patients after 12 weeks. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Dec 32: 1879-83 |
| PMID | 18801405 |
| Title | Effect of ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. |
| Abstract | It was reported that ritanserin, a 5HT2A/2C antagonist, improves negative symptoms when added to neuroleptics in inpatients with predominantly negative symptoms. Nevertheless, the results of published studies are contradictory so far. This study was designed to investigate the effect of ritanserin added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double blind and randomized clinical trial. Eligible participants in this study were 40 patients with chronic schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion, 20 to risperidone 6 mg/day plus ritanserin 12 mg/day (6 mg BID) and 20 to risperidone 6 mg/day plus placebo. The principal measure of the outcome was Positive and Negative Syndrome Scale (PANSS). Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and ritanserin showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores. The present study indicates ritanserin as a potential adjunctive treatment strategy for the negative symptoms of schizophrenia. Nevertheless, results of larger controlled trials are needed, before recommendation for a broad clinical application can be made. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Hum Psychopharmacol 2008 Mar 23: 79-86 |
| PMID | 17972359 |
| Title | Efficacy of selegiline add on therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. |
| Abstract | It has been reported that selegiline, a Selective Monoamine Oxidase Inhibitor B (MAOI-B), at low doses would be helpful for treating negative symptoms in schizophrenia. Nevertheless, the results are contradictory so far. This study was designed to investigate the effect of selegiline added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in an 8 week, double blind and randomized clinical trial. Eligible participants in this study were 40 patients with chronic schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion, 20 to risperidone 6 mg/day plus selegiline 10 mg/day (5 mg BID) and 20 to risperidone 6 mg/day plus placebo. The principal measure of the outcome was Positive and Negative Syndrome Scale (PANSS). Although both protocols significantly decreased the score of the positive, negative, and general psychopathological symptoms over the trial period, the combination of risperidone and selegiline showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores. The present study indicates selegiline as a potential adjunctive treatment strategy for the negative symptoms of schizophrenia. Nevertheless, results of larger controlled trials are needed before recommendation for a broad clinical application can be made. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Int. J. Clin. Pract. 2009 Dec 63: 1762-84 |
| PMID | 19840150 |
| Title | Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic. |
| Abstract | To describe the efficacy and safety of asenapine for the treatment of schizophrenia and bipolar disorder. The pivotal registration trials were accessed by querying http://www.pubmed.gov, http://www.fda.gov and http://www.clinicaltrials.govfor the search terms 'asenapine' or 'ORG 5222'. All available clinical reports of studies were identified, as well as preclinical animal and receptor affinity studies that describe potential mechanisms of action. Extensive documents available from the US Food and Drug Administration and Schering-Plough Corporation as posted on http://www.fda.gov provided much of this data. Product labelling also provided additional information. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the study reports and synopses. Additional safety outcomes subject to NNH analysis were obtained from product labelling. A sublingual formulation of asenapine has received regulatory approval for the acute treatment of schizophrenia and manic/mixed episodes of bipolar I disorder. Bioavailability is 35% when taken sublingually, but < 2% if ingested. Similar to other second-generation antipsychotics, asenapine's binding profile includes 5-HT2A and D2 antagonism. Binding at the alpha-1 adrenergic and histamine H1 receptors predicts asenapine's propensity to cause orthostasis and sedation in some patients. Efficacy in the treatment of acute schizophrenia is supported by 2 of 4 completed phase II/III randomised, placebo and active-controlled 6-week trials, principally at a dose of 5 mg BID. Responder analysis for one of the studies reveals a NNT of asenapine vs. placebo of six for response as defined by a minimum of a 20% decrease in the Positive and Negative Syndrome Scale total score from baseline, and a NNT of 8 for the threshold of a 30% decrease. Efficacy in the treatment of manic or mixed episodes of bipolar I disorder is supported by 2 of 2 completed phase III randomised, placebo and active-controlled 3-week trials and by a 9-week extension trial. The dose tested in the bipolar trials was 10 mg BID. Longer-term studies have been completed in patients with schizophrenia or bipolar disorder, but complete results have not yet been published. Asenapine has a relatively favourable tolerability profile. For the patients with schizophrenia, the NNH values for asenapine vs. placebo for commonly observed adverse reactions were 13 (95% CI 8-30) for akathisia (10 mg BID), 20 (95% CI 13-50) for oral hypoesthesia (5 mg BID) and 13 (95% CI 8-32) for somnolence (5 mg BID). For patients with bipolar disorder, the NNH values for asenapine 5-10 mg BID vs. placebo were 6 (95% CI 5-9) for somnolence, 13 (95% CI 9-25) for dizziness, 20 (95% CI 13-56) for extra-pyramidal symptoms (EPS) other than akathisia and 25 (95% CI 16-71) for increased weight. Asenapine is associated with a lower frequency for EPS than haloperidol. Asenapine has a mild effect on the ECG QT interval similar to that seen with quetiapine. Asenapine's effect on prolactin is similar to that observed with olanzapine. Asenapine has a more favourable weight gain and metabolic profile compared with olanzapine. Asenapine sublingual tablets are a new option for the treatment of acute episodes of schizophrenia and for the treatment of acute manic or mixed episodes of bipolar I disorder. Although there is no evidence for asenapine's efficacy to be superior to currently available agents, asenapine's favourable weight and metabolic profile are of clinical interest. A caveat is that the data reviewed regarding asenapine are from its manufacturer. No independent studies of asenapine's efficacy or safety are available. Obstacles to the use of asenapine are the recommendations for twice daily dosing and the need to avoid food or liquids for 10 min after administration. As asenapine's bioavailability is very low if ingested, asenapine is unique among the antipsychotics, in that it needs to be swallowed to be covertly 'cheeked'. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | J Clin Pharmacol 2009 Nov 49: 1297-308 |
| PMID | 19843656 |
| Title | Exposure-response analysis in patients with schizophrenia to assess the effect of asenapine on QTc prolongation. |
| Abstract | An exposure-response (E-R) analysis using linear mixed effects modeling was conducted on data from a thorough QTc trial for asenapine in 148 patients with schizophrenia. In a parallel design, patients received asenapine 5 mg twice daily (BID) for 10 days (10d) followed by 10 mg BID (6d), asenapine 15 mg BID (10d) followed by 20 mg BID (6d), quetiapine 375 mg BID (for assay sensitivity; 16d) or placebo (16d). Triplicate 12-lead electrocardiograms and concentration measurements were obtained on day -1 (baseline), 1, 10, and 16 at 8 scheduled times on each day. At mean C(max) for all asenapine doses, the E-R model predicted that the mean QTcF increase was less than 5 milliseconds, the International Conference on Harmonisation-established threshold for clinical concern. The model predicted a mean increase of 7 to 8 milliseconds for quetiapine. The corresponding upper bounds of the 95% confidence intervals were 7.5 milliseconds and 11.2 milliseconds for asenapine and quetiapine, respectively. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Schizophr. Res. 2009 Apr 109: 66-9 |
| PMID | 19195842 |
| Title | A double-blind trial of adjunctive allopurinol for schizophrenia. |
| Abstract | To investigate if adjunctive allopurinol reduces symptoms in schizophrenia outpatients with persistent symptoms despite adequate pharmacotherapy. N=59 schizophrenia outpatients were randomly assigned to receive adjunctive allopurinol 300 mg BID or identical-looking placebo for 8 weeks after a 2-week placebo run-in. Symptoms were assessed biweekly. A total of n=51 patients completed the trial. Including all n=59 randomized patients, a total of 4 of 31 in the allopurinol group and 0 of 28 in the placebo group had at least a 20% reduction in total PANSS score at the final study visit (chi-square=3.88, p=.049). Among the n=51 completers, individuals in the allopurinol group rated themselves as more improved than did those in the placebo group (z=-2.24, p=.025). The allopurinol medication was well tolerated and there were not any adverse events attributed to the study medication. Allopurinol may be an effective adjunctive medication for some patients with persistent schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Bipolar Disord 2009 Nov 11: 673-86 |
| PMID | 19839993 |
| Title | A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. |
| Abstract | Asenapine is approved for bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute bipolar mania. After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5-20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values. Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean +/- SE changes in YMRS scores were observed on day 2 with asenapine (-3.0 +/- 0.4) and olanzapine (-3.4 +/- 0.4) versus placebo (-1.5 +/- 0.5, both p < 0.01) and were maintained until day 21 (-10.8 +/- 0.8 with asenapine, -12.6 +/- 0.8 with olanzapine; both p < or = 0.0001 versus placebo, -5.5 +/- 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures. These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with bipolar I disorder experiencing an acute manic episode. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | J Clin Psychopharmacol 2010 Apr 30: 106-15 |
| PMID | 20520283 |
| Title | Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. |
| Abstract | Asenapine is approved by the Food and Drugs Administration in adults for acute treatment of schizophrenia or of manic or mixed episodes associated with bipolar I disorder with or without psychotic features. In a double-blind 6-week trial, 458 patients with acute schizophrenia were randomly assigned to fixed-dose treatment with asenapine at 5 mg twice daily (BID), asenapine at 10 mg BID, placebo, or haloperidol at 4 mg BID (to verify assay sensitivity). With last observations carried forward (LOCF), mean Positive and Negative Syndrome Scale total score reductions from baseline to endpoint were significantly greater with asenapine at 5 mg BID (-16.2) and haloperidol (-15.4) than placebo (-10.7; both P < 0.05); using mixed model for repeated measures (MMRM), changes at day 42 were significantly greater with asenapine at 5 and 10 mg BID (-21.3 and -19.4, respectively) and haloperidol (-20.0) than placebo (-14.6; all P < 0.05). On the Positive and Negative Syndrome Scale positive subscale, all treatments were superior to placebo with LOCF and MMRM; asenapine at 5 mg BID was superior to placebo on the negative subscale with MMRM and on the general psychopathology subscale with LOCF and MMRM. Treatment-related adverse events (AEs) occurred in 44% and 52%, 57%, and 41% of the asenapine at 5 and 10 mg BID, haloperidol, and placebo groups, respectively. Extrapyramidal symptoms reported as AEs occurred in 15% and 18%, 34%, and 10% of the asenapine at 5 and 10 mg BID, haloperidol, and placebo groups, respectively. Across all groups, no more than 5% of patients had clinically significant weight change. Post hoc analyses indicated that efficacy was similar with asenapine and haloperidol; greater contrasts were seen in AEs, especially extrapyramidal symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Aug 34: 997-1000 |
| PMID | 20470848 |
| Title | Switching from conventional antipsychotics to ziprasidone: a randomized, open-label comparison of regimen strategies. |
| Abstract | In clinical psychopharmacology, the optimal method of switching from treatment A to treatment B with regard to efficacy and tolerability is an important area of study. We investigated the effects on efficacy and tolerability of switching patients from conventional antipsychotics to ziprasidone. This was a 6-week open-label, randomized study of 54 patients with persistent schizophrenia or schizoaffective disorder. Patients received ziprasidone 40 mg BID for 2 days, with titration up to 80 mg BID thereafter. The switch from conventional antipsychotics to ziprasidone was achieved using one of three discrete schedules: (1) abrupt discontinuation of conventional antipsychotics on day 1; (2) fast taper-50% of conventional antipsychotic dosage on days 1 through 7, followed by discontinuation and (3) slow taper-100% of conventional antipsychotic dosage on days 1 and 2, followed by 50% on days 3 through 7, then discontinuation. We found some evidence that the slow-taper strategy was associated with greater reductions in BPRS total scores early in the study compared to the other two strategies. However, these differences did not remain significant at endpoint, suggesting that there was no overall difference between the strategies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Pharmacopsychiatry 2010 Jun 43: 138-46 |
| PMID | 20205074 |
| Title | Long-term assessment of Asenapine vs. Olanzapine in patients with schizophrenia or schizoaffective disorder. |
| Abstract | We conducted a double-blind 1-year trial of asenapine in patients with schizophrenia or schizoaffective disorder. Patients were randomized to asenapine (5 or 10 mg BID; n=913) or olanzapine (10-20 mg QD; n=312), and monitored regularly. Trial completion rates were 38% with asenapine, 57% with olanzapine; main reasons for discontinuation were withdrawal of consent (22%, 16%) and insufficient response (25%, 14%); fewer discontinuations were due to adverse events (6%, 7%). Mean weight gain was 0.9 kg with asenapine, 4.2 kg with olanzapine. Extrapyramidal symptoms reported as adverse events were more common with asenapine. Mean reductions in PANSS total score with asenapine and olanzapine were -21.0 and -27.5 ( P<0.0001); the exclusion of patients who had previous poor experience with olanzapine may have biased the results in favor of olanzapine. Scores on the subjective well-being on neuroleptics scale and functionality measures were similar between groups. Asenapine was well tolerated over 1 year of treatment, causing less weight gain than olanzapine but more frequent extrapyramidal symptoms. PANSS total score improved with both agents; the improvement was greater with olanzapine than with asenapine using last observations carried forward but not in an observed-case analysis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | J Clin Psychiatry 2011 -1 72 Suppl 1: 19-23 |
| PMID | 22217439 |
| Title | Iloperidone: a clinical overview. |
| Abstract | Iloperidone is a new second-generation (atypical) antipsychotic medication approved for the treatment of schizophrenia in adults. The target dose of 6 mg BID can be achieved in 4 days, with titration recommended to minimize postural hypotension. The maximum recommended dose is 12 mg BID. The tolerability profile of iloperidone is noteworthy in terms of modest weight gain, no medically important changes in lipid and glucose levels, little in the way of prolactin elevation, and absence of extrapyramidal side effects, including akathisia. However, iloperidone can prolong the QTc interval on electrocardiogram. Iloperidone may be best suited for patients who are sensitive to akathisia or who are unable to tolerate the sedation and weight gain that can occur more frequently with other antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | J Clin Psychiatry 2011 -1 72 Suppl 1: 14-8 |
| PMID | 22217438 |
| Title | Asenapine: a clinical overview. |
| Abstract | Asenapine is a new, second-generation (atypical) antipsychotic medication with demonstrated efficacy for the acute and maintenance treatment of schizophrenia. It is administered as sublingual tablets in doses of 5 or 10 mg BID. It is well tolerated, with a dropout rate for adverse events similar to that of placebo. Asenapine is associated with a mean weight gain of less than 1 kg over a year and a relatively neutral effect on lipid and glucose levels. It can cause sedation and mild extrapyramidal side effects. Asenapine has a broad receptor affinity profile for most serotonergic, dopaminergic, and adrenergic receptors, with no appreciable affinity for muscarinic receptors. Asenapine may be a helpful treatment option for patients with schizophrenia when weight gain, dyslipidemia, and endocrine abnormalities are a concern. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Iran J Psychiatry 2011 -1 6: 1-6 |
| PMID | 22952513 |
| Title | C677T Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism in Schizophrenia and Bipolar Disorder: An Association Study in Iranian Population. |
| Abstract | The methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T is suspected to be a risk factor for psychiatric disorders, but it remains inconclusive whether the MTHFR polymorphism C677T is imputed to vulnerability to schizophrenia and bipolar disorder. We prompted impetus to appraise this polymorphism in an Iranian population. Therefore, 90 patients with bipolar disorder type I (BID), 66 patients with schizophrenia diagnosed according to DSM-IV criteria, and 94 unrelated controls with no history of psychiatric disorders were recruited for this study. Genotype distribution and allelic frequencies of C677T polymorphism were investigated. We found no robust differences between patients with BID and schizophrenia with control participants either for allele frequencies or genotype distribution of MTHFR C677T polymorphism. However, a trend toward an increased risk for T allele was observed in the BID patients [with odds ratio (OR) of 1.28(CI 95%: 0.8-1.31), p>0.05]. However, the present and some previous studies failed to elucidate possible interaction between MTHFR C677T polymorphism and vulnerability to schizophrenia and bipolar disorder; still some associations have been revealed in performed meta-analyses that warrant further studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | Clin Psychopharmacol Neurosci 2011 Dec 9: 117-21 |
| PMID | 23430042 |
| Title | The Diagnostic Stability of DSM-IV Diagnoses: An Examination of Major Depressive Disorder, Bipolar I Disorder, and Schizophrenia in Korean Patients. |
| Abstract | We examined the stability of diagnoses defined by the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) (major depressive disorder [MDD], bipolar I disorder [BID], and schizophrenia [SPR]) by means of retrospective reviews of medical records. Data from patients who met the DSM-IV criteria for the aforementioned disorders according to two psychiatrists and who were followed for at least 2 years were included in this study. We reviewed the medical records and compared the diagnosis given at the index admission with assessments made every 6 months for 2 years after discharge to determine diagnostic stability. A total of 138 patients with MDD, 56 patients with BID, and 107 patients with SPR who were followed for 2 years were included in the final analyses. The data showed that 84.8% of the sample retained their initial diagnosis of MDD during the first year; this figure decreased to 79.0% during the second year. During the first year, 93.5% retained their initial diagnosis of BID, and this figure decreased to 89.3% during the second year; 86.8% and 86.9% retained their diagnosis of SPR during the first and second years, respectively. This study showed the instability of three major DSM-IV diagnoses among Korean patients. Additionally, the results demonstrated that accurate diagnosis using the current diagnostic system requires longitudinal observation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Zhong Nan Da Xue Xue Bao Yi Xue Ban 2011 Aug 36: 712-9 |
| PMID | 21937794 |
| Title | Concentration change of DA, DOPAC, Glu and GABA in brain tissues in schizophrenia developmental model rats induced by MK-801. |
| Abstract | To explore the related neurobiochemical mechanism by comparing the concentration change of dopamine (DA), dihydroxy-phenyl acetic acid (DOPAC), glutamate (Glu), and ?-aminobutyric acid (GABA) in the brain tissues in schizophrenia (SZ) developmental model rats and chronic medication model rats. A total of 60 neonatal male Spragur-Dawley (SD) rats were randomly assigned to 3 groups at the postnatal day 6: an SZ developmental rat model group (subcutaneous injection with MK-801 at the postnatal day 7-10, 0.1 mg/kg, BID), a chronic medication model group (intraperitoneal injection at the postnatal day 47-60, 0.2 mg/kg,Qd), and a normal control group (injection with 0.9% normal saline during the corresponding periods). DA, DOPAC, Glu, and GABA of the tissue homogenate from the medial prefrontal cortex (mPFC) and hippocampus were examined with Coularray electrochemic detection by high performance liquid chromatogram technique. The utilization rate of DA and Glu was calculated. Compared with the normal control group, the concentration of DA and DOPAC in the mPFC and the hippocampus in the SZ developmental model group significantly decreased (P<0.05), and the GABA concentration and Glu utilization rate in the mPFC also decreased (P<0.05). Compared with the chronic medication model group, the DA concentration of the mPFC in the SZ developmental group decreased (P<0.05), and the DOPAC concentration and the utility rate of DA in the hippocampus also decreased (P<0.01, P<0.05, respectively). The activities of DA, Glu and GABA system decrease in the mPFC and the DA system function reduces in the hippocampus of SZ developmental rats. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Schizophr. Res. 2011 Nov 132: 101-7 |
| PMID | 21889878 |
| Title | Double-blind comparison of the safety and efficacy of lurasidone and ziprasidone in clinically stable outpatients with schizophrenia or schizoaffective disorder. |
| Abstract | Lurasidone is a new atypical antipsychotic agent with high affinity for D(2), 5-HT(2A) and 5-HT(7) receptors. The current study evaluated the safety and efficacy of lurasidone and ziprasidone in stable outpatients diagnosed with schizophrenia or schizoaffective disorder. Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder that was chronic (?6 months duration) and stable were randomized to 21 days of double-blind treatment with a fixed dose of lurasidone 120 mg once daily (N=150) or ziprasidone 80 mg BID (N=151). Changes from baseline in efficacy measures were evaluated using mixed model for repeated measures (MMRM) analyses. The proportion of patients who discontinued from the study was similar for lurasidone and ziprasidone (32.5% vs. 30.7%); the proportion who discontinued due to adverse events was similar (10.4% vs. 11.1%). Treatment with lurasidone and ziprasidone was associated with a small endpoint reduction in median weight (-0.65 kg vs. -0.35 kg) and median total cholesterol (-6.4 vs. -4.4 mg/dL); no endpoint change was observed in median triglycerides (0.0 vs. 0.0 mg/dL). There were no clinically significant changes in other laboratory or ECG parameters. Improvement was observed on an MMRM analysis of the PANSS total score for lurasidone and ziprasidone at Week 1 (-4.1 vs. -1.6; P=0.020), Week 2, (-6.1 vs. -3.6; P=0.074), and Week 3 (-6.3 vs. -4.5; P=0.229). In this double-blind, fixed-dose comparison of lurasidone 120 mg and ziprasidone 160 mg, treatment with lurasidone was well-tolerated and safe, and was not associated with clinically significant changes from baseline in weight, metabolic parameters, or QTc interval. Study limitations include the relatively short trial duration and lack of placebo control. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Neuropsychiatr Dis Treat 2011 -1 7: 77-85 |
| PMID | 21552309 |
| Title | Double-blind comparison of ziprasidone and risperidone in the treatment of Chinese patients with acute exacerbation of schizophrenia. |
| Abstract | The aim of the study was to evaluate the efficacy and safety of ziprasidone versus risperidone in Chinese subjects with acute exacerbation of schizophrenia. In patients meeting the Chinese Classification of Mental Disorders criteria for schizophrenia and with a Positive and Negative Syndrome Scale (PANSS) total score ?60 were randomly assigned to six weeks of double-blind treatment with ziprasidone 40-80 mg twice daily or risperidone 1-3 mg BID, flexibly dosed. Noninferiority was demonstrated if the upper limit of the two-sided 95% confidence interval (CI) for the difference in PANSS total score improvement from baseline in the evaluable population was smaller than the prespecified noninferiority margin of 10 units. The intent-to-treat population comprised 118 ziprasidone-treated and 121 risperidone-treated subjects. Improvement (reduction) from baseline to week 6 in PANSS total score was (-35.6 [95% CI: -38.6, -32.6]) for ziprasidone and (-37.1 [95% CI: -39.9, -34.4]) for risperidone. Noninferiority was demonstrated in the evaluable population with a difference score of 1.5 [95% CI: -2.5, 5.5]. Mean prolactin levels decreased at week 6 compared with baseline for ziprasidone (-3.5 ng/mL), but significantly increased for risperidone (61.1 ng/mL; P < 0.001). More risperidone-treated subjects (14.9%) than ziprasidone-treated subjects (4.2%) reported weight gain ?7%. Akathisia and somnolence in the ziprasidone group and akathisia and insomnia in the risperidone group were the most common side effects. Treatment-related/treatment-emergent adverse events were reported by 79.7% and 71.1% of ziprasidone-treated and risperidone-treated subjects, respectively. In Chinese subjects, ziprasidone was as effective as risperidone, with less weight gain and less prolactin elevation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Early Interv Psychiatry 2011 May 5: 91-9 |
| PMID | 21535421 |
| Title | Integrated genetic and genomic approach in the SingaporeTranslational and Clinical Research in Psychosis Study: an overview. |
| Abstract | schizophrenia is a severe mental disorder with onset frequently in adolescence and followed by a chronic and disabling course. Although the exact pathophysiology of this devastating disorder has not been clearly elucidated, a large part of it has been attributed to genetic influences. This article seeks to provide an overview on what our group has embarked on--to elucidate genetic risk factors for schizophrenia within the Chinese ethnic group. We plan to conduct an integrated approach to interrogate comprehensively the genome from different angles and in stages. The first stage involves a genome-wide association study of 1000 cases of schizophrenia-control pairs, with a follow-up replication study in another 1000 cases of schizophrenia and in 1000 controls, and combination analyses with groups from other places including China and Hong Kong. Other than the genome-wide association study, gene sequencing for purported candidate genes and copy number variation analysis will be performed. Neurocognitive intermediate phenotypes will be employed to deconstruct the complex schizophrenia phenotype in a BID to improve association findings. Promising leads from longitudinal gene and protein expression in ultra-high-risk subjects who develop psychosis and schizophrenia (in a parallel study) will be followed up as candidate genes and sequenced in the genetic analysis. Functional analysis forms the last stage of this integrated approach. This integrated genetic and genomic approach will hopefully help in further characterizing and deepening our understanding of molecular pathophysiological mechanisms underlying schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Schizophr. Res. 2011 Apr 127: 188-94 |
| PMID | 21277745 |
| Title | Performance and interview-based assessments of cognitive change in a randomized, double-blind comparison of lurasidone vs. ziprasidone. |
| Abstract | Improving cognitive functioning in people with schizophrenia is a major treatment goal. In addition, interview-based measures have been developed to supplement performance-based assessments. However, few data are available regarding whether interview-based measures are sensitive to treatment-related changes. Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomized to 21 days of double-blind treatment with lurasidone 120 mg once daily (N=150) or ziprasidone 80 mg BID (N=151). A similar proportion of patients completed the study on lurasidone (67.5%) and ziprasidone (69.3%). Study participants were assessed with the majority of the tests from the MATRICS Consensus Cognitive Battery (MCCB) and an interview-based assessment of cognitive functioning, the schizophrenia Cognition Rating Scale (SCoRS). SCoRS ratings were based on the interviewer's best judgment, after interviews with the patient and a caregiver when available. The study was conducted from April 2006 to January 2007. There were no between-group treatment differences in performance on the MCCB or the SCoRS ratings. Lurasidone patients demonstrated significant within group-improvement from baseline on the MCCB composite score (p=0.026) and on the SCoRS (p<0.001), but ziprasidone patients did not improve on either the MCCB composite (p=0.254) or the SCoRS (p=0.185). At endpoint there was a statistical trend (p=0.058) for lurasidone to demonstrate greater improvement from baseline in SCoRS ratings. Improvements in interview-based aspects of cognition were not related to MCCB test changes, and had minimal correlations with changes in symptoms. These data suggest that interview-based cognitive measures such as the SCoRS may be sensitive to changes after 3weeks of treatment in patients with schizophrenia. Lurasidone is being assessed further in ongoing clinical trials with additional outcome measures. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Pharmacopsychiatry 2012 Jul 45: 196-203 |
| PMID | 22454251 |
| Title | Long-term efficacy and safety of asenapine or olanzapine in patients with schizophrenia or schizoaffective disorder: an extension study. |
| Abstract | Safety and efficacy results, collected in schizophrenia and schizoaffective disorder patients treated for up to nearly 3 years, are presented for asenapine and olanzapine. Patients completing a 52-week randomized double-blind core study on flexible-dose asenapine (5 or 10 mg BID) or olanzapine (10 or 20 mg QD) could continue treatment until study blind was broken.290 patients on asenapine and 150 on olanzapine continued treatment for variable lengths of time [mean ± SD (range) 311.0 ± 146.1 (10 - 653) d and 327.4 ± 139.6 (15 - 631) d, respectively]. Adverse event (AE) incidence was lower during the extension (asenapine, 62%; olanzapine, 55%) than during the core study (78%, 80%). In both groups, body weight increase and incidence of extrapyramidal AEs were negligible during the extension. Mean PANSS total score changes during first year of treatment were - 37.0 for asenapine and - 35.3 for olanzapine, with further changes of 1.6 for asenapine and - 0.8 for olanzapine at the extension study endpoint. Clinical stability on asenapine as well as olanzapine was maintained, with few recurrent or newly emerging AEs beyond 1 year of treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Int J Geriatr Psychiatry 2012 May 27: 472-82 |
| PMID | 21755540 |
| Title | Short-term safety and pharmacokinetic profile of asenapine in older patients with psychosis. |
| Abstract | The aim of this study was to assess the short-term tolerability of two titration schedules of sublingual asenapine in older patients with psychosis, not associated with organic brain disease, and to compare asenapine pharmacokinetics in older patients versus younger adults with schizophrenia. Patients ? 65 years with psychosis without dementia were randomized for 6 weeks to two dose-escalation regimens: 2 days at 2 mg twice daily (BID), 2 days at 5 mg BID, and 10 mg BID thereafter (slow escalation); or 4 days at 5 mg BID and 10 mg BID thereafter (rapid escalation). Clinical and pharmacokinetic assessments were performed in each group. Of 122 randomized patients, 76 (62.3%) completed the trial. The incidence of treatment-emergent adverse events (AEs) was comparable (72.1%) with both regimens. The most frequently reported AEs were hypertension, headache, and somnolence; incidence of extrapyramidal symptom-related AEs was 5.7%. Mean end point weight change was 0.4 kg. For asenapine 5 and 10 mg BID, median times to maximum concentration were 1.00 and 1.06 h, respectively; maximum concentrations (C(max) ) were 4.73 and 7.93 ng/mL; areas under the concentration versus time curve (0-12 h; AUC(0-12) ) were 32.1 and 56.3 ng?h/mL. Despite 12-30% increases in asenapine C(max) and AUC(0-12) in older patients compared with previously published findings in younger schizophrenia patients, possibly as a result of slower drug clearance, asenapine was generally well tolerated during both dose-escalation schedules. No dose adjustment appears to be necessary in older patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | PLoS ONE 2012 -1 7: e35511 |
| PMID | 22545112 |
| Title | Gene expression analysis implicates a death receptor pathway in schizophrenia pathology. |
| Abstract | An increase in apoptotic events may underlie neuropathology in schizophrenia. By data-mining approaches, we identified significant expression changes in death receptor signaling pathways in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, particularly implicating the Tumor Necrosis Factor Superfamily member 6 (FAS) receptor and the Tumor Necrosis Factor [ligand] Superfamily member 13 (TNFSF13) in schizophrenia. We sought to confirm and replicate in an independent tissue collection the noted mRNA changes with quantitative real-time RT-PCR. To test for regional and diagnostic specificity, tissue from orbital frontal cortex (OFC) was examined and a bipolar disorder group included. In schizophrenia, we confirmed and replicated significantly increased expression of TNFSF13 mRNA in the DLPFC. Also, a significantly larger proportion of subjects in the schizophrenia group had elevated FAS receptor expression in the DLPFC relative to unaffected controls. These changes were not observed in the bipolar disorder group. In the OFC, there were no significant differences in TNFSF13 or FAS receptor mRNA expression. Decreases in BH3 interacting domain death agonist (BID) mRNA transcript levels were found in the schizophrenia and bipolar disorder groups affecting both the DLPFC and the OFC. We tested if TNFSF13 mRNA expression correlated with neuronal mRNAs in the DLPFC, and found significant negative correlations with interneuron markers, parvalbumin and somatostatin, and a positive correlation with PPP1R9B (spinophilin), but not DLG4 (PSD-95). The expression of TNFSF13 mRNA in DLPFC correlated negatively with tissue pH, but decreasing pH in cultured cells did not cause increased TNFSF13 mRNA nor did exogenous TNFSF13 decrease pH. We concluded that increased TNFSF13 expression may be one of several cell-death cytokine abnormalities that contribute to the observed brain pathology in schizophrenia, and while increased TNFSF13 may be associated with lower brain pH, the change is not necessarily causally related to brain pH. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Pharmacopsychiatry 2012 Sep 45: 236-40 |
| PMID | 22592506 |
| Title | Efficacy and tolerability of switching to ziprasidone in italian patients with acute exacerbation of schizophrenia: an open-label trial. |
| Abstract | The long-term maintenance of a stable condition is an important aim of schizophrenia therapy, which frequently requires the switch between 2 antipsychotic agents. This 8-week multicenter study, conducted in Italy, evaluates the switch from a previous antipsychotic to ziprasidone.Adult acute schizophrenic patients requiring a change in antipsychotic for lack of efficacy or tolerability issues took ziprasidone 20?-?80?mg/BID. Dosages could be adjusted during the study. The primary efficacy outcomes were the differences in positive and negative syndrome scale (PANSS) and clinical global impression severity (CGI-S) scores from baseline to study end. Other efficacy variables were clinical global impression improvement, global assessment of functioning, patient preference scale and drug attitude inventory.189 patients were evaluated; the mean (±SD) ziprasidone dose was 95.9±34.5?mg/day. PANSS and CGI-S scores significantly decreased throughout the study. All secondary outcomes significantly improved at the end of the study vs. baseline values. Ziprasidone was well tolerated; 13 patients reported a QTc prolongation (mild in 12 patients).Notwithstanding the limitations of any non-comparative study, these results suggest that ziprasidone may be an effective and well-tolerated option in acute schizophrenia patients who discontinued a previous antipsychotic agent. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Pharmacopsychiatry 2012 Sep 45: 236-40 |
| PMID | 22592506 |
| Title | Efficacy and tolerability of switching to ziprasidone in italian patients with acute exacerbation of schizophrenia: an open-label trial. |
| Abstract | The long-term maintenance of a stable condition is an important aim of schizophrenia therapy, which frequently requires the switch between 2 antipsychotic agents. This 8-week multicenter study, conducted in Italy, evaluates the switch from a previous antipsychotic to ziprasidone.Adult acute schizophrenic patients requiring a change in antipsychotic for lack of efficacy or tolerability issues took ziprasidone 20?-?80?mg/BID. Dosages could be adjusted during the study. The primary efficacy outcomes were the differences in positive and negative syndrome scale (PANSS) and clinical global impression severity (CGI-S) scores from baseline to study end. Other efficacy variables were clinical global impression improvement, global assessment of functioning, patient preference scale and drug attitude inventory.189 patients were evaluated; the mean (±SD) ziprasidone dose was 95.9±34.5?mg/day. PANSS and CGI-S scores significantly decreased throughout the study. All secondary outcomes significantly improved at the end of the study vs. baseline values. Ziprasidone was well tolerated; 13 patients reported a QTc prolongation (mild in 12 patients).Notwithstanding the limitations of any non-comparative study, these results suggest that ziprasidone may be an effective and well-tolerated option in acute schizophrenia patients who discontinued a previous antipsychotic agent. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | Zhongguo Dang Dai Er Ke Za Zhi 2012 Nov 14: 869-74 |
| PMID | 23146738 |
| Title | [Changes in expression levels of PV, GAD67 and KCC2 in the brain tissue of rats with schizophrenia induced by MK-801]. |
| Abstract | To study changes in the expression levels of parvalbumin (PV), glutamate decarboxylase 67 (GAD67) and K+-Cl- cotransporter 2 (KCC2) in the brain tissue of rats with schizophrenia (SZ) induced by dizocilpine (MK-801), and to investigate the mechanism involving gamma-aminobutyric acid (GABA) by which NMDA receptor blocker induces SZ in the perinatal period. Thirty-six neonatal male Sprague-Dawley rats were randomly assigned to two batches on postnatal day 6. Each batch was divided into normal control (treated by 0.9% normal saline), SZ-development model (treated by subcutaneous injection of 0.1 mg/kg MK-801 on postnatal days 7-10; BID), and SZ-chronic medication model groups (treated by intraperitoneal injection of 0.2 mg/kg MK-801 on postnatal days 47-60; qd). On postnatal day 63, the brain tissue of the first batch of rats was obtained and then fixed with paraform for histological sections; expression levels of PV and GAD67 in the medial prefrontal cortex (mPFC) and hippocampus CA1 were measured by immunohistochemistry. Simultaneously, the second batch of rats was sacrificed and the mPFC and hippocampus were obtained and homogenized; expression levels of KCC2 in the mPFC and hippocampus were measured by Western blot. Expression levels of PV and GAD67 in the mPFC and hippocampus CA1 were significantly lower in the SZ-development and chronic medication model groups than in the normal control group (P<0.05). Expression levels of KCC2 in the mPFC and hippocampus were significantly lower in the SZ-development model group than in the SZ-chronic medication model and normal control groups (P<0.05). The expression changes of PV and GAD67 in SZ can be simulated using the SZ development model induced by MK-801, which might affect the development of the GABA system in the PFC and hippocampus by downregulating KCC2 expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Eur Neuropsychopharmacol 2012 Oct 22: 721-33 |
| PMID | 22464973 |
| Title | A double-blind, randomized, placebo-controlled study with JNJ-37822681, a novel, highly selective, fast dissociating D? receptor antagonist in the treatment of acute exacerbation of schizophrenia. |
| Abstract | JNJ-37822681 is a novel, highly selective dopamine D? receptor antagonist characterized by a rapid dissociation rate from the dopamine D? receptor. This profile was hypothesized to confer antipsychotic efficacy and improved tolerability. In this 12-week study, the efficacy and safety of JNJ-37822681 were evaluated in patients with an acute exacerbation of schizophrenia, randomly assigned (1:1:1:1:1) to JNJ-37822681 (10-, 20- or 30-mg BID), olanzapine (15 mg once-daily), or placebo (for 6 weeks followed by olanzapine for 6 weeks). Of 498 randomized patients, 298 (60%) completed the study. All JNJ-37822681 dose groups and the olanzapine group showed significantly greater reduction in PANSS total score from baseline to week 6 versus placebo (all p-values < 0.001). Least-squares adjusted mean changes from baseline to week 6 in PANSS total score were: -6.4 (placebo); -18.4 (10 mg JNJ-37822681), -17.7 (20 mg JNJ-37822681), -20.0 (30 mg JNJ-37822681) and -22.9 (olanzapine). All JNJ-37822681 groups showed significant improvement versus placebo from baseline to week 6 in the PANSS subscales, Marder factors, Clinical Global Impression of Severity, and in the Subjective Well-Being on Neuroleptics scale (all p-values < 0.05). The most common treatment-emergent adverse events with JNJ-37822681 were insomnia (17%) and akathisia (13%). Incidences of extrapyramidal symptoms were dose-related and were comparable for JNJ-37822681 10 mg BID and olanzapine groups. All JNJ-37822681 dose groups showed lesser weight gain compared with olanzapine. The efficacy and tolerability profile of the JNJ-37822681 10 mg BID was consistent with the study hypothesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | Neuropharmacology 2012 Mar 62: 1182-90 |
| PMID | 21856317 |
| Title | Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats. |
| Abstract | A number of selective phosphodiesterase (PDE) inhibitors have been demonstrated to improve learning in several rodent models of cognition. Given that schizophrenia is associated with impairments in frontal lobe-dependent cognitive functions (e.g., working memory and cognitive flexibility), we examined whether PDE inhibitors would attenuate cognitive deficits associated with schizophrenia. Persistent suppression of N-methyl-D-aspartate (NMDA) receptor function produces enduring structural changes in neocortical and limbic regions in a pattern similar to changes reported in schizophrenia. This similarity suggests that subchronic treatment with NMDA receptor antagonists (e.g., phencyclidine, PCP) may represent a useful preclinical model of neurobiological and related cognitive deficits associated with schizophrenia. We treated male Long-Evans rats with subchronic PCP (5 mg/kg, ip, BID, 7 d) or saline and then examined the effects of acute treatment with selected doses of PDE inhibitors that have been demonstrated to regulate both intracellular levels of cAMP and/or cGMP, and to improve cognitive function. We used an extradimensional-intradimensional (ED/ID) test of cognitive flexibility similar to those used in humans and non-human primates for assessing executive function. Subchronic treatment with PCP produced a selective impairment on ED shift (EDS) performance without significant impairment on any other discrimination problem when compared to saline-treated control animals. Selected doses of the four PDEIs evaluated (PDE2: BAY 60-7550; PDE4: rolipram; PDE5: sildenafil; PDE10A: papaverine) were able to significantly attenuate this cognitive deficit in EDS performance. This suggests that this rodent model of executive function was sensitive to pro-cognitive effects of intracellular effects resulting from PDE inhibition. Together, these data suggest that inhibition of PDE activity may represent valuable therapeutic targets to improve cognition associated with neuropsychiatric disorders that feature cognitive dysfunction as a key symptom. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | J Clin Pharmacol 2012 May 52: 757-65 |
| PMID | 21628604 |
| Title | Valproate reduces the glucuronidation of asenapine without affecting asenapine plasma concentrations. |
| Abstract | Asenapine is indicated for treatment of schizophrenia in the United States and acute treatment of manic or mixed episodes, as monotherapy (United States and European Union) or adjunct therapy (United States only), associated with bipolar I disorder. It is extensively metabolized; the 2 main metabolites are asenapine N-glucuronide and N-desmethyl-asenapine. The authors investigated the pharmacokinetic interactions between asenapine and valproate in an open-label, randomized, 2-way crossover study. Twenty-four healthy male volunteers received sublingual doses of asenapine 5 mg alone or under steady-state valproate (500 mg BID for 9 days). Blood samples collected until 72 hours postdosing were analyzed for asenapine, N-desmethyl-asenapine, and asenapine N-glucuronide. Compared with asenapine alone, valproate substantially reduced N-glucuronide formation (area under the curve from 0 to infinity [AUC(0-?)] reduced 7.4-fold, maximum concentration [C(max)] reduced 6.6-fold) and moderately reduced N-desmethyl-asenapine formation (AUC(0-?) reduced 30%, C(max) unchanged). Coadministration of valproate did not affect asenapine AUC(0-?) and C(max) (confidence intervals for the ratios of asenapine AUC(0-?) and C(max) were contained within the predefined 0.80-1.25 acceptance range). Low-dose valproate, although almost completely inhibiting glucuronidation of asenapine, did not affect the pharmacokinetics of asenapine itself, the entity primarily responsible for the pharmacologic effects of the drug. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | Psychopharmacology (Berl.) 2013 Nov 230: 23-7 |
| PMID | 23828160 |
| Title | The effect of reboxetine co-administration with olanzapine on metabolic and endocrine profile in schizophrenia patients. |
| Abstract | We previously demonstrated that the addition of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Using the same study sample, we also sought to determine whether reboxetine's weight-attenuating effect was accompanied by a beneficial effect on metabolic and endocrine parameters relevant to antipsychotic-induced weight gain and obesity. Blood samples at baseline and at the end of the 6-week trial were available for 54 participants who participated in previous double-blind, placebo-controlled studies of reboxetine (4 mg BID) addition to olanzapine-treated schizophrenia patients. Fasting glucose, lipid profile, insulin, leptin, cortisol, dehydroepiandrosterone (DHEA), prolactin, and thyroid-stimulating hormone (TSH) were analyzed. In contrast to the olanzapine/placebo group, the olanzapine/reboxetine group exhibited a reduction in blood triglyceride (p?Reboxetine addition resulted in meaningful improvement of some metabolic and endocrine measures associated with olanzapine-induced weight gain. The potential role of reboxetine in the prevention of olanzapine-induced weight gain and cardio-metabolic morBIDity merits further large-scale, long-term investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | BMC Psychiatry 2013 -1 13: 143 |
| PMID | 23694720 |
| Title | A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia. |
| Abstract | We compared the time to discontinuation due to lack of tolerability over 24 weeks in patients suffering from schizophrenia treated with pomaglumetad methionil (LY2140023 monohydrate, the prodrug of metabotropic glutamate 2/3 receptor agonist, LY404039) or standard of care (SOC: olanzapine, risperidone, or aripiprazole). Study HBBR was a multicenter, randomized, open-label study comparing the long-term safety and tolerability of LY2140023 with SOC for schizophrenia. Patients had moderate symptomatology with prominent negative symptoms and evidence of functional impairment. Those who met entry criteria were randomized to open-label treatment with either LY2140023 (target dose: 40 mg twice daily [BID]; n?=?130) or SOC (n?=?131). There was no statistically significant difference between LY2140023 and SOC for time to discontinuation due to lack of tolerability (primary objective; P?=?.184). The Kaplan-Meier estimates revealed comparable time to event profiles. Only 27% of LY2140023 and 45% of SOC patients completed the 24-week open-label, active treatment phase. Twenty-seven patients (20.8%) in the LY2140023 group and 15 patients (11.5%) in the SOC group discontinued due to lack of efficacy (P?=?.044). Twenty-three patients (17.7%) in the LY2140023 group and 19 patients (14.5%) in the SOC group discontinued due to adverse events (physician and subject decision combined, P?=?.505). The incidence of serious adverse events was comparable between groups. LY2140023-treated patients reported significantly more treatment-emergent adverse events of vomiting, agitation, and dyspepsia, while SOC-treated patients reported significantly more akathisia and weight gain. The incidence of treatment-emergent parkinsonism (P?=?.011) and akathisia (P?=?.029) was significantly greater in SOC group. Improvement in PANSS total score over the initial 6 to 8 weeks of treatment was similar between groups, but improvement was significantly greater in the SOC group at 24-week endpoint (P?=?.004). LY2140023 and SOC groups had comparable negative symptom improvement at 24-week endpoint (P?=?.444). These data provide further evidence that the potential antipsychotic LY2140023 monohydrate, with a glutamatergic mechanism of action, may have a unique tolerability profile characterized by a low association with some adverse events such as extrapyramidal symptoms and weight gain that may characterize currently available dopaminergic antipsychotics. A Long-term, Phase 2, Multicenter, Randomized, Open-label, Comparative Safety Study of LY2140023 Versus Atypical Antipsychotic Standard of Care in Patients with DSM-IV-TR schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | Schizophr. Res. 2013 Apr 145: 110-5 |
| PMID | 23415472 |
| Title | Effects of adjunctive intranasal oxytocin on olfactory identification and clinical symptoms in schizophrenia: results from a randomized double blind placebo controlled pilot study. |
| Abstract | Deficits in olfactory identification have been widely reported in patients with schizophrenia (SZ) and are associated with negative symptomatology. Adjunctive oxytocin delivered intranasally has been shown to improve some aspects of social cognition as well as positive and negative symptoms in patients with schizophrenia. Given the intranasal delivery route of oxytocin to olfactory pathways and that olfactory abnormalities are a potential endophenotype in SZ, we investigated the effect of intranasal oxytocin on olfactory identification as well as positive and negative symptoms in people with schizophrenia. Individuals with schizophrenia or schizoaffective disorder (n=28; 16 outpatients, 12 inpatients) were randomized to receive adjunctive intranasal oxytocin 20 IU BID or placebo for 3 weeks. All 28 participants completed the clinical trial. Odor identification performance significantly improved on the University of Pennsylvania Smell Identification Test (UPSIT) total score and subscore for pleasant smells. UPSIT score (F=5.20, df=1,23, p=0.032) and subscore for pleasant smells (F=4.56, df=1,23, p=0.044), in patients treated with oxytocin were compared to placebo from baseline to endpoint. Global symptomatology as well as positive and negative symptoms were not improved by intranasal oxytocin. In fact, global symptoms, not positive or negative symptoms, improved in the placebo group. Secondary analysis shows that intranasal oxytocin improved negative symptoms in the small group of inpatients. Intranasal oxytocin was well tolerated during the three week trial. Adjunctive intranasal oxytocin may improve olfactory identification, particularly in items of positive valence. Larger studies are needed to determine the effects of oxytocin on negative symptoms in SZ. (NCT00884897; http://www.clinicaltrials.gov). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | J Clin Psychopharmacol 2013 Feb 33: 3-10 |
| PMID | 23277250 |
| Title | A thorough QTc study of 3 doses of iloperidone including metabolic inhibition via CYP2D6 and/or CYP3A4 and a comparison to quetiapine and ziprasidone. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 59 | Eur Neuropsychopharmacol 2013 Sep 23: 1043-50 |
| PMID | 22995972 |
| Title | Does early improvement predict response to the fast-dissociating D? receptor antagonist JNJ-37822681 in patients with acute schizophrenia? |
| Abstract | Early predictability of sustained response to atypical antipsychotics in patients with schizophrenia has important implications for clinical decision making. In order to investigate whether early onset of efficacy correlates with week-6 response for the selective fast-dissociating D2 receptor antagonist JNJ-37822681, we analysed data from a 12-week placebo- and active-controlled (olanzapine) study designed to evaluate efficacy and safety of JNJ-37822681. Factors, including baseline Positive and Negative Syndrome Scale (PANSS) total score, waist circumference, weight, body mass index group, number of previous hospitalisations, age at diagnosis, race, sex and age at study entry, and relative (%) change from baseline on day 3 (early improvement) in PANSS total score, were analysed using logistic regression models and receiver operator characteristic (ROC) curve analysis, to predict the week-6 efficacy response (? 30% improvement in PANSS total score). Results showed that week-6 response with JNJ-37822681 30 mg BID treatment could be reliably predicted by improvement in PANSS total score on day 3, the number of previous hospitalisations, and race (80% accuracy [ROC area under curve]). Early improvement (day 3) in PANSS score had the highest predictive value as a single factor across all JNJ-37822681 doses. At a specificity of 70%, sensitivity for predicting week-6 response was: 0.60, 0.64, and 0.74 in the 10-, 20-, and 30 mg BID JNJ-37822681 groups, respectively; 0.40 in olanzapine group. Early improvement in PANSS may be a simple and reliable way to predict sustained response with JNJ-37822681 in patients with acute schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 60 | Schizophr. Res. 2014 Mar 153: 160-8 |
| PMID | 24529610 |
| Title | A trial evaluating gradual- or immediate-switch strategies from risperidone, olanzapine, or aripiprazole to iloperidone in patients with schizophrenia. |
| Abstract | In a 12-week randomized open-label trial, adults diagnosed with schizophrenia experiencing inadequate efficacy and/or poor tolerability on risperidone, olanzapine, or aripiprazole were randomized to switch to iloperidone either gradually (ie, down-titration of current therapy over the first 2weeks [to 50% on Day 1, 25% by Week 1, 0% by Week 2]) or immediately. All patients were titrated on iloperidone to 6mg BID by Day 4, then flexibly dosing between 6 and 12mg BID, as needed. The primary variable was the Integrated Clinical Global Impression of Change (I-CGI-C) and the primary analysis time point was Week 12. A total of 500 patients were randomized and received iloperidone (gradual switch, 240; immediate switch, 260), with 175, 155, and 170 patients switched from risperidone, olanzapine, and aripiprazole, respectively. I-CGI-C Results confirmed improved outcomes at Week 12, with scores that were similar between the gradual- and immediate-switch groups, respectively, for risperidone, 2.82 and 2.67 (95% CI: -0.229, 0.511); olanzapine, 2.87 and 3.03 (95% CI: -0.548, 0.235); and aripiprazole, 2.79 and 2.81 (95% CI: -0.405, 0.368). Incidence of adverse events (AEs) was similar in both switch groups, with the most frequently reported (?10%) being dizziness, dry mouth, somnolence, and weight increase. In conclusion, switching to iloperidone by either a gradual or an immediate method did not reveal any clinically significant differences in ratings of overall efficacy and safety/tolerability outcomes, based on the I-CGI-C at 12weeks. Similar overall safety/AE profiles were observed regardless of the specific agent from which patients were switched. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 61 | ScientificWorldJournal 2014 -1 2014: 256584 |
| PMID | 25431782 |
| Title | Lifetime prevalence of psychiatric disorders among parents of children with bipolar I disorder: parental difference. |
| Abstract | Evaluation of family system is an important area in the context of child and adolescent mental health. This study aimed to estimate psychiatric disorders in parents of children and adolescents with bipolar I disorder (BID). In this cross-sectional study, during 2012-2013, all of the children and adolescents diagnosed with BID based on Kiddie Schedule for Affective Disorders and schizophrenia-Present and Lifetime Version were included. All of the parents (both mother and father) were evaluated by Structured Clinical Interview for DSM-IV-TR. Prevalence rates are reported and independent-sample t-test and chi-square test were used when appropriate. A total of 108 families were interviewed. 25% of mothers and 33% of fathers met the criteria for at least one psychiatric disorder, with major depressive disorder, BMD, and cluster B personality disorder being more prevalent. Fathers were more likely to receive a dual psychiatric diagnosis. Cluster B personality disorder and substance dependence were more prevalent among fathers while major depressive disorder was more prevalent among mothers. This study confirmed a higher prevalence of psychiatric disorders in parents of children with BID and emphasizes parental evolution. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 62 | BMC Psychiatry 2014 -1 14: 351 |
| PMID | 25539791 |
| Title | A Double-Blind, Placebo-Controlled Comparator Study of LY2140023 monohydrate in patients with schizophrenia. |
| Abstract | Pomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia. Enrolled adult patients (ages 18-65) with schizophrenia who had experienced an exacerbation of symptoms within 2 weeks prior to study entry. Patients (N?=?1013) were randomized 2:2:2:1 to treatment with placebo, LY40 mg twice daily (BID), LY80 mg BID, or risperidone (RIS) 2 mg BID for 6 weeks after a one-week blinded placebo lead-in. The primary outcome assessed change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in an overall schizophrenia population and a predefined subpopulation which excluded non-Hispanic white patients with the A/A genotype at the HTR2A SNP rs7330461. Neither LY2140023 dose showed significant improvement compared to placebo on PANSS total in either population (1-sided p-value [significance level], overall: LY40, p?=?.154 [0.01]; LY80, p?=?.698 [0.01], subpopulation: LY40, p?=?.033 [0.0025]; LY80, p?=?.659 [0.0025], MMRM analysis). RIS statistically separated from placebo in both populations (p?LY2140023 treatment did not demonstrate efficacy in populations studied. Overall, LY2140023 treatment was generally well tolerated with no new adverse safety findings compared to previous trials. Further understanding of the role of glutamate as a therapeutic target in schizophrenia is needed. A Phase 2, Multicenter, Double-Blind, Placebo-Controlled Comparator Study of 2 Doses of LY2140023 Versus Placebo in Patients With DSM-IV-TR schizophreniaClinicalTrials.gov identifier: NCT01086748. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 63 | BMC Psychiatry 2014 -1 14: 351 |
| PMID | 25490958 |
| Title | A double-blind, placebo-controlled comparator study of LY2140023 monohydrate in patients with schizophrenia. |
| Abstract | Pomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia. Enrolled adult patients (ages 18-65) with schizophrenia who had experienced an exacerbation of symptoms within 2 weeks prior to study entry. Patients (N = 1013) were randomized 2:2:2:1 to treatment with placebo, LY40 mg twice daily (BID), LY80 mg BID, or risperidone (RIS) 2 mg BID for 6 weeks after a one-week blinded placebo lead-in. The primary outcome assessed change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in an overall schizophrenia population and a predefined subpopulation which excluded non-Hispanic white patients with the A/A genotype at the HTR2A SNP rs7330461. Neither LY2140023 dose showed significant improvement compared to placebo on PANSS total in either population (1-sided p-value [significance level], overall: LY40, p = .154 [0.01]; LY80, p = .698 [0.01], subpopulation: LY40, p = .033 [0.0025]; LY80, p = .659 [0.0025], MMRM analysis). RIS statistically separated from placebo in both populations (p < .001 [0.05]). There were no statistically significant differences in the incidence of serious adverse events, and no seizures on LY2140023. LY2140023 treatment did not demonstrate efficacy in populations studied. Overall, LY2140023 treatment was generally well tolerated with no new adverse safety findings compared to previous trials. Further understanding of the role of glutamate as a therapeutic target in schizophrenia is needed. A Phase 2, Multicenter, Double-Blind, Placebo-Controlled Comparator Study of 2 Doses of LY2140023 Versus Placebo in Patients With DSM-IV-TR schizophrenia ClinicalTrials.gov identifier: NCT01086748 . |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 64 | Biol. Psychiatry 2015 Dec 78: 754-62 |
| PMID | 25890643 |
| Title | Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia. |
| Abstract | Accumulating evidence indicates that glutamatergic tone in schizophrenia may vary as a function of illness duration or medication history. We conducted an exploratory analysis of the existing clinical trial database of pomaglumetad methionil (pomaglumetad) to demonstrate treatment response in targeted patient populations. Results of the H8Y-MC-HBBM (HBBM) study and an integrated analysis based on five placebo-controlled trials were summarized. Patients with schizophrenia were randomly assigned to receive either pomaglumetad, 40 or 80 mg twice daily (BID), placebo, or risperidone, 2 mg BID, for up to 6 weeks. Patient subgroups were analyzed to determine the efficacy of pomaglumetad treatment in patients early-in-disease (?3 years) and late-in-disease (?10 years) (HBBM, 40 mg, n = 206, 80 mg, n = 198; integrated analysis, 40 mg, n = 382, 80 mg, n = 381) and in patients previously treated with central nervous system drugs with prominent serotonin 2A receptor antagonist activity (S2 group) or with predominant dopamine D2 receptor antagonist activity (D2 group; HBBM, 40 mg, n = 275, 80 mg, n = 269; integrated analysis, 40 mg, n = 590, 80 mg, n = 506). In the HBBM study and integrated analysis, only patients early-in-disease or previously treated with D2 drugs exhibited significantly greater improvement relative to those receiving placebo, when treated with pomaglumetad, 40 mg (but not 80 mg) BID. Treatment response to risperidone did not appear to depend upon these patient subgroups. Demonstration of antipsychotic efficacy of a potential glutamate-based pharmacotherapy for schizophrenia may require the identification of appropriate patient subgroups whose treatment responsiveness may be fundamentally related to dysregulation of central nervous system glutamatergic tone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 65 | Psychopharmacology (Berl.) 2016 Feb 233: 649-60 |
| PMID | 26558619 |
| Title | Serotonin (5-HT)1A receptor agonism and 5-HT7 receptor antagonism ameliorate the subchronic phencyclidine-induced deficit in executive functioning in mice. |
| Abstract | Reversal learning (RL), a type of executive function, dependent on prefrontal cortical function, is impaired in rodents by subchronic (sc) treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), a widely studied model of cognitive impairment in schizophrenia (CIS). The principal objective of this study was to determine the ability of serotonin (5-HT)1A partial agonism and 5-HT7 receptor antagonism to improve RL in scPCP-treated mice. Male C57BL/6J mice were trained on an operant RL (ORL) task, then received PCP, 10 mg/kg, or saline, BID, for 7 days, followed by a 7-day washout period. scPCP significantly diminished the percent correct responding, increased total incorrect trials, and total incorrect responses, in the reversal phase performance of the ORL task. Pre-treatment with the selective 5-HT1A partial agonist, tandospirone, or the selective 5-HT7 antagonist, SB269970, but not the 5-HT7 agonist, AS 19, reversed the scPCP-induced deficit in RL. Pre-treatment with atypical antipsychotic drug lurasidone, which is a 5-HT1A partial agonist and 5-HT7 antagonist, as well as a 5-HT2A and dopamine (D)2 antagonist, also reversed RL deficit in the scPCP-treated mice. Furthermore, the selective 5-HT1A antagonist, WAY100635, blocked the ability of lurasidone to reverse the scPCP-induced RL deficit. These results indicate that 5-HT7 antagonism and 5-HT1A partial agonism contribute to restoration of RL in scPCP-treated mice. It is suggested that these two mechanisms are effective in restoring RL by decreasing excessive GABAergic inhibition of cortical pyramidal neurons following withdrawal of scPCP treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |