The long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release in patients with schizophrenia.

OBJECTIVE: To evaluate the long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release (XR) from an oral antipsychotic in patients with schizophrenia. Reasons for switching included insufficient efficacy, tolerability, and/or non-acceptability. The primary endpoint was the percentage of patients achieving an improvement in Clinical Global Impression - Clinical Benefit (CGI-CB) scale scores. RESEARCH DESIGN AND METHODS: A 24-week, international, multicentre, open-label, prospective study ( www.clinicaltrials.gov : NCT00640601). After a 7-14 day enrolment period (depending whether prior antipsychotic mono- or combination therapy), all patients received quetiapine XR 300 mg once daily (day 1), 600 mg/day (day 2), 600-800 mg/day (day 3) and 400-800 mg/day thereafter, with down-titration and discontinuation of prior antipsychotic by day 4. RESULTS: A total of 62% of patients completed the study and 56.9% (LOCF, ITT) achieved a significant improvement in CGI-CB (95% CI [0.51, 0.63]; p = 0.02). Switches due to insufficient efficacy showed a significant improvement (60%, 95% CI [0.51, 0.68]; p = 0.02), compared to 54.4% ([0.44, 0.64]; p = 0.38) and 52.4% ([0.36, 0.68]; p = 0.76) of switches due to insufficient tolerability and non-acceptability respectively (both p = ns). Patients previously on olanzapine and quetiapine IR showed a significant improvement in CGI-CB (62.6% [p = 0.02] and 61.2% [p = 0.04], respectively). Somnolence (18.0%) and dizziness (14.6%) were the main adverse events. Anticholinergic use decreased from 7.1 to 2.7%. Overall mean weight gain was 0.4 kg; 12.9% of patients experienced a weight gain of ≥7% and 15% experienced a clinically relevant shift in triglycerides from baseline. CONCLUSIONS: A majority of patients switched from other antipsychotics to quetiapine XR experienced clinical benefit. This was supported by all other efficacy outcomes regardless of the reason for switching. Safety data confirmed quetiapine XR was safe and well tolerated. The open-label design and lack of a placebo group represent limitations.

Loxapine for schizophrenia.

BACKGROUND: Some authors have suggested that loxapine is more effective than typical antipsychotics in reducing the negative symptoms of schizophrenia, that extrapyramidal adverse effects are not usually seen at clinically effective antipsychotic doses and that it should therefore be classed as atypical. OBJECTIVES: To determine the effects of loxapine compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: For this 2007 update, we searched the Cochrane Schizophrenia Group's Register (January 2007). SELECTION CRITERIA: We included all randomised controlled clinical trials relevant to the care of schizophrenia that compared loxapine to other treatments. DATA COLLECTION AND ANALYSIS: We independently inspected abstracts ordered papers, re-inspected and quality assessed these. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a fixed effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed effects model. MAIN RESULTS: We were able to include 41 studies in this review. Compared with placebo, loxapine has an antipsychotic effect (Global effect - not improved at six weeks: n=78, 2 RCTs, RR 0.30 CI 0.1 to 0.6 NNT 3 CI 3 to 5). It is as effective as typical drugs in the short term (4 -12 weeks) (Global effect: n=580, 13 RCTs, RR 0.86 CI 0.7 to 1.1; mental state: n=915, 6 RCTs, RR 0.89 CI 0.8 to 1.1). Very limited heterogeneous data suggest that, given intramuscularly (IM), loxapine may be at least as sedating as IM haloperidol and thiothixene. Loxapine is also as effective as atypicals (risperidone, quetiapine) (n=468, 6 RCTs, RR mental state not improved 1.07 CI 0.8 to 1.5). Adverse effect profile is similar to typicals but loxapine may cause more extrapyramidal adverse effects when compared with atypicals (n=340, 4 RCTs, RR 2.18 CI 1.6 to 3.1). AUTHORS' CONCLUSIONS: Loxapine is an antipsychotic which is not clearly distinct from typical or atypical drugs in terms of its effects on global or mental state. Loxapines profile of adverse effects is similar to that of the older generation of antipsychotic drugs.

Modelling the impact of compliance on the costs and effects of long-acting risperidone in Canada.

Schizophrenia is a chronic, relapsing disease that requires more healthcare resources to manage than any other single psychiatric illness. The main cost of treatment is hospitalization as a result of the exacerbation of symptoms often caused by poor compliance. Although the costs of hospitalization and relapse have been well documented, the differential effects of various medications on healthcare expenditure are still being determined. The aim of the present study was to estimate the cost effectiveness of long-acting risperidone in the treatment of high-risk, non-compliant patients with schizophrenia over a 5-year period in Canada. A discrete event model was developed comparing three scenarios, each with a different starting treatment: haloperidol depot, long-acting risperidone or oral risperidone. Second and third-line treatment options were olanzapine and clozapine, respectively, for all three scenarios. On the basis of 3000 simulated patient characteristics, the model generated individual patient histories. Outcomes included the number and duration of psychotic episodes, the cumulative Positive and Negative Syndrome Scale (PANSS) score and direct medical costs. The time horizon of the model was 5 years and a 5% discount rate was used for costs and effects. The perspective of the model was that of the Canadian healthcare system. After 5 years, treatment with long-acting risperidone saved Canada dollars 6908 and Canada dollars 13,130 (discounted) and avoided 0.28 and 0.54 relapses per patient, compared with haloperidol depot and oral risperidone, respectively. In this model, initiating treatment of high-risk, non-compliant patients with schizophrenia with long-acting risperidone was the dominant strategy. With long-acting risperidone, direct costs were lower and clinical effectiveness was greater, compared with haloperidol depot or oral risperidone, during years 4 and 5.

Paroxetine: a review.

Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with currently approved indications for the treatment of depression, obsessive-compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder and chronic headache. Paroxetine, a phenylpiperidine derivative, is the most potent inhibitor of the reuptake of serotonin (5-hydroxytryptamine, 5-HT) of all the currently available antidepressants including the class of SSRIs. It is a very weak inhibitor of norepinephrine (NE) uptake but it is still more potent at this site than the other SSRIs. The selectivity of paroxetine, i.e., the ratio of inhibition of uptake of norepinephrine to serotonin (NE/5-HT) is amongst the highest of the SSRIs. Paroxetine has little affinity for catecholaminergic, dopaminergic or histaminergic systems and by comparison with tricyclic antidepressants (TCAs) has, therefore, a reduced propensity to cause central and autonomic side effects. Paroxetine exhibits some affinity for the muscarinic cholinergic receptor but much less than the TCAs. In addition, the adaptive changes of somatodendritic (5-HT(1A)) and terminal (5-HT(1B/1D)) autoreceptors observed with paroxetine are different to those observed with TCAs; it also inhibits nitric oxide synthase. It is both a substrate and an inhibitor of cytochrome isoenzyme P450 2D6. Paroxetine is well absorbed orally and undergoes extensive first pass metabolism that is partially saturable. Its metabolites are pharmacologically inactive in vivo. Steady state levels are achieved after 4-14 days and an elimination half-life of 21 h is consistent with once-daily dosing. There is wide inter-individual variation in the pharmacokinetics of paroxetine in adults as well as in the young and the elderly with higher plasma concentrations and slower elimination noted in the latter. Elimination is also reduced in severe renal and hepatic impairment. Serious adverse events are, however, extremely rare even in overdose. In summary, paroxetine is well tolerated and effective in the treatment of both depressive and anxiety disorders across the age range.

Global assessment of functioning following assertive community treatment in Edmonton, Alberta: a longitudinal study.

OBJECTIVE: To examine longitudinally the effects of Assertive Community Treatment (ACT) on Global Assessment of Functioning (GAF) scores in Edmonton, Alberta. METHODS: We acquired GAF scores for all clients at initial registration in the ACT program and at subsequent 18- and 36-month time points while in ACT. We analyzed both the entire ACT cohort and separate diagnostic groups. RESULTS: We obtained baseline and follow-up GAF scores for 411 clients, of whom the largest diagnostic group suffered from schizophrenia (n = 189), followed by bipolar disorder (n = 98). Collapsed across all groups, GAF scores significantly improved at both 18 (P < 0.0001) and 36 months (P < 0.0001). By group, at 18-month follow-up, significant improvements were seen in patients with delusional disorder (P < 0.05), dysthymia (P < 0.05), schizoaffective disorder (P < 0.05), and schizophrenia (P < 0.001). This was also seen at 36-month follow-up, with the addition of significant improvements in those with bipolar disorder (P < 0.05). Those patients with major affective disorder or psychosis not otherwise specified (NOS) did not show significant improvements over time. Regardless of diagnosis, those clients with baseline GAF scores of < or = 40 significantly improved at both 18-month (P < 0.0001) and 36-month (P < 0.0001) follow-up, while those with baseline GAF scores above 40 did not show significant improvement. CONCLUSIONS: GAF scores improved at 18- and 36-month follow-up from enrolment in an ACT program. Groups with different diagnoses and levels of functioning at time of enrolment may not benefit to the same degree.

Quetiapine and obsessive-compulsive symptoms (OCS): case report and review of atypical antipsychotic-induced OCS.

The atypical antipsychotics have advanced the treatment of schizophrenia and have proved to be effective agents in treating other disorders with or without psychotic features. We review the literature concerning an increasingly reported and interesting adverse effect, atypical antipsychotic-induced obsessive-compulsive symptoms (OCS). The first known report of quetiapine exacerbating OCS in a 43-year-old man with obsessive-compulsive disorder (OCD), trichotillomania, delusional disorder and bipolar II disorder is presented. Mechanisms, including 5-HT2A and 5-HT2C antagonism, serotonergic regulation of dopamine systems and putative dopaminergic subtypes of OCS and OCD, are discussed. Given the paradoxical efficacy of the atypical antipsychotics in pure OCD, the neurobiology and comorbidity of OCD and schizophrenia, as well as the increasing use of atypical antipsychotics, a cautious and rational pharmacotherapeutic treatment approach is recommended.

Hepatitis C virus infection among teenagers in an endemic township in Taiwan: epidemiological and clinical follow-up studies.

The aim of the study was to elucidate the epidemiological features of Hepatitis C virus (HCV) infection among teenagers in an endemic area by conducting a mass screening study. We also investigated the clinical outcome of the anti-HCV-positive subjects by conducting subsequent short-term and long-term follow-up studies. All 2837 students of two junior middle schools in Tzukuan, aged 13-16 years, were invited to be screened for anti-HCV, HBsAg, AST and ALT in October 1995. A total of 2726 (96%) students responded. Anti-HCV, HCV RNA and aminotransferase levels were evaluated among anti-HCV-positive students 1 month and 30 months later, respectively. A total of 38 (1.4%; M/F = 22/16) participants were anti-HCV-positive. The anti-HCV-positive students had higher rates of exposures to transfusion, anti-HCV-positive families and surgery. The prevalence (2.8%) of the 7 maritime villages was markedly higher than that (0.7%) of the other 8 villages (P < 0.001). Subsequent follow-up studies demonstrated that there might be 5 cases of acute or recent HCV infection, and 6 cases who had recovered from chronic HCV infection.

Investigation of Turner syndrome in schizophrenia.

Both Turner syndrome and schizophrenia are relatively infrequent conditions. Consequently, individuals having both illnesses are rare. Previous reviews of sex chromosome abnormalities in schizophrenia have focused primarily on the presence of supernumerary X-chromosomes. After identifying two female patients with schizophrenia and Turner syndrome, we reevaluated the available literature that survey female schizophrenics for the presence of chromosomal abnormalities. Eleven patients with Turner syndrome were identified among 6,483 females with schizophrenia in non-case-report studies. These survey results indicate that Turner syndrome occurs approximately three-fold more frequently in schizophrenic females than in the general female population (P < 0.02). Including 6 other case reports and our 2 cases, a total of 19 females with both schizophrenia and Turner syndrome were reported. Interestingly, whereas most Turner syndrome patients have the 45,X karyotype, the majority (18/19) of women with both illnesses have a mosaic karyotype (P < 0.0002). Given the potential role of genes on the X-chromosome in the pathogenesis of schizophrenia, the study of unique populations with abnormalities in this chromosome, such as women with Turner syndrome, may offer clues into this illness.

Sex differences in schizophrenia, a review of the literature.

OBJECTIVE: To comprehensively and critically review the literature on gender differences in schizophrenia. METHOD: An initial search of MEDLINE abstracts (1966-1999) was conducted using the terms sex or gender and schizophrenia, followed by systematic search of all relevant articles. RESULTS: Males have consistently an earlier onset, poorer premorbid functioning and different premorbid behavioral predictors. Males show more negative symptoms and cognitive deficits, with greater structural brain and neurophysiological abnormalities. Females display more affective symptoms, auditory hallucinations and persecutory delusions with more rapid and greater responsivity to antipsychotics in the premenopausal period but increased side effects. Course of illness is more favorable in females in the short- and middle-term, with less smoking and substance abuse. Families of males are more critical, and expressed emotion has a greater negative impact on males. There are no clear sex differences in family history, obstetric complications, minor physical anomalies and neurological soft signs. CONCLUSION: This review supports the presence of significant differences between schizophrenic males and females arising from the interplay of sex hormones, neurodevelopmental and psychosocial sex differences.

Loxapine for schizophrenia.

BACKGROUND: Loxapine is a drug with D2/D3 receptor antagonist activity and a higher affinity for D3 than D2. Some authors have suggested that loxapine is more effective than typical antipsychotics in reducing the negative symptoms of schizophrenia, that extrapyramidal side-effects are not usually seen at clinically effective antipsychotic doses and that it should therefore be classed as atypical. OBJECTIVES: To determine the effects of loxapine compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1996), PSYNDEX (1977-1995) and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. Pharmaceutical companies and authors of trials were contacted. SELECTION CRITERIA: All randomised controlled clinical trials relevant to the care of schizophrenia that compared loxapine to other treatments. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted but excluded if loss to follow up was greater than 50%. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, weighted mean differences were calculated (WMD). All data were inspected for heterogeneity. MAIN RESULTS: Compared to placebo, loxapine is antipsychotic (Global effect - not improved at 6 weeks, n=66, RR 0.6 CI 0.4-0.9 NNT 4 CI 2-62) with similar adverse effect profile to typical drugs. Is as effective as typical drugs in the short term (4-12 weeks) (Global effect - not improved, n=411, RR 0.89 CI 0.7-1.2). Very limited heterogeneous data suggest that, given intramuscularly (IM), loxapine may be at least as sedating as IM haloperidol and thiothixene. REVIEWER'S CONCLUSIONS: Loxapine is antipsychotic but its effects are under researched. It is not clearly different from typical drugs in either its positive or adverse effects.

Sulpiride for schizophrenia.

BACKGROUND: The antipsychotic drug sulpiride was formulated over 20 years ago and was marked as having a low incidence of adverse effects and an effect on the negative symptoms of schizophrenia. This relatively inexpensive antipsychotic drug has a similar neuropharmacological profile to several novel atypical drugs. OBJECTIVES: To estimate the clinical efficacy and tolerability of sulpiride. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1997), CINAHL (1982-1998), Cochrane Schizophrenia Group's Register (March 1998), Cochrane Library (Issue 1, 1998), EMBASE (1980-1998), MEDLINE (1966-1998), PsycLIT (1974-1997), SIGLE (1994-1998), and Sociofile (1974-1997) were supplemented by reference searching, contacting authors and the manufacturers of sulpiride. SELECTION CRITERIA: All randomised or quasi-randomised clinical trials focusing on the use of different doses of sulpiride or comparing sulpiride to (i) placebo; (ii) typical antipsychotic drugs; or (iii) atypical antipsychotic drugs, for those with schizophrenia or serious mental illness were selected. DATA COLLECTION AND ANALYSIS: Trials were reliably selected and quality rated. Data were independently extracted, by two reviewers (BGOS, MF), and analysed on an intention-to-treat basis. It was assumed that people who did not complete the follow up had no improvement. Authors of trials were contacted for additional and missing data. Relative risk (RR) and 95% confidence intervals (CI) of dichotomous data were calculated with the random effects model and weighted mean difference (WMD) was calculated for continuous data. MAIN RESULTS: The review currently includes 18 studies (30 citations). Studies are generally small and of poor quality. Limited evidence suggests that there is little difference between sulpiride and other drugs although the incidence of side effects may be less for sulpiride. There are no clear findings relating to negative symptoms. REVIEWER'S CONCLUSIONS: Sulpiride may be an effective antipsychotic drug but evidence is limited and data relating to claims for its value against negative symptoms is not trial-based.

Obsessive-compulsive disorder in schizophrenia.

OBJECTIVE: To examine the differences in demographic and clinical features of patients with schizophrenia, with or without comorbid obsessive-compulsive disorder (OCD). METHODS: Fifty-two subjects were recruited from clinical services in the city of Edmonton, Alberta and assessed for schizophrenia and OCD with structured clinical interviews and standardized clinical rating scales. RESULTS: The prevalence of OCD in individuals meeting criteria for schizophrenia was 25%. Those subjects having both schizophrenia and OCD scored significantly higher on the Y-BOCS, Hollingshead scale, and GAF; plus significantly lower PANSS negative symptoms and a trend in increased Parkinsonian symptoms compared with individuals with schizophrenia alone. CONCLUSION: Our preliminary findings indicate that patients with schizophrenia and OCD vary in selected demographic and clinical measures when compared to patients with schizophrenia alone. Patients with schizophrenia and OCD appear to have less negative symptoms, which may thus be reflected in the decreased GAF scores. It is speculated that patients with schizophrenia and OCD may have a greater propensity to basal ganglia dysfunction than those with schizophrenia alone resulting in increased Parkinsonian symptoms.

Antipsychotic agents and QT changes.

Recently, antipsychotic medications of the novel or atypical classes have received increased attention because of concerns with respect to potential lengthening of the QT interval, yet the currently available and commonly prescribed conventional antipsychotics are significantly more cardiotoxic, particularly agents in the butyrophenone and phenothiazine classes. Lengthening of the QT interval can be associated with a fatal paroxysmal ventricular arrhythmia known as torsades de pointes. The specific duration of the QT interval at which the risk of an adverse cardiac event is greatest, is not established. There is not only significant variation in the applied definition of an abnormal interval, but the maximal QT interval in healthy volunteers is greater than the currently accepted standards. The QT interval is influenced by normal physiological and pathologic factors, but the mechanisms remain unclear. Using recombinant technology, haloperidol and sertindole have been demonstrated to be high-affinity antagonists of a human cardiac potassium channel encoded by the human ether-a-go-go-related gene. Pimozide, however, has been shown to act principally through calcium channel antagonism, and chlorpromazine may affect sodium channels. Nevertheless, it is possible that these effects are significant only in the presence of predisposing factors, either genetic or acquired. Despite proven efficacy in clinical trials and subsequent supervised use in Europe, a number of recently developed antipsychotic medications are not available to patients in North America. Yet, conventional antipsychotic medications that would not be approved by current safety standards continue to be widely used.

Drug metabolism and atypical antipsychotics.

The introduction of the atypical antipsychotics clozapine, risperidone, olanzapine, quetiapine and sertindole for the treatment of schizophrenia has coincided with an increased awareness of the potential of drug-drug interactions, particularly involving the cytochrome P450 (CYP) enzymes. The current literature describing the pharmacokinetics of the metabolism of these agents, including their potential to influence the metabolism of other medications, is reviewed. Clozapine appears to be metabolized primarily by CYP1A2 and CYP3A4, with additional contributions by CYP2C19 and CYP2D6. In addition, clozapine may inhibit the activity of CYP2C9 and CYP2C19, and induce CYP1A, CYP2B and CYP3A. Risperidone is metabolized by CYP2D6, and possibly CYP3A4. In vitro data indicate that olanzapine is metabolized by CYP1A2 and CYP2D6. Quetiapine is metabolised by CYP3A4 and sertindole by CYP2D6. There is, however, a general paucity of in vivo data regarding the metabolism of the atypical antipsychotics, indicating a need for further research in this area.

Hospital outcome measures following assertive community treatment in Edmonton, Alberta.

OBJECTIVE: To examine hospital outcome measures for individuals with chronic and severe mental illnesses before and after their registration in an assertive community treatment (ACT) program in Edmonton, Alberta. METHODS: Data were collected from Alberta Health on individuals who were registered in ACT from April 1993 to April 1995. For each individual, hospital outcome measures were calculated for the 365 days prior to and 365 days after registration for ACT (thus covering April 1, 1992-March 31, 1996). RESULTS: Data were collected from 295 individuals. Compared with 1 year prior to beginning ACT, there was a 34% reduction in hospital separations for patients with psychiatric diagnoses. The average length of stay (LOS) for each separated patient decreased by 56%, and the hospitalization days for each patient separated also decreased by 39%. The number of emergency visits for psychiatric reasons was reduced by 32%, and the number of clients visiting emergency departments for psychiatric reasons declined by 30%. CONCLUSIONS: In the 1-year period after registration in an ACT program, hospital outcome measures were improved in this cohort of 295 individuals with severe and chronic mental illnesses.

Gd(DTPA-BBA) as a contrast agent in magnetic resonance imaging in rats.

Gadolinium (III)-di(benzyl carbamoylmethyl) diethylenetrinitrilotriacetic acid [Gd(DTPA-BBA)] is a newly developed paramagnetic complex designed for use as a hepatobiliary-specific contrast agent. The purpose of this study was to examine the relaxivity, biodistribution, and magnetic resonance (MR) imaging characteristics of Gd(DTPA-BBA) in rats. Our results showed that the T1 relaxivity of Gd(DTPA-BBA) (3.89 dm3/mmol/s in aqueous solution) was similar to that of Gd(III) diethylenetriamine-pentaacetate [Gd(DTPA)]2- (4.08 dm3/mmol/s) and Gd(III) benzyloxypropionicte-traacetate [Gd(BOPTA)]2- (4.40 dm3/mmol/s). Biodistribution studies indicated that Gd(DTPA-BBA) exhibited hepatobiliary and urinary elimination. In MR imaging studies, Gd(DTPA-BBA) provided biphasic enhancement of normal liver parenchyma, which was characterized by an initial steep increase in enhancement followed by a plateau. The initial relative enhancement (RE%) of the liver, at 1 minute after administration of 0.2 mmol/kg Gd(DTPA-BBA) was 113 +/- 19. The plateau RE% of the liver (48 +/- 13) occurred within 10 minutes and persisted for at least 60 minutes after injection of the contrast agent. In addition, Gd(DTPA-BBA) provided better RE% of the liver than [Gd(DTPA)]2-. The contrast RE% of liver abscess capsules reached a plateau within 5 minutes after injection of 0.1 mmol/kg Gd(DTPA-BBA). Although the hepatic enhancement of Gd(DTPA-BBA) was inferior to that of [Gd(BOPTA)]2-, the results suggest that Gd(DTPA-BBA) has potential as an MR contrast agent for nonspecific and hepatobiliary uses.