| 1 | J Clin Pharmacol 2000 Nov 40: 1296-7 |
|---|---|
| PMID | 11075316 |
| Title | Effect of chlorpromazine and clozapine on plasma concentrations of haloperidol in a patient with schizophrenia. |
| Abstract | A 40-year-old patient being treated for schizophrenia developed elevated plasma levels of haloperidol (HAL) in combination with chlorpromazine (CPZ) and during overlap treatment with clozapine. Competitive inhibition of HAL by first CPZ and then clozapine is discussed as a possible mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 2 | Hum Psychopharmacol 2000 Mar 15: 79-85 |
| PMID | 12404336 |
| Title | Extrapyramidal symptoms and residual psychopathology with low-dose neuroleptics. |
| Abstract | Residual psychopathology associated with EPS has been mainly assessed in experimental studies where neuroleptics were administered at standard, fixed dosages. The present study evaluates residual psychopathology in 69 schizophrenic patients treated with moderate, flexible doses of neuroleptics (430 mg eq. CPZ) at the out-patient Community Mental Health Services (CMHSs) in Bologna. Akathisia was present in 27.5 per cent of patients and parkinsonism in 27.5 per cent. A more severe psychopathological state was associated with both side-effects, as seen by significantly higher BPRS global scores. This severity was due to tension and anxiety-depression symptoms in patients with akathisia and to negative symptomatology in patients with parkinsonism, as shown by significant associations with BPRS subscales ANS-DEP and NEG, respectively. In conclusion, the present study underlines that EPS are frequent even in an out-patient setting where moderate neuroleptic doses are employed, and more importantly shows that in these conditions, the residual psychopathology resulting from EPS is clinically very significant. Copyright 2000 John Wiley & Sons, Ltd. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 3 | Fortschr Neurol Psychiatr 2000 Jul 68: 321-31 |
| PMID | 10945158 |
| Title | [Clinical characteristics of patients with tardive dyskinesias]. |
| Abstract | Although there is a great number of studies on the relationship between tardive dyskinesia and patient characteristics, too often their validity is impaired by the lack of operationalized criteria for the description of patients and signs. Reliable phenotyping is of utmost importance for linking clinical data with data from methods in neurobiology or molecular genetics. 241 patients with the DSM IV diagnosis "schizophrenia" or "schizoaffective disorder" were examined with the instruments SADS-L, OPCRIT, BPRS and PANSS. Motor phenomena were analyzed on 2 separate days within 3 months with the scales TDRS, AIMS, SAS, BAS. Tardive dyskinesia was diagnosed following the research criteria of Schooler and Kane. Lifetime medication with neuroleptics and anticholinergic drugs was assessed quantitatively. 97 out of 233 patients (= 41.6%) displayed persistent tardive dyskinesia. In univariate analysis, significant associations were found between tardive dyskinesia and the following independent variables (higher values means greater risk): Age (p = 0.0001), years from onset of the disorder (p = 0.001), total length of stay in hospital (p = 0.001), PANSS (single scales and sum score) (p = 0.0001), total amount of neuroleptics expressed as CPZ equivalents (p = 0.004). Logistic regression analysis showed that only the variables "age" and "negative symptoms" expressed as score on the PANSS negative subscale showed an association with tardive dyskinesia that could not be explained by covariation with other variables. The same results were found when, instead of the dichotomous variable "tardive dyskinesia yes/no" the associations with the TDRS score were analyzed. Future research should aim to approach the neurobiological correlates of "age" and "negative symptoms" in relationship to tardive dyskinesia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 4 | Behav Pharmacol 2000 Jun 11: 317-30 |
| PMID | 11103886 |
| Title | Neuropsychological and conditioned blocking performance in patients with schizophrenia: assessment of the contribution of neuroleptic dose, serum levels and dopamine D2-receptor occupancy. |
| Abstract | Patients with schizophrenia show impairments of attention and neuropsychological performance, but the extent to which this is attributable to antipsychotic medication remains largely unexplored. We describe here the putative influence of the dose of antipsychotic medication (chlorpromazine equivalents, CPZ), the antipsychotic serum concentration of dopamine (DA) D2-blocking activity and the approximated central dopamine D2-receptor occupancy (DA D2-occupancy), on conditioned blocking (CB) measures of attention and performance on a neuropsychological battery, in 108 patients with schizophrenia (compared with 62 healthy controls). Antipsychotic serum concentration and D2-occupancy were higher in patients with a paranoid versus non-paranoid diagnosis, and in female versus male patients (independent of symptom severity). Controlling for D2-occupancy removed the difference between high CB in paranoid and impaired low CB in non-paranoid patients. Similar partial correlations for antipsychotic drug dose and serum levels of DA D2-blocking activity with performance of the trail-making and picture completion tests (negative) and the block-design task (positive) showed the functional importance of DA-related activity. High estimates of central DA D2-occupancy were related to impaired verbal fluency but were associated with improved recall of stories, especially in paranoid patients. This, the first study of its kind, tentatively imputes a role for DA D2-related activity in left frontal (e.g. CB, verbal fluency) and temporal lobe functions (verbal recall) as well as in some non-verbal abilities mediated more in the right hemisphere in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 5 | Schizophr Bull 2002 -1 28: 607-17 |
| PMID | 12795494 |
| Title | Antipsychotic dosing and concurrent psychotropic treatments for Medicaid-insured individuals with schizophrenia. |
| Abstract | Antipsychotic medications have been first line treatment for schizophrenia for half a century, yet few studies have assessed outpatient maintenance treatment in large populations. This article describes oral antipsychotic dosing patterns and psychotropic treatments using computerized Medicaid claims data for individuals who were diagnosed with schizophrenia and received treatment on an outpatient basis during 1991. The findings show that the mean daily oral antipsychotic dose was 729 +/- 586 chlorpromazine equivalents (CPZ-EQ) for high-potency agents and 304 +/- 328 CPZ-EQ for low-potency agents. Males, younger individuals, and African-Americans received larger mean daily doses of high-potency agents, ranging from 747 to 800 CPZ-EQ. Antiparkinsonian agents were prescribed for over 90 percent of the outpatient antipsychotic treatment exposure. In summary, young adults, males, and African-Americans were given high-potency antipsychotic medications at outpatient maintenance doses that exceeded the maximum recommended levels, despite well-established evidence that high-dose treatment offers no additional benefit. Likewise, concurrent antiparkinsonian treatment exceeded the 1990 World Health Organization recommendations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 6 | Pharmacopsychiatry 2002 Mar 35: 37-43 |
| PMID | 11951144 |
| Title | A case control study on psychopharmacotherapy before suicide committed by 61 psychiatric inpatients. |
| Abstract | The pharmacotherapy of 61 suicide victims (0.24 % of 27,078 admissions from January 1, 1980 to December 31, 1999) was compared to that of a control group matched for age, gender and diagnosis at the time of discharge. Both groups were also comparable regarding stay in hospital, history of psychiatric disease, and frequency of hospitalisations during the year preceding the index evaluation. Multiple but not single suicide attempts were significantly more frequent in patients who were later to complete the suicide than in controls. schizophrenia (ICD-9, ICD-10) was the most frequent diagnosis among suicide victims (44.3 %). Affective psychosis (ICD-9, ICD-10) bore the highest relative risk (0.8 %). 50 % of the schizophrenic patients in the suicide group had been continuously treated with full-dose tricyclic antidepressants. The CPZ-equivalents in the patients treated with antipsychotics were not of discriminating value. Four of 27 schizophrenic patients in the suicide group had been off neuroleptics for ten days or more; this was never observed among the controls. Lorazepam applied in 40% of the schizophrenic and in 25 % of the affective psychosis suicide victims had more often been withdrawn or reduced during the ten days preceding suicide than among controls. No schizophrenic suicide victims but five controls had been on mood stabilisers. The use of antipsychotics (classical and atypical) and a recent change in tricyclic drug or drug dose were more frequent in suicide victims with affective psychosis. Lithium had been given to one patient, but it had also been administered to six controls; this difference is significant. Mood stabilisers, especially lithium, should be considered more often in patients with previous suicide attempt(s). When changing antidepressants in affective psychosis, benzodiazepines might be given more deliberate consideration. Patients in all diagnostic categories should be closely guided by means of intensified psychotherapeutic interventions while undergoing a benzodiazepine reduction. The treatment of patients suffering from schizophrenia with full-dose tricyclic regimens should be considered as possibly enhancing the acute suicide risk in some individuals. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 7 | Pharmacopsychiatry 2002 Mar 35: 37-43 |
| PMID | 11951144 |
| Title | A case control study on psychopharmacotherapy before suicide committed by 61 psychiatric inpatients. |
| Abstract | The pharmacotherapy of 61 suicide victims (0.24 % of 27,078 admissions from January 1, 1980 to December 31, 1999) was compared to that of a control group matched for age, gender and diagnosis at the time of discharge. Both groups were also comparable regarding stay in hospital, history of psychiatric disease, and frequency of hospitalisations during the year preceding the index evaluation. Multiple but not single suicide attempts were significantly more frequent in patients who were later to complete the suicide than in controls. schizophrenia (ICD-9, ICD-10) was the most frequent diagnosis among suicide victims (44.3 %). Affective psychosis (ICD-9, ICD-10) bore the highest relative risk (0.8 %). 50 % of the schizophrenic patients in the suicide group had been continuously treated with full-dose tricyclic antidepressants. The CPZ-equivalents in the patients treated with antipsychotics were not of discriminating value. Four of 27 schizophrenic patients in the suicide group had been off neuroleptics for ten days or more; this was never observed among the controls. Lorazepam applied in 40% of the schizophrenic and in 25 % of the affective psychosis suicide victims had more often been withdrawn or reduced during the ten days preceding suicide than among controls. No schizophrenic suicide victims but five controls had been on mood stabilisers. The use of antipsychotics (classical and atypical) and a recent change in tricyclic drug or drug dose were more frequent in suicide victims with affective psychosis. Lithium had been given to one patient, but it had also been administered to six controls; this difference is significant. Mood stabilisers, especially lithium, should be considered more often in patients with previous suicide attempt(s). When changing antidepressants in affective psychosis, benzodiazepines might be given more deliberate consideration. Patients in all diagnostic categories should be closely guided by means of intensified psychotherapeutic interventions while undergoing a benzodiazepine reduction. The treatment of patients suffering from schizophrenia with full-dose tricyclic regimens should be considered as possibly enhancing the acute suicide risk in some individuals. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 8 | Schizophr. Res. 2003 Jan 59: 73-6 |
| PMID | 12413645 |
| Title | Negative symptoms and neuroleptics in catatonic schizophrenia. |
| Abstract | The association between neuroleptic treatment and the negative symptom dimension (ND) was evaluated in 1528 schizophrenia patients. In patients receiving more than 820 mg chlorpromazine (CPZ), those with catatonic-type disorder had significantly (p<0.05) higher ND scores than those in any of the other diagnostic subtypes. Even in patients receiving 450 mg CPZ or more, catatonic patients had significantly (p=0.046) higher ND scores than other patients. Patients with catatonic schizophrenia are highly vulnerable to negative symptoms related to neuroleptic drugs, probably because of a defect in their dopaminergic neuronal pathways. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 9 | Eur Arch Psychiatry Clin Neurosci 2003 Apr 253: 84-8 |
| PMID | 12799746 |
| Title | Premorbid IQ and schizophrenia. Increasing cognitive reduction by episodes. |
| Abstract | In order to test the hypothesis that acute schizophrenia episodes have a negative impact on cognitive function, 35 consecutive non-abuse schizophrenia outpatients (age < 60) were enrolled in this study. All subjects for whom grades from the 9(th) year of the Swedish school system were available, had to complete a comprehensive computerized neuropsychological test session. Symptoms were rated by PANSS and GAF, previous episodes were tallied, and medication was logged. A premorbid cognitive score was calculated on the basis of school grades and validated by comparison with academic career and current cognitive performance (r = 0.56). Half had college level studies or higher, and the overall school grades for the group were above average. PANSS (sum = 59) and GAF [59] ratings as well as medication (M = 230 CPZ units) suggested a moderate symptom level. Two patients had no neuroleptic drugs, 16 had atypical and 17 had conventional neuroleptics. Vocabulary was intact. On average, patients had lost 1 standard deviation (SD) in most cognitive tests but response time slowing amounted to 3.5 SD. There were no differences in cognition between drug types and no correlation with CPZ dose. The number of previous episodes was positively correlated with reaction time prolongation and negatively correlated with short-term verbal memory, consistent with a previous study suggesting that acute episodes cause specific cognitive reduction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 10 | Neuropsychopharmacology 2003 May 28: 995-1003 |
| PMID | 12700715 |
| Title | Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. |
| Abstract | The purported advantages of second-generation or "atypical" antipsychotics relative to first-generation antipsychotics have not been examined in patients with a first episode of schizophrenia. This flexible-dose study examined efficacy and safety in a randomized, double-blind, 52-week trial, comparing chlorpromazine (CPZ) and clozapine (CLZ) in treatment naive patients experiencing their first episode of schizophrenia. In all, 160 inpatients with first-episode schizophrenia or schizophreniform disorder were randomized to CPZ or CLZ and followed them for 52 weeks or until dropout. The primary efficacy measure was time to first remission and proportion of time remaining in remission. The analysis was supplemented by comparisons on a profile of clinical symptoms and side effects. Of these first-episode patients, 80% achieved remission within 1 year (79% CPZ, 81% CLZ). The Kaplan-Meier estimated median time to first remission was 8 weeks for CLZ vs 12 weeks for CPZ (chi(2)(1)=5.56, p=0.02). Both the rate of first achieving remission and the odds for being in remission during the trial were almost doubled for the CLZ group in comparison with the CPZ group. At 12 weeks, CLZ was superior on many rating scale measures of symptom severity while CPZ was not superior on any. These symptom differences remained significant when controlling for EPS differences. By 52 weeks many of the symptom differences between groups were no longer significantly different. Generally, CLZ produced fewer side effects than CPZ, particularly extrapyramidal side effects. There was no significant difference between treatments in weight change or glucose metabolism. For each prior year of untreated psychosis, there was a 15% decrease in the odds of achieving remission (OR=0.85; CI 0.75-0.95). A high proportion of first-episode patients remitted within 1 year. We detected no difference in the proportion of first-episode patients receiving CLZ or CPZ that achieved remission. However, first-episode patients receiving CLZ remitted significantly faster and remained in remission longer than subjects receiving CPZ. While the CLZ group showed significantly less symptomatology on some measures and fewer side effects at 12 weeks, the two treatment groups seemed to converge by 1 year. Longer duration of untreated psychosis was associated with lower odds of achieving remission. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 11 | Psychiatry Clin. Neurosci. 2004 Jun 58: 324-9 |
| PMID | 15149301 |
| Title | Clinical correlates of antipsychotic polytherapy in patients with schizophrenia in Singapore. |
| Abstract | The purpose of the present study wa to determine the prevalence of antipsychotic polytherapy (use of more than one antipsychotic drug at one time) and its clinical correlates among 300 hospitalized psychotic Asian patients diagnosed with schizophrenia. It was hypothesized that such treatment would be associated with more severe illness than in comparable monotherapy patients, and with higher chlorpromazine-equivalent (CPZ) total daily doses. Clinical and demographic details were obtained from the medical records and direct clinical examinations. Polytherapy was encountered in 215 of the 300 patients (71.7%), with an average number of 1.8 antipsychotics (range 1-4) prescribed at a mean CPZ daily dose of 612 +/- 528 mg (median: 464 mg, range: 25-2500 mg). The 215 patients prescribed more than one antipsychotic agents were younger, ill longer, more likely to be taking at least one high-potency agent, in receipt of higher average daily CPZ doses, and more likely to be prescribed anticholinergic agents but with similar admission illness severity rating (Brief Psychiatric Rating Scale) scores compared to the 85 patients given only one antipsychotic drug at one time. The high rate of antipsychotic polytherapy that appeared to be unrelated to current illness severity suggests that this practice may not consistently be based on rational therapeutic principles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 12 | Br J Clin Pharmacol 2004 Aug 58: 178-83 |
| PMID | 15255800 |
| Title | Antipsychotic polypharmacy in patients with schizophrenia: a multicentre comparative study in East Asia. |
| Abstract | Previous studies of the prescription patterns of psychotropic medications in patients with schizophrenia have highlighted a high rate of antipsychotic polypharmacy, but data in Asia are sparse. This study seeks to examine the prevalence of antipsychotic polypharmacy in patients with schizophrenia and compare the differences between patients receiving one vs. those receiving more than one antipsychotic. Antipsychotic prescription for a sample of 2399 patients with schizophrenia from six countries and territories was evaluated. Daily doses of antipsychotic medications were converted to standard chlorpromazine equivalents (CPZ). Antipsychotic polypharmacy was found in 45.7% (n = 1097) of the patients with wide intercountry variations. Polypharmacy was associated with male gender [odds ratio (OR) 1.24, 95% confidence interval (CI) 1.06, 1.46, P < 0.01], advanced age (t = -7.81, d.f. = 2396, P < 0.001), psychiatric hospital setting (OR 1.34, 95% CI 1.11, 1.62) as well as higher daily CPZeq doses (411.47 vs. 983.10 CPZeq day(-1), z = -25.94, P < 0.001), anticholinergic use (OR 3.17, 95% CI 2.65, 3.79, P < 0.001) and less use of an atypical antipsychotic drug (OR 0.83, 95% CI 0.71, 0.98, P < 0.05). On multivariate analysis, country, age and duration of illness were significantly associated with antipsychotic polypharmacy. This study highlighted the wide intercountry variations of antipsychotic polypharmacy which are likely to be influenced by a complex combination of clinical, setting, cultural and personal practice factors, requiring more research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 13 | J ECT 2004 Jun 20: 99-106 |
| PMID | 15167426 |
| Title | One-year outcome after response to ECT in middle-aged and elderly patients with intractable catatonic schizophrenia. |
| Abstract | ECT is one of the most efficacious treatments for catatonic schizophrenia. However, there has been no study on the efficacy of ECT in elderly patients with catatonic schizophrenia. Thus, we conducted prospective studies on the short-term (phase 1 study) and long-term (phase 2 study) effects of acute ECT on intractable catatonic schizophrenia in middle-aged and elderly patients. The phase 1 study included 11 consecutive patients over 45 years of age who fulfilled the DSM-IV criteria for catatonic schizophrenia and were referred to Tohoku University Hospital for the first time for acute ECT between January 1, 1998, and August 31, 2003, after other treatments had failed. We evaluated the clinical response of these patients to acute ECT by means of the Brief Psychiatric Rating Scale (BPRS). We also evaluated adverse effects of acute ECT. The patient or guardian provided written informed consent. Exclusion criterion was a history of dementia or substance abuse. Patients were considered clinical responders if they had a BPRS score ;ek 25 for 1 week after the final ECT session. The phase 2 study included 11 consecutive patients who responded to acute ECT in the phase 1 study. Patients provided written informed consent. Patients' BPRS scores were evaluated weekly (18 items, rated 0-6) for 48 weeks or until relapse/recurrence, during which time they received pharmacotherapy. Patients were considered clinical "relapsers" if they had a BPRS score of at least 37 for 3 consecutive days. Differences in clinical characteristics between patients with and without recurrence were analyzed statistically by the Mann-Whitney U test. All 11 patients completed the phase 1 study, and the acute ECT response rate was 100%. No patient experienced a severe adverse cognitive or physical effect during the course of acute ECT. All 11 patients also completed the phase 2 study. The mean dose of continuation neuroleptics in all 11 cases was 296.8 +/- 277.6 mg (range, 0-982 mg) (chlorpromazine [CPZ] equivalent). Relapse occurred in 7 cases, and all occurred within 6 months. The 1-year recurrence rate was 63.6%. The mean (+/-SD) relapse prevention time in the 7 cases was 76.0 +/- 64.7 days (range, 11-163 days). A significant difference in daily neuroleptic dose before acute ECT was found between the patients suffering recurrence and those not suffering recurrence (766.7 +/- 521.8 CPZ-equivalent mg with recurrence versus 101.9 +/- 75.2 CPZ-equivalent mg without recurrence, U = 2.0, P = 0.923). There was a trend toward a lower Global Assessment of Functioning (GAF) score just before ECT (7.3 +/- 4.0 with recurrence versus 16.8 +/- 11.2 without recurrence, U = 4.5, P = 0.073). The short-term efficacy of acute ECT for middle-aged and elderly patients with intractable catatonic schizophrenia is excellent. However, the 1-year recurrence rate, especially the 6-month relapse rate, after response to acute ECT is high, despite continuation pharmacotherapy. The need for more effective relapse-prevention strategies, such as continuation ECT, is urgent. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 14 | Hum Psychopharmacol 2004 Mar 19: 103-9 |
| PMID | 14994320 |
| Title | Depot antipsychotic use in schizophrenia: an East Asian perspective. |
| Abstract | Few studies have examined the use of depot antipsychotics in East Asian patients with schizophrenia. This study examined the prevalence of depot antipsychotic use and its clinical correlates. Across six East Asian countries and territories, 2399 patients with schizophrenia were surveyed using a standardized protocol. Depot antipsychotic medications were prescribed in 15.3% (n=368) of the patients, being the most common in Singapore, followed by Taiwan, Japan and China. Being on depot antipsychotic drugs was significantly associated with male gender (particularly in Taiwan and Japan), delusions in Japan, aggression, higher daily CPZ equivalent dose and co-prescription of anticholinergic drugs but less likely with disorganized speech (particularly in China) and negative symptoms (particularly in Japan and Singapore). On multivariate analysis, the significant associated factors were treatment setting, younger age, longer duration of illness, aggression and the lack of use of an oral, atypical antipsychotic. There was a wide variation in the prevalence of depot antipsychotic prescription, suggesting that it may not be guided by any recognizable principles and is more likely determined by local traditions and prescription culture. There is a need to re-examine the risk-benefit profile of each patient before deciding on the initiation or continuation of depot antipsychotic medication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 15 | BMC Med 2005 -1 3: 15 |
| PMID | 16229742 |
| Title | Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials. |
| Abstract | Chlorpromazine (CPZ) remains one of the most common drugs used for people with schizophrenia worldwide, and a benchmark against which other treatments can be evaluated. Quantitative reviews are rare; this one evaluates the effects of chlorpromazine in the treatment of schizophrenia in comparison with placebo. We sought all relevant randomised controlled trials (RCT) comparing chlorpromazine to placebo by electronic and reference searching, and by contacting trial authors and the pharmaceutical industry. Data were extracted from selected trials and, where possible, synthesised and random effects relative risk (RR), the number needed to treat (NNT) and their 95% confidence intervals (CI) calculated. Fifty RCTs from 1955-2000 were included with 5276 people randomised to CPZ or placebo. They constitute 2008 person-years spent in trials. Meta-analysis of these trials showed that chlorpromazine promotes a global improvement (n = 1121, 13 RCTs, RR 0.76 CI 0.7 to 0.9, NNT 7 CI 5 to 10), although a considerable placebo response is also seen. People allocated to chlorpromazine tended not to leave trials early in both the short (n = 945, 16 RCTs, RR 0.74 CI 0.5 to 1.1) and medium term (n = 1861, 25 RCTs, RR 0.79 CI 0.6 to 1.1). There were, however, many adverse effects. Chlorpromazine is sedating (n = 1242, 18 RCTs, RR 2.3 CI 1.7 to 3.1, NNH 6 CI 5 to 8), increases a person's chances of experiencing acute movement disorders, Parkinsonism and causes low blood pressure with dizziness and dry mouth. It is understandable why the World Health Organization (WHO) have endorsed and included chlorpromazine in their list of essential drugs for use in schizophrenia. Low- and middle-income countries may have more complete evidence upon which to base their practice compared with richer nations using recent innovations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 16 | Hum Psychopharmacol 2005 Oct 20: 485-92 |
| PMID | 16116665 |
| Title | Use of combinations of antipsychotics: McLean Hospital inpatients, 2002. |
| Abstract | The empirical use of combinations of antipsychotic agents appears to be increasing with little research support for the relative efficacy, safety or cost-effectiveness of this practice. Such treatment was evaluated in hospitalized psychiatric patients. Samples of consecutive inpatients treated with > or = 2 ('polytherapy') vs 1 antipsychotic ('monotherapy') were matched on age, sex, diagnosis and admission clinical ratings, and these groups were compared on total daily chlorpromazine-equivalent doses, days in hospital, and changes in clinical ratings between admission and discharge. The study sample included 69 polytherapy and 115 well-matched monotherapy subjects. Despite matching for initial CGI and GAF ratings, polytherapy was associated with high PANSS subscale scores of positive symptoms among affective psychosis, and relatively greater PANSS subscale ratings of excitement-agitation among patients diagnosed with schizophrenia. Estimated clinical improvement during hospitalization was similar among poly- and monotherapy patients, but total daily CPZ-eq doses at discharge averaged twice-greater with polytherapy, and hospitalization lasted 1.5 times longer. Antipsychotic polytherapy as well as the types of agents combined may reflect clinician responses to particular symptom patterns. The value of specific combinations of antipsychotic agents and their comparison with monotherapies requires specific, prospective, randomized and well-controlled trials that consider matching on clinical characteristics and truly comparable doses across regimens. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 17 | Schizophr. Res. 2006 Feb 82: 95-106 |
| PMID | 16442781 |
| Title | Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus. |
| Abstract | The results of mostly short-term treatment studies in human patients and animals suggest that second-generation antipsychotics (SGAs) such as risperidone (RISP) and olanzapine (OLZ) compared to first-generation antipsychotics (FGAs) such as haloperidol (HAL) and chlorpromazine (CPZ) have neuroprotective effects. The animal studies indicate that these effects are probably mediated through increased expression of neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). However, since antipsychotics are commonly used for very long-term treatment periods, particularly in schizophrenic patients, it is important to measure the effects of chronic administration of antipsychotic drugs on the aforementioned growth factors. This study determined the effects of 90- and 180-day treatments with two FGAs, HAL and CPZ, and two SGAs, RISP and OLZ, on the levels of NGF and BDNF protein in hippocampus and striatum of rat. Furthermore, since a preliminary study showed that 90-day treatment of HAL caused significant reductions in the expression of both NGF and BDNF the HAL-treated animals were then switched to SGAs for the next 90 days to assess the potential for restoration of trophic factor levels. After the 90-day treatment, NGF levels in the hippocampus were reduced by 60-70% with HAL or CPZ, and by only 25-30% with RISP or OLZ compared to levels with vehicle only. After the 180-day treatment, NGF levels were further reduced with HAL, RISP, and OLZ, but not with CPZ. The magnitude of the NGF decreases in the striatum was larger (70-90%) with all the antipsychotics compared to the hippocampus. However, the pattern of BDNF changes in the hippocampus differed significantly from the striatum after 90- or 180-day treatment with the antipsychotics. In hippocampus, compared to controls, BDNF levels remained unchanged with OLZ both after 90 and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with HAL or CPZ and intermediate decreases were observed with RISP after 90 days of treatment that continued to decline up to 180 days. Furthermore, switching HAL animals after 90 days of treatment to either RISP or OLZ for the next 90 days significantly restored levels of both NGF and BDNF in both the brain regions. These data indicate that SGAs compared to FGAs induce less deleterious effects on neurotrophic factor levels in the brain and may also offer ability to reverse the more pronounced negative effects of FGAs as well. These data may have significant clinical implications for long-term antipsychotic selection as well as the common practice of antipsychotic switchover. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 18 | J Psychiatry Neurosci 2006 Jul 31: 271-9 |
| PMID | 16862245 |
| Title | Levomepromazine versus chlorpromazine in treatment-resistant schizophrenia: a double-blind randomized trial. |
| Abstract | We compared the effect of levomepromazine (LMP) with chlorpromazine (CPZ) in treatment-resistant schizophrenia (TRS). We carried out a double-blind, parallel group study (n = 19/arm) with balanced randomization in blocks of 4 and stratification by sex. Subjects entered a 30-week trial, of which phases I-III were open: phase I (wk 0-6) baseline; phase II (wk 7-9) stepwise transition to haloperidol (HAL), 30 mg/d, plus benztropine (BT), 4 mg/d; phase III (wk 10-15) HAL, 40-60 mg/d, plus BT, 4-6 mg/d; phase IV (wk 16-20) stepwise transition to LMP or CPZ (500 mg/d) following randomization; phase V (wk 21-28) stepwise increase of LMP or CPZ (600-1000 mg/d, dose reduction permitted) to establish optimum dose; and phase VI (wk 29-30) optimized dose maintained. Criteria for TRS were based on those established by Kane et al in 1988. The criterion for a response to treatment was a reduction of 25% or more in total Brief Psychiatric Rating Scale score. Both LMP (p = 0.007) and CPZ (p = 0.030) improved TRS relative to baseline. Although there was no significant difference between the 2 groups in treatment response at study end point, hierarchical linear modelling of longitudinal outcome revealed a significant (p = 0.006) advantage of LMP over CPZ for the BPRS total score. Ten of 19 participants on LMP and 8 of 19 on CPZ met the criterion for treatment response, and 9 of the 18 responders did so on 200-700 mg/d phenothiazine. The mean dose of responders was 710 (standard deviation [SD] 265) mg/d (LMP) and 722 (SD 272) mg/d (CPZ). Akathisia was associated with a nonresponse to phenothiazines (p = 0.010). BPRS scores increased significantly on HAL (p = 0.006). Two of 19 participants on LMP and 5 of 19 on CPZ withdrew early from the study. LMP and CPZ may be useful in the management of TRS. A modest advantage of LMP compared with CPZ was seen in longitudinal analysis. High doses of neuroleptics may contribute to TRS; reduction of neuroleptics to modest or moderate doses should be considered before categorizing a patient as treatment resistant. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 19 | Med Care 2006 Sep 44: 827-34 |
| PMID | 16932134 |
| Title | Associations between adherence to guidelines for antipsychotic dose and health status, side effects, and patient care experiences. |
| Abstract | One approach to improving quality of care is to encourage physicians to follow evidence-based practice guidelines. Examples of evidence-based guidelines are the PORT recommendations for the treatment of schizophrenia. However, few studies have examined the relationship between adherence to guidelines and patient outcomes in clinical settings. The purpose of this article is to report the relationship between guideline adherence to antipsychotic medication dose and self-reported health status, side effects, and perceptions of care. This report is based on a subsample of patients from a larger prospective observational study of disabled Massachusetts Medicaid beneficiaries treated for schizophrenia. Participants were 329 acutely ill, vulnerable, high-risk Medicaid adult beneficiaries enrolled after visiting any 1 of 8 psychiatric emergency screening teams for hospital admission evaluation. Dose levels, symptoms, and functioning from medical records; self-reports as data collected from BASIS-32, SF-12, and CABHS; and paid health benefit claims for psychiatric treatment were measured. Approximately 40% of the patients in this study had daily antipsychotic doses well above the recommended range, but there was no evidence that their health status was better than those on doses below 1000 CPZ units recommended for acute episodes. High-dose levels had no relationship to baseline symptom profile or referral source. There was no evidence that health status was better on higher-than-recommended doses, but we cannot conclude that lower doses for some would have led to poorer outcomes. Physicians who believe that higher doses are more therapeutic for patients need to demand rigorous effectiveness research that tests whether there are benefits of higher doses and determine the ratio of those benefits to the clinical costs, including the risk of side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 20 | Psychiatry Res 2007 May 151: 11-20 |
| PMID | 17292483 |
| Title | Early and late auditory sensory gating: moderating influences from schizotypal personality, tobacco smoking status, and acute smoking. |
| Abstract | Early (P50) and late (P200) auditory sensory gating were assessed in low and high schizotypal personality groups using Raine's schizotypal Personality Questionnaire. We also assessed the impact of smoking as it relates to low and high schizotypal personalities. Low and high schizoptypal personality groups were divided into subgroups of participants who either smoked or did not smoke tobacco cigarettes. Participants were 39 (18 men) right-handed undergraduates. Using a paired-tone paradigm (40 pairs, 70 dB, 1000 Hz), smokers were tested while abstaining from smoking, and 5 min after smoking. Non-smokers were tested similarly without smoking. Midline and hemispheric sites were evaluated at frontal (F3/Fz/F4), fronto-central (FC3/FCz/FC4), central (C3/Cz/C4), centro-parietal (CP3/CPZ/CP4), and parietal (P3/Pz/P4) regions. P50 sensory gating was better at midline sites than left/right hemispheric sites, whereas there was no difference in activation with respect to location for P200 sensory gating. Cz had better P50 sensory gating than other midline regions, whereas Fz, FCz and Cz had better P200 sensory gating than CPZ and Pz. Hemispheric comparisons were made. At the central region for non-smokers, high schizotypys showed poorer P50 sensory gating than low schizotypys. Among low schizotypys, smokers showed poorer P50 sensory gating than non-smokers at the fronto-central and central regions smokers showed better P200 sensory gating than non-smokers at the central region. Smoking had no acute impact on either early (P50) or late (P200) sensory gating. Our data support the notion that early sensory gating and late sensory gating represent different sensory gating mechanisms with respect to low and high schizotypy personalities. Individual differences in early and late sensory gating need further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 21 | Psychiatry Res 2007 May 151: 11-20 |
| PMID | 17292483 |
| Title | Early and late auditory sensory gating: moderating influences from schizotypal personality, tobacco smoking status, and acute smoking. |
| Abstract | Early (P50) and late (P200) auditory sensory gating were assessed in low and high schizotypal personality groups using Raine's schizotypal Personality Questionnaire. We also assessed the impact of smoking as it relates to low and high schizotypal personalities. Low and high schizoptypal personality groups were divided into subgroups of participants who either smoked or did not smoke tobacco cigarettes. Participants were 39 (18 men) right-handed undergraduates. Using a paired-tone paradigm (40 pairs, 70 dB, 1000 Hz), smokers were tested while abstaining from smoking, and 5 min after smoking. Non-smokers were tested similarly without smoking. Midline and hemispheric sites were evaluated at frontal (F3/Fz/F4), fronto-central (FC3/FCz/FC4), central (C3/Cz/C4), centro-parietal (CP3/CPZ/CP4), and parietal (P3/Pz/P4) regions. P50 sensory gating was better at midline sites than left/right hemispheric sites, whereas there was no difference in activation with respect to location for P200 sensory gating. Cz had better P50 sensory gating than other midline regions, whereas Fz, FCz and Cz had better P200 sensory gating than CPZ and Pz. Hemispheric comparisons were made. At the central region for non-smokers, high schizotypys showed poorer P50 sensory gating than low schizotypys. Among low schizotypys, smokers showed poorer P50 sensory gating than non-smokers at the fronto-central and central regions smokers showed better P200 sensory gating than non-smokers at the central region. Smoking had no acute impact on either early (P50) or late (P200) sensory gating. Our data support the notion that early sensory gating and late sensory gating represent different sensory gating mechanisms with respect to low and high schizotypy personalities. Individual differences in early and late sensory gating need further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 22 | J Psychiatr Res 2007 Aug 41: 372-86 |
| PMID | 16564057 |
| Title | Long-term antipsychotic treatments and crossover studies in rats: differential effects of typical and atypical agents on the expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. |
| Abstract | Short-term (<45 days) treatment studies in rats have reported increased oxidative stress and oxidative (i.e., oxygen free radical-mediated) neural cell injury with typical antipsychotics such as haloperidol, but not with the atypicals such as clozapine, olanzapine or risperidone. However, now these and several other atypical antipsychotics that differ in their neurotransmitter receptor affinity profiles are being used for a long-term treatment of schizophrenia. Therefore, understanding of their long-term treatment effects on the expression of antioxidant enzymes and oxidative neural cell injury in rats may be important to explain the possible differential mechanisms underlying their long-term clinical and side effects profiles. The effect of 90 and 180 day exposure to haloperidol (HAL, 2mg/kg/day), a representative typical antipsychotic was compared to exposure to chlorpromazine (CPZ, 10mg/kg/day), ziprasidone (ZIP, 12mg/kg/day), risperidone (RISP, 2.5mg/kg/day), clozapine (CLOZ, 20mg/kg/day) or olanzapine (OLZ, 10mg/kg/day) on the expression of antioxidant defense enzymes and levels of lipid peroxidation in the rat brain. The drug-induced effects on various antioxidant defense enzymes; manganese-superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT) were assessed by determination of their enzymatic activity and protein content. Immunohistochemical analysis was also carried out to assess the cellular levels of MnSOD and CuZnSOD and cellular morphology. The oxidative membrane damage was assessed by determination of levels of the lipid peroxidation product, hydroxyalkanals (HAEs) in the rat brain. Both 90 and 180 days of HAL treatment very significantly decreased the levels of MnSOD (50%) and CuZnSOD (80%) and increased the levels of HAEs compared to vehicle treatment. Smaller reduction was found in CAT (25%) and no change in the glutathione peroxidase (GSHPx). The levels of enzymatic activity correlated generally well with the levels of enzyme protein indicating that the changes were in the expression of net protein. Though atypical antipsychotics like ZIP, RISP and OLZ did not show any change in the HAEs levels up to 90 days, further treatment up to 180 days resulted in significantly increased levels of HAEs in CPZ, ZIP and RISP, but not in OLZ treated rats. Post-treatment with several atypical antipsychotics (OLZ=CLOZ>RISP) for 90 days after 90 day of HAL treatment significantly restored the HAL-induced loss in MnSOD and CuZnSOD activities and increase in lipid peroxidation products as well as cellular morphology. These data may be very helpful in planning long-term use as well as switch over of these antipsychotics for the management of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 23 | J Clin Psychiatry 2007 Jun 68: 854-61 |
| PMID | 17592908 |
| Title | Psychoeducation in schizophrenia: 7-year follow-up concerning rehospitalization and days in hospital in the Munich Psychosis Information Project Study. |
| Abstract | According to most of the relevant guidelines, psychoeducation is considered a basic part of routine therapy for patients with schizophrenia; scientific proofs of its efficacy are based mainly on the results of 1- and 2-year follow-ups. Therefore, the long-term effects of psychoeducation over a period of 7 years were investigated in regard to rehospitalization rates and hospital days. Of 101 patients with DSM-III-R or ICD-9 schizophrenia randomly allocated to either an intervention group or a control group between 1990 and 1994, 48 patients were available for follow-up after 7 years. During their index stay, the 24 patients of the intervention group and their key relatives each received a separate psychoeducational group therapy. The 24 patients of the control group received the usual treatment. After index discharge, all 48 patients received a comparable outpatient treatment. Main outcome measures were rehospitalization rate, number of intervening hospital days, compliance, and mean number of consumed chlorpromazine (CPZ) units. Seven years after index discharge, the rate of rehospitalization was 54% in the intervention group and 88% in the control group. The rate of rehospitalization per patient was 1.5 in the intervention group and 2.9 in the control group (p < .05). In the intervening period, the mean number of hospital days spent in a psychiatric hospital was 75 in the intervention group and 225 days in the control group. (p < .05). The mean number of consumed CPZ units after 7 years was 354 in the intervention and 267 in the control group. Seven years after psychoeducational group therapy, significant effects on the long-term course of the illness can be found. Therefore, the integration of psychoeducation into standard therapy for schizophrenia should become obligatory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 24 | Schizophr. Res. 2008 Dec 106: 182-91 |
| PMID | 18938062 |
| Title | Quetiapine alleviates the cuprizone-induced white matter pathology in the brain of C57BL/6 mouse. |
| Abstract | Recent human studies employing new magnetic resonance imaging techniques and micro-array analyses feature schizophrenia as a brain disease with alterations in white matter (WM), which is mainly composed of oligodendrocytes (OLs) and their processes wrapping around neuronal axons. To examine the putative role of OLs in the pathophysiology and treatment of schizophrenia, animal studies are essential. In the present study, C57BL/6 mice were given 0.2% cuprizone (CPZ) in their diet for five weeks during which they drank distilled water without or with quetiapine (QTP, 10 mg/kg). The mice fed with normal chow were used as controls. CPZ is a copper chelator and has been reported to induce consistent demyelination in the brain of C57BL/6 mouse by specifically damaging OLs. QTP is an atypical antipsychotic widely used in the treatment of schizophrenia and other psychotic disorders. In accordance with previous studies, CPZ-exposed mice showed pervasive myelin breakdown and demyelination. The amount of myelin basic protein (MBP) in the cerebral cortex was decreased by CPZ-exposure as shown in Western-blot analysis. In addition, the demyelinated sites were teemed with activated microglia and astrocytes but a few myelin forming OLs. Moreover, the activity of copper-zinc superoxide dismutase decreased in the cerebral cortex of CPZ-exposed mice. However, all of these pathological changes in WM were either prevented or alleviated in CPZ-exposed mice co-administered with QTP. These results suggest that the CPZ-exposed C57BL/6 mouse is a potential animal model to study possible roles of OLs in the pathogenesis and treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 25 | J. Pineal Res. 2008 Mar 44: 115-20 |
| PMID | 18289161 |
| Title | The co-catalytic effect of chlorpromazine on peroxidase-mediated oxidation of melatonin: enhanced production of N1-acetyl-N2-formyl-5-methoxykynuramine. |
| Abstract | Accumulating evidence points to relationships between increased production of reactive oxygen or decreased antioxidant protection in schizophrenic patients. Chlorpromazine (CPZ), which remains a benchmark treatment for people with schizophrenia, has been described as a pro-oxidant compound. Because the antioxidant compound melatonin exerts protective effects against CPZ-induced liver disease in rats, in this investigation, our main objective was to study the effect of CPZ as a co-catalyst of peroxidase-mediated oxidation of melatonin. We found that melatonin was an excellent reductor agent of preformed CPZ cation radical (CPZ(*+)). The addition of CPZ during the horseradish peroxidase (HRP)-catalyzed oxidation of melatonin provoked a significant increase in the rate of oxidation and production of N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK). Similar results were obtained using myeloperoxidase. The effect of CPZ on melatonin oxidation was rather higher at alkaline pH. At pH 9.0, the efficiency of oxidation of melatonin was 15 times higher and the production of AFMK was 30 times higher as compared with the assays in the absence of CPZ. We suggest that CPZ is able to exacerbate the rate of oxidation of melatonin by an electron transfer mechanism where CPZ(*+), generated during the peroxidase-catalyzed oxidation, is able to efficiently oxidize melatonin. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 26 | J. Pineal Res. 2008 Mar 44: 115-20 |
| PMID | 18289161 |
| Title | The co-catalytic effect of chlorpromazine on peroxidase-mediated oxidation of melatonin: enhanced production of N1-acetyl-N2-formyl-5-methoxykynuramine. |
| Abstract | Accumulating evidence points to relationships between increased production of reactive oxygen or decreased antioxidant protection in schizophrenic patients. Chlorpromazine (CPZ), which remains a benchmark treatment for people with schizophrenia, has been described as a pro-oxidant compound. Because the antioxidant compound melatonin exerts protective effects against CPZ-induced liver disease in rats, in this investigation, our main objective was to study the effect of CPZ as a co-catalyst of peroxidase-mediated oxidation of melatonin. We found that melatonin was an excellent reductor agent of preformed CPZ cation radical (CPZ(*+)). The addition of CPZ during the horseradish peroxidase (HRP)-catalyzed oxidation of melatonin provoked a significant increase in the rate of oxidation and production of N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK). Similar results were obtained using myeloperoxidase. The effect of CPZ on melatonin oxidation was rather higher at alkaline pH. At pH 9.0, the efficiency of oxidation of melatonin was 15 times higher and the production of AFMK was 30 times higher as compared with the assays in the absence of CPZ. We suggest that CPZ is able to exacerbate the rate of oxidation of melatonin by an electron transfer mechanism where CPZ(*+), generated during the peroxidase-catalyzed oxidation, is able to efficiently oxidize melatonin. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 27 | J. Proteome Res. 2009 Jul 8: 3633-41 |
| PMID | 19441803 |
| Title | A comparative proteomics analysis of rat mitochondria from the cerebral cortex and hippocampus in response to antipsychotic medications. |
| Abstract | An increasing number of experiments have found anomalies in mitochondria in the brains of psychotics, which suggests that mitochondrial dysfunction or abnormal cerebral energy metabolism might play an important role in the pathophysiology of schizophrenia (SCZ). We adopted a proteomic approach to identify the differential effects on the cerebral cortex and hippocampus mitochondrial protein expression of Sprague-Dawley (SD) rats by comparing exposure to typical and atypical antipsychotic medications. Differential mitochondrial protein expressions were assessed using two-dimensional (2D) gel electrophoresis for three groups with Chlorpromazine (CPZ), Clozapine (CLZ), quetiapine (QTP) and a control group. A total of 14 proteins, of which 6 belong to the respiratory electron transport chain (ETC) of oxidative phosphorylation (OXPHOS), showed significant changes in quantity including NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 10 (Ndufa10), NADH dehydrogenase (ubiquinone) flavoprotein 2 (Ndufv2), NADH dehydrogenase (ubiquinone) Fe-S protein 3 (Ndufs3), F1-ATPase beta subunit (Atp5b), ATPase, H+ transporting, lysosomal, beta 56/58 kDa, isoform 2 (Atp6v1b2) and ATPase, H+ transporting, V1 subunit A, isoform 1 (Atp6v1a1). The differential proteins subjected to 2D were assessed for levels of mRNA using quantitative real time PCR (Q-RT-PCR), and we also made partial use of Western blotting for assessing differential expression. The results of our study may help to explain variations in SD rats as well as in human response to antipsychotic drugs. In addition, they should improve our understanding of both the curative effects and side effects of antipsychotics and encourage new directions in SCZ research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 28 | Behav. Neurosci. 2009 Apr 123: 418-29 |
| PMID | 19331464 |
| Title | Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone. |
| Abstract | C57BL/6 mice were given 0.2% cuprizone (CPZ) for 2 to 6 weeks while controls ate the same diet without CPZ. At various time points the animals were subjected to behavioral tests and their brains were analyzed. Mice exposed to CPZ for 2 and 3 weeks displayed more climbing behavior and lower prepulse inhibition, suggesting an increase in central nervous system activity and impaired sensorimotor gating. In addition, they showed lower activities of monoamine oxidase and dopamine beta hydroxylase in the hippocampus and prefrontal cortex, and had higher dopamine but lower norepinephrine levels in the prefrontal cortex. Mice exposed to CPZ for 4 to 6 weeks had less social interaction, which is an animal correlate of social withdrawal of patients with schizophrenia. Also, these CPZ-exposed mice showed evident brain demyelination, myelin break down, and loss of oligodendrocytes. At all time points the CPZ-exposed mice spent more time in the open arms of an elevated plus maze and exhibited spatial working memory impairment. These data are in line with evidence from human studies suggesting a putative role of white matter abnormality in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 29 | Brain Res. 2009 May 1270: 121-30 |
| PMID | 19306847 |
| Title | Region-specific susceptibilities to cuprizone-induced lesions in the mouse forebrain: Implications for the pathophysiology of schizophrenia. |
| Abstract | Cuprizone (CPZ) is a neurotoxic agent acting as a copper chelator. In our recent study, C57BL/6 mice given dietary CPZ (0.2%) showed impairments in spatial working memory, social interaction, and prepulse inhibition. These abnormalities are reminiscent of certain schizophrenia symptoms and are not likely due to damage in the whole brain or in any single white matter tract/brain region. We hypothesized that white matter damage resulting from CPZ-treatment may be site-specific rather than universal. We examined the forebrains of C57BL/6 mice given the CPZ-containing diet and compared them with those of controls. We assessed CPZ-induced demyelination in main white matter tracts of the forebrain, evaluated myelin break down in the neuropil of the main olfactory bulb (MOB), cerebral cortex (CTX), caudate putamen (CP), hippocampus (HP), thalamus (TH), and hypothalamus (HY), and counted the number of myelin sheath forming oligodendrocytes (OLs) in CTX, CP, TH, and HY. Obvious demyelination was observed in the corpus callosum, external capsule, CP, and dorsal hippocampal commissure whereas other tracts seemed to be unaffected. The neuropil of CTX, HP and MOB showed myelin break down, which was mild in TH and HY. The number of OLs was decreased in all the above regions of CPZ-treated mice although the degree of OL loss was not consistent across regions. The data provide further support for white matter abnormalities contributing to schizophrenia-like behaviors in mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 30 | Schizophr. Res. 2009 Sep 113: 277-87 |
| PMID | 19570651 |
| Title | Downregulation of oligodendrocyte transcripts is associated with impaired prefrontal cortex function in rats. |
| Abstract | Abnormalities of brain white matter and oligodendroglia are among the most consistent findings in schizophrenia (Sz) research. Various gene expression microarray studies of post-mortem Sz brains showed a downregulation of myelin transcripts, while imaging and microscopy studies demonstrated decreases in prefrontal cortical (PFC) white matter volume and oligodendroglia density. Currently, the extent to which reduced oligodendrocyte markers contribute to pathophysiological domains of Sz is unknown. We exposed adolescent rats to cuprizone (CPZ), a copper chelator known to cause demyelination in mice, and examined expression of oligodendrocyte mRNA transcripts and PFC-mediated behavior. Rats on the CPZ diet showed decreased expression of mRNA transcripts encoding oligodendroglial proteins within the medial PFC, but not in the hippocampus or the striatum. These rats also displayed a specific deficit in the ability to shift between perceptual dimensions in the attentional set-shifting task, a PFC-mediated behavioral paradigm modeled after the Wisconsin Card Sorting Test (WCST). The inability to shift strategies corresponds to the deficits exhibited by Sz patients in the WCST. The results demonstrate that a reduction in oligodendrocyte markers is associated with impaired PFC-mediated behaviors. Thus, CPZ exposure of rats can serve as a model to examine the contribution of oligodendrocyte perturbation to cognitive deficits observed in Sz. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 31 | Schizophr. Res. 2010 Jun 119: 191-7 |
| PMID | 20303713 |
| Title | Dysfunctional gamma-band activity during face structural processing in schizophrenia patients. |
| Abstract | This study investigated gamma-band activity (GBA) and its phase synchrony in schizophrenia patients viewing human faces. Twenty-five schizophrenia patients were compared with 25 normal controls. Event-related potentials were recorded from all participants while they were viewing emotionally neutral faces. The spectral power and phase synchrony in the frequency band from 30 to 55 Hz were analyzed in midline electrodes (FCz, Cz, CPZ, Pz, and POz). Three windows of interest, which showed discernable GBA differences between schizophrenia patients and normal controls, were selected by visual inspection: 0-100 ms (30-33 Hz), 250-300 ms (34-38 Hz), and 700-800 ms (40-45 Hz). And the phase synchrony of gamma band was analyzed. Repeated-measures ANOVA revealed that the GBA was lower in schizophrenia patients than in normal controls. Also there were significant location and time differences in GBA. GBA was significantly lower in the schizophrenia patients than in the normal controls at around 700-800 ms at the FCz electrode. The frontal (FCz) and central (Cz) GBA were significantly correlated with the number of hospitalization, and the negative symptoms of schizophrenia, respectively. The phase synchronization was significantly lower at 200-300 ms in the schizophrenia patients than in the normal controls. These findings suggest that the schizophrenia patients have impaired GBA and gamma-band synchronization during face perception. Furthermore, our results also suggest that the decreased GBA observed at the midline cortex of schizophrenia patients is closely related to their negative symptoms and disease progress. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 32 | Protein Sci. 2010 Aug 19: 1500-12 |
| PMID | 20521334 |
| Title | Effect of ligand binding on human D-amino acid oxidase: implications for the development of new drugs for schizophrenia treatment. |
| Abstract | In human brain the flavoprotein D-amino acid oxidase (hDAAO) is responsible for the degradation of the neuromodulator D-serine, an important effector of NMDA-receptor mediated neurotransmission. Experimental evidence supports the concept that D-serine concentration increase by hDAAO inhibition may represent a valuable therapeutic approach to improve the symptoms in schizophrenia patients. This study investigated the effects on hDAAO conformation and stability of the substrate D-serine (or of the pseudo-substrate trifluoro-D-alanine), the FAD cofactor, and two inhibitors (benzoate, a classical substrate-competitive inhibitor and the drug chlorpromazine (CPZ), which competes with the cofactor). We demonstrated that all these compounds do not alter the interaction of hDAAO with its physiological partner pLG72. The ligands used affect the tertiary structure of hDAAO differently: benzoate or trifluoro-D-alanine binding increases the amount of the holoenzyme form in solution and stabilizes the flavoprotein, while CPZ binding favors a protein conformation resembling that of the apoprotein, which is more sensitive to degradation. Interestingly, the apoprotein form of hDAAO binds the substrate D-serine: this interaction increases FAD binding thus increasing the amount of active holoenzyme in solution. Benzoate and CPZ similarly modify the short-term cellular D-serine concentration but affect the cellular concentration of hDAAO differently. In conclusion, the different alteration of hDAAO conformation and stability by the ligands used represents a further parameter to take into consideration during the development of new drugs to cope schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 33 | Schizophr Res Treatment 2011 -1 2011: 826976 |
| PMID | 22937274 |
| Title | White matter abnormalities and animal models examining a putative role of altered white matter in schizophrenia. |
| Abstract | schizophrenia is a severe mental disorder affecting about 1% of the population worldwide. Although the dopamine (DA) hypothesis is still keeping a dominant position in schizophrenia research, new advances have been emerging in recent years, which suggest the implication of white matter abnormalities in schizophrenia. In this paper, we will briefly review some of recent human studies showing white matter abnormalities in schizophrenic brains and altered oligodendrocyte-(OL-) and myelin-related genes in patients with schizophrenia and will consider abnormal behaviors reported in patients with white matter diseases. Following these, we will selectively introduce some animal models examining a putative role of white matter abnormalities in schizophrenia. The emphasis will be put on the cuprizone (CPZ) model. CPZ-fed mice show demyelination and OLs loss, display schizophrenia-related behaviors, and have higher DA levels in the prefrontal cortex. These features suggest that the CPZ model is a novel animal model of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 34 | Schizophr Res Treatment 2011 -1 2011: 826976 |
| PMID | 22937274 |
| Title | White matter abnormalities and animal models examining a putative role of altered white matter in schizophrenia. |
| Abstract | schizophrenia is a severe mental disorder affecting about 1% of the population worldwide. Although the dopamine (DA) hypothesis is still keeping a dominant position in schizophrenia research, new advances have been emerging in recent years, which suggest the implication of white matter abnormalities in schizophrenia. In this paper, we will briefly review some of recent human studies showing white matter abnormalities in schizophrenic brains and altered oligodendrocyte-(OL-) and myelin-related genes in patients with schizophrenia and will consider abnormal behaviors reported in patients with white matter diseases. Following these, we will selectively introduce some animal models examining a putative role of white matter abnormalities in schizophrenia. The emphasis will be put on the cuprizone (CPZ) model. CPZ-fed mice show demyelination and OLs loss, display schizophrenia-related behaviors, and have higher DA levels in the prefrontal cortex. These features suggest that the CPZ model is a novel animal model of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 35 | Yakugaku Zasshi 2011 -1 131: 1111-6 |
| PMID | 21720142 |
| Title | Inhibition of D-amino acid oxidase activity by antipsychotic drugs evaluated by a fluorometric assay using D-kynurenine as substrate. |
| Abstract | A facile fluorometric assay using D-kynurenine as a substrate was utilized for evaluating the inhibition of D-amino acid oxidase (DAAO), which is one of the products of a susceptibility gene for schizophrenia, by commercial antipsychotic drugs, namely, chlorpromazine (CPZ), carbamazepine, sulpiride, quetiapine, and imipramine. CPZ inhibited DAAO (65.8 ± 13.2 ?M, n = 3) as reported previously, and other drugs also inhibited DAAO activity. Among these, quetiapine had the smallest IC(50) value (19.5 ± 2.60 ?M, n = 3). The proposed assay can be useful for the evaluation or screening of DAAO-inhibitory drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 36 | Front Behav Neurosci 2011 -1 5: 31 |
| PMID | 21747763 |
| Title | Recovery of behavioral changes and compromised white matter in C57BL/6 mice exposed to cuprizone: effects of antipsychotic drugs. |
| Abstract | Recent animal and human studies have suggested that the cuprizone (CPZ, a copper chelator)-fed C57BL/6 mouse may be used as an animal model of schizophrenia. The goals of this study were to see the recovery processes of CPZ-induced behavioral changes and damaged white matter and to examine possible effects of antipsychotic drugs on the recovery processes. Mice were fed a CPZ-containing diet for 5?weeks then returned to normal food for 3?weeks, during which period mice were treated with different antipsychotic drugs. Various behaviors were measured at the end of CPZ-feeding phase as well as on the 14th and 21st days after CPZ withdrawal. The damage to and recovery status of white matter in the brains of mice were examined. Dietary CPZ resulted in white matter damage and behavioral abnormalities in the elevated plus-maze (EPM), social interaction (SI), and Y-maze test. EPM performance recovered to normal range within 2?weeks after CPZ withdrawal. Alterations in SI showed no recovery. Antipsychotics did not alter animals' behavior in either of these tests during the recovery period. Altered performance in the Y-maze showed some recovery in the vehicle group; atypical antipsychotics, but not haloperidol, significantly promoted this recovery process. The recovery of damaged white matter was incomplete during the recovery period. None of the drugs significantly promoted the recovery of damaged white matter. These results suggest that CPZ-induced white matter damage and SI deficit may be resistant to the antipsychotic treatment employed in this study. They are in good accordance with the clinical observations that positive symptoms in schizophrenic patients respond well to antipsychotic drugs while social dysfunction is usually intractable. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 37 | Front Behav Neurosci 2011 -1 5: 31 |
| PMID | 21747763 |
| Title | Recovery of behavioral changes and compromised white matter in C57BL/6 mice exposed to cuprizone: effects of antipsychotic drugs. |
| Abstract | Recent animal and human studies have suggested that the cuprizone (CPZ, a copper chelator)-fed C57BL/6 mouse may be used as an animal model of schizophrenia. The goals of this study were to see the recovery processes of CPZ-induced behavioral changes and damaged white matter and to examine possible effects of antipsychotic drugs on the recovery processes. Mice were fed a CPZ-containing diet for 5?weeks then returned to normal food for 3?weeks, during which period mice were treated with different antipsychotic drugs. Various behaviors were measured at the end of CPZ-feeding phase as well as on the 14th and 21st days after CPZ withdrawal. The damage to and recovery status of white matter in the brains of mice were examined. Dietary CPZ resulted in white matter damage and behavioral abnormalities in the elevated plus-maze (EPM), social interaction (SI), and Y-maze test. EPM performance recovered to normal range within 2?weeks after CPZ withdrawal. Alterations in SI showed no recovery. Antipsychotics did not alter animals' behavior in either of these tests during the recovery period. Altered performance in the Y-maze showed some recovery in the vehicle group; atypical antipsychotics, but not haloperidol, significantly promoted this recovery process. The recovery of damaged white matter was incomplete during the recovery period. None of the drugs significantly promoted the recovery of damaged white matter. These results suggest that CPZ-induced white matter damage and SI deficit may be resistant to the antipsychotic treatment employed in this study. They are in good accordance with the clinical observations that positive symptoms in schizophrenic patients respond well to antipsychotic drugs while social dysfunction is usually intractable. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 38 | Seishin Shinkeigaku Zasshi 2011 -1 113: 612-8 |
| PMID | 21815472 |
| Title | [Antipsychotic medication change and reduction of rehospitalization in clients of ACT-J]. |
| Abstract | Polypharmacy and high-dose treatment of antipsychotics have been major problems in Japanese mental health. Although importance of simplifying prescription has been recognized, polypharmacy and high-dose medication especially for schizophrenia remains prevalent. It's considered that psycho-social approach; for example, improvement of coping skills and social support such as care management can make reform of treatment efficiently and also improve patient's QOL. In ACT service, Medication, rehabilitation and social support work closely together and it could make prescription change even for SMI patients. Low-dose medication leads improvement of cognitive function and furthermore social activity. Considering the higher dose of antipsychotics prescribed concurrency in Japan, it's important to evaluate the change in medication for patients of ACT in Japan. We did one year follow up study about prescription change for 52 patients who have used ACT program at ACT-J team for more than one year at the end of December 2009. It was found that the dosage antipsychotics significantly decreased from 1131.3 mg converted to the relative potency equivalent of 100 mg of Chlorpromazine (CPZ eq), to 731.3 mg (CPZ eq) over the course of the 12 months. But there was no significant change about polyphamacy. Also it could be possible to reduce rehospitalization under the ACT program. Because recovery model could make improve not only drop out from psychiatric service, but user's dependency for hospitalization. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 39 | Med Chem 2012 Nov 8: 1032-8 |
| PMID | 22757658 |
| Title | Impact of clozapine, N-desmethylclozapine and chlorpromazine on thromboxane production in vitro. |
| Abstract | Thromboxane A2 (TxA2) and the activation of its receptor have been shown to modulate vasoconstriction and platelet aggregation as well as dopaminergic and serotonergic signalling. Dopaminergic and serotonergic systems play a crucial role in the pathophysiology of schizophrenia and these systems are the main targets of antipsychotics (APs). As the first antipsychotic (AP) chlorpromazine (CPZ) has already been shown to reduce TxA2, we hypothesized that the AP clozapine and its metabolite N-desmethylclozapine (NDMC) might also influence TxA2 production. We measured levels of thromboxane B2 (TxB2), the metabolite of the very unstable molecule TxA2, in unstimulated and stimulated blood samples of 10 healthy female subjects in a whole blood assay using toxic shock syndrome toxin-1 (TSST-1) and monoclonal antibody against surface antigen CD3 combined with protein CD40 (OKT3/CD40) as stimulants. Blood was supplemented with the APs CPZ, clozapine or NDMC in one of four different concentrations. Additionally, thromboxane levels were measured in blood without the addition of APs under different stimulation conditions. Under TSST-1 as well as OKT3/CD40 stimulation, mean TxB2 concentrations were significantly (p < 0.05) decreased by clozapine over all applied concentrations. NDMC led to a decrease in TxB2 levels under unstimulated conditions as well as under TSST-1 stimulation. CPZ reduced TxB2 production at low concentrations under unstimulated and TSST-1- stimulated conditions. Clozapine, NDMC and CPZ possibly act on neurotransmitter systems via modulation of TxA2 or TxB2 production. Additionally, known side effects of APs such as orthostatic hypotension may be a result of changes in the concentrations of TxA2 or TxB2. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 40 | PLoS ONE 2012 -1 7: e37087 |
| PMID | 22615901 |
| Title | Association of typical versus atypical antipsychotics with symptoms and quality of life in schizophrenia. |
| Abstract | Several reports on patients with chronic schizophrenia suggest that atypical versus typical antipsychotics are expected to lead to better quality of life (QOL) and cognitive function. Our aim was to examine the association of chronic treatment with typical or atypical antipsychotics with cognitive function, psychiatric symptoms, QOL, and drug-induced extrapyramidal symptoms in long-hospitalized patients with schizophrenia. The Hasegawa Dementia Scale-Revised (HDS-R), Brief Psychiatric Rating Scale (BPRS), the schizophrenia Quality of Life Scale, translated into Japanese (JSQLS), and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) were used to evaluate cognitive function, psychiatric symptoms, QOL, and drug-induced extrapyramidal symptoms. We examined the correlation between the dose of antipsychotics and each measure derived from these psychometric tests. The student t-test was used to compare scores obtained from psychometric tests between patients receiving typical and atypical antipsychotics. Results showed significant correlations between chlorpromazine (CPZ)-equivalent doses of typical antipsychotics and atypical antipsychotics, and the total BPRS score and BPRS subscale scores for positive symptoms. CPZ-equivalent doses of typical antipsychotics were correlated with the JSQLS subscale score for dysfunction of psycho-social activity and DIEPSS score. Furthermore, the total BPRS scores, BPRS subscale score for positive symptoms, the JSQLS subscale score for dysfunction of psycho-social activity, and the DIEPSS score were significantly higher in patients receiving typical antipsychotics than atypical antipsychotics. These findings suggest that long-term administration of typical antipsychotics has an unfavorable association with feelings of difficulties mixing in social situations in patients with chronic schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 41 | PLoS ONE 2012 -1 7: e40247 |
| PMID | 22802957 |
| Title | Decrease in temporal gyrus gray matter volume in first-episode, early onset schizophrenia: an MRI study. |
| Abstract | Loss of gray matter has been previously found in early-onset schizophrenic patients. However, there are no consistent findings between studies due to different methods used to measure grey matter volume/density and influences of confounding factors. The volume of gray matter (GM) was measured in 29 first episode early-onset schizophrenia (EOS) and 34 well-matched healthy controls by using voxel-based morphometry (VBM). Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The correlations between the GM volume and PANSS scores, age of psychosis onset, duration of psychosis, and chlorpromazine (CPZ) equivalent value were investigated. Relative to healthy subjects, the patients with first episode EOS showed significantly lower GM volume in the left middle and superior temporal gyrus. The loss of GM volume negatively correlated with PANSS-positive symptoms (p?=?0.002), but not with PANSS-negative symptoms, PANSS-general psychopathology, and PANSS-total score. No significant correlation was found between GM volume and age of psychosis onset, duration of psychosis, and CPZ equivalent value. Patients with first episode EOS have evidence of reduced GM in the left middle and superior temporal gyrus. Structural abnormalities in the left middle and superior temporal gyrus may contribute to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 42 | PLoS ONE 2012 -1 7: e40247 |
| PMID | 22802957 |
| Title | Decrease in temporal gyrus gray matter volume in first-episode, early onset schizophrenia: an MRI study. |
| Abstract | Loss of gray matter has been previously found in early-onset schizophrenic patients. However, there are no consistent findings between studies due to different methods used to measure grey matter volume/density and influences of confounding factors. The volume of gray matter (GM) was measured in 29 first episode early-onset schizophrenia (EOS) and 34 well-matched healthy controls by using voxel-based morphometry (VBM). Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The correlations between the GM volume and PANSS scores, age of psychosis onset, duration of psychosis, and chlorpromazine (CPZ) equivalent value were investigated. Relative to healthy subjects, the patients with first episode EOS showed significantly lower GM volume in the left middle and superior temporal gyrus. The loss of GM volume negatively correlated with PANSS-positive symptoms (p?=?0.002), but not with PANSS-negative symptoms, PANSS-general psychopathology, and PANSS-total score. No significant correlation was found between GM volume and age of psychosis onset, duration of psychosis, and CPZ equivalent value. Patients with first episode EOS have evidence of reduced GM in the left middle and superior temporal gyrus. Structural abnormalities in the left middle and superior temporal gyrus may contribute to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 43 | J. Am. Chem. Soc. 2012 Mar 134: 4184-95 |
| PMID | 22296285 |
| Title | Kinetics and thermodynamics of chlorpromazine interaction with lipid bilayers: effect of charge and cholesterol. |
| Abstract | Passive transport across cell membranes is the major route for the permeation of xenobiotics through tight endothelia such as the blood?brain barrier. The rate of passive permeation through lipid bilayers for a given drug is therefore a critical step in the prediction of its pharmacodynamics. We describe a detailed study on the kinetics and thermodynamics for the interaction of chlorpromazine (CPZ), an antipsychotic drug used in the treatment of schizophrenia, with neutral and negatively charged lipid bilayers. Isothermal titration calorimetry was used to study the partition and translocation of CPZ in lipid membranes composed of pure POPC, POPC:POPS (9:1), and POPC:Chol:POPS (6:3:1). The membrane charge due to the presence of POPS as well as the additional charge resulting from the introduction of CPZ in the membrane were taken into account, allowing the calculation of the intrinsic partition coefficients (K(P)) and the enthalpy change (?H) associated with the process. The enthalpy change upon partition to all lipid bilayers studied is negative, but a significant entropy contribution was also observed for partition to the neutral membrane. Because of the positive charge of CPZ, the presence of negatively charged lipids in the bilayer increases both the observed amount of CPZ that partitions to the membrane (KP(obs)) and the magnitude of ?H. However, when the electrostatic effects are discounted, the intrinsic partition coefficient was smaller, indicating that the hydrophobic contribution was less significant for the negatively charged membrane. The presence of cholesterol strongly decreases the affinity of CPZ for the bilayer in terms of both the amount of CPZ that associates with the membrane and the interaction enthalpy. A quantitative characterization of the rate of CPZ translocation through membranes composed of pure POPC and POPC:POPS (9:1) was also performed using an innovative methodology developed in this work based on the kinetics of the heat evolved due to the interaction of CPZ with the membranes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 44 | Psychiatry Res 2013 Dec 214: 365-73 |
| PMID | 24045051 |
| Title | Altered phospholipid metabolism in schizophrenia: a phosphorus 31 nuclear magnetic resonance spectroscopy study. |
| Abstract | Phospholipid (PL) metabolism is investigated by in vivo 31P magnetic resonance spectroscopy (MRS). Inconsistent alterations of phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) have been described in schizophrenia, which might be overcome by specific editing techniques. The selective refocused insensitive nuclei-enhanced polarization transfer (RINEPT) technique was applied in a cross-sectional study involving 11 schizophrenia spectrum disorder patients (SZP) on stable antipsychotic monotherapy and 15 matched control subjects. Metabolite signals were found to be modulated by cerebrospinal fluid (CSF) content and gray matter/brain matter ratio. Corrected metabolite concentrations of PC, GPC and PE differed between patients and controls in both subcortical and cortical regions, whereas antipsychotic medication exerted only small effects. Significant correlations were found between the severity of clinical symptoms and the assessed signals. In particular, psychotic symptoms correlated with PC levels in the cerebral cortex, depression with PC levels in the cerebellum and executive functioning with GPC in the insular and temporal cortices. In conclusion, after controlling for age and tissue composition, this investigation revealed alterations of metabolite levels in SZP and correlations with clinical properties. RINEPT 31P MRS should also be applied to at-risk-mental-state patients as well as drug-naïve and chronically treated schizophrenic patients in order to enhance the understanding of longitudinal alterations of PL metabolism in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 45 | Psychiatry Res 2013 Dec 214: 365-73 |
| PMID | 24045051 |
| Title | Altered phospholipid metabolism in schizophrenia: a phosphorus 31 nuclear magnetic resonance spectroscopy study. |
| Abstract | Phospholipid (PL) metabolism is investigated by in vivo 31P magnetic resonance spectroscopy (MRS). Inconsistent alterations of phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) have been described in schizophrenia, which might be overcome by specific editing techniques. The selective refocused insensitive nuclei-enhanced polarization transfer (RINEPT) technique was applied in a cross-sectional study involving 11 schizophrenia spectrum disorder patients (SZP) on stable antipsychotic monotherapy and 15 matched control subjects. Metabolite signals were found to be modulated by cerebrospinal fluid (CSF) content and gray matter/brain matter ratio. Corrected metabolite concentrations of PC, GPC and PE differed between patients and controls in both subcortical and cortical regions, whereas antipsychotic medication exerted only small effects. Significant correlations were found between the severity of clinical symptoms and the assessed signals. In particular, psychotic symptoms correlated with PC levels in the cerebral cortex, depression with PC levels in the cerebellum and executive functioning with GPC in the insular and temporal cortices. In conclusion, after controlling for age and tissue composition, this investigation revealed alterations of metabolite levels in SZP and correlations with clinical properties. RINEPT 31P MRS should also be applied to at-risk-mental-state patients as well as drug-naïve and chronically treated schizophrenic patients in order to enhance the understanding of longitudinal alterations of PL metabolism in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 46 | Schizophr. Res. 2013 Nov 150: 366-72 |
| PMID | 24035561 |
| Title | Proteoglycan abnormalities in olfactory epithelium tissue from subjects diagnosed with schizophrenia. |
| Abstract | Emerging evidence points to proteoglycan abnormalities in the pathophysiology of schizophrenia (SZ). In particular, markedly abnormal expression of chondroitin sulfate proteoglycans (CSPGs), key components of the extracellular matrix, was observed in the medial temporal lobe. CSPG functions, including regulation of neuronal differentiation and migration, are highly relevant to the pathophysiology of SZ. CSPGs may exert similar functions in the olfactory epithelium (OE), a continuously regenerating neural tissue that shows cell and molecular abnormalities in SZ. We tested the hypothesis that CSPG expression in OE may be altered in SZ. CSPG-positive cells in postmortem OE from non-psychiatric control (n=9) and SZ (n=10) subjects were counted using computer-assisted light microscopy. 'Cytoplasmic' CSPG (c-CSPG) labeling was detected in sustentacular cells and some olfactory receptor neurons (c-CSPG+ORNs), while 'pericellular' CSPG (p-CSPG) labeling was found in basal cells and some ORNs (p-CSPG+ORNs). Dual labeling for CSPG and markers for mature and immature ORNs suggests that c-CSPG+ORNs correspond to mature ORNs, and p-CSPG+ORNs to immature ORNs. Previous studies in the same cohort demonstrated that densities of mature ORNs were unaltered (Arnold et al., 2001). In the present study, numerical densities of c-CSPG+ORNs were significantly decreased in SZ (p<0.025; 99.32% decrease), suggesting a reduction of CSPG expression in mature ORNs. Previous studies showed a striking increase in the ratios of immature neurons with respect to basal cells. In this study, we find that the ratio of p-CSPG+ORNs/CSPG+basal cells was significantly increased (p=0.03) in SZ, while numerical density changes of p-CSPG+ORNs (110.71% increase) or CSPG+basal cells (53.71% decrease), did not reach statistical significance. Together, these results indicate that CSPG abnormalities are present in the OE of SZ and specifically point to a reduction of CSPG expression in mature ORNs in SZ. Given the role CSPGs play in OE cell differentiation and axon guidance, we suggest that altered CSPG expression may contribute to ORN lineage dysregulation, and olfactory identification abnormalities, observed in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 47 | Neurosci Bull 2013 Apr 29: 251-9 |
| PMID | 23558591 |
| Title | Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit. |
| Abstract | schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 48 | J. Psychopharmacol. (Oxford) 2013 Apr 27: 396-400 |
| PMID | 23427194 |
| Title | Comparison of the anti-dopamine D? and anti-serotonin 5-HT(2A) activities of chlorpromazine, bromperidol, haloperidol and second-generation antipsychotics parent compounds and metabolites thereof. |
| Abstract | Second-generation antipsychotics, which have become the standard drug therapies for schizophrenia, are known to have a serotonin 5-HT(2A) receptor blocking effect in addition to a dopamine D? receptor blocking effect. However, although chlorpromazine (CPZ) has a 5-HT(2A) receptor blocking effect and has the profile of a second-generation antipsychotic in vitro, it loses this pharmacological profile in vivo. In order to elucidate the differences between the in vivo and in vitro pharmacological characteristics of CPZ, we used a radioreceptor assay to measure the anti-D? activity and the anti-5-HT(2A) activity of CPZ and five major metabolites of CPZ, and compared the results to the anti-D? activity and anti-5-HT(2A) activity of risperidone, zotepine, perospirone, the major metabolites of each of these drugs, and olanzapine, bromperidol, and haloperidol. The subjects were 182 patients who had received diagnoses of schizophrenia based on the DSM-IV criteria. The results revealed that CPZ exhibited little anti-5-HT(2A) activity, regardless of the anti-D? activity level, and that none of the metabolites possessed anti-5-HT(2A) activity. However, both the parent compounds and the metabolites of each of the second-generation antipsychotics possessed both anti-D? activity and anti-5-HT(2A) activity. This clarified that, unlike second-generation antipsychotics, the reason CPZ loses its second-generation antipsychotic profiles in vivo is because it does not have any metabolites that possess anti-5-HT(2A) activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 49 | Schizophr Bull 2013 Sep 39: 1159-68 |
| PMID | 23112292 |
| Title | Guideline-concordant antipsychotic use and mortality in schizophrenia. |
| Abstract | To determine if care concordant with 2009 schizophrenia Patient Outcomes Research Team (PORT) pharmacological recommendations for schizophrenia is associated with decreased mortality. We conducted a retrospective cohort study of adult Maryland Medicaid beneficiaries with schizophrenia and any antipsychotic use from 1994 to 2004 (N = 2132). We used Medicaid pharmacy data to measure annual and average antipsychotic continuity, to calculate chlorpromazine (CPZ) dosing equivalents, and to examine anti-Parkinson medication use. Cox proportional hazards regression models were used to examine the relationship between antipsychotic continuity, antipsychotic dosing, and anti-Parkinson medication use and mortality. Annual antipsychotic continuity was associated with decreased mortality. Among patients with annual continuity greater than or equal to 90%, the hazard ratio [HR] for mortality was 0.75 (95% confidence interval [CI] 0.57-0.99) compared with patients with annual medication possession ratios (MPRs) of less than 10%. The HRs for mortality associated with continuous annual and average antipsychotic continuity were 0.75 (95% CI 0.58-0.98) and 0.84 (95% CI 0.58-1.21), respectively. Among users of first-generation antipsychotics, doses greater than or equal to 1500 CPZ dosing equivalents were associated with increased risk of mortality (HR 1.88, 95% CI 1.10-3.21), and use of anti-Parkinson medication was associated with decreased risk of mortality (HR 0.72, 95% CI 0.55-0.95). Mental health visits were also associated with decreased mortality (HR 0.96, 95% CI 0.93-0.98). Adherence to PORT pharmacological guidelines is associated with reduced mortality among patients with schizophrenia. Adoption of outcomes monitoring systems and innovative service delivery programs to improve adherence to the PORT guidelines should be considered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 50 | Glia 2014 Oct 62: 1629-44 |
| PMID | 24890315 |
| Title | Gender influence on schizophrenia-relevant abnormalities in a cuprizone demyelination model. |
| Abstract | The aim of this study was to determine whether early demyelination can impact behavior in young adulthood. For this purpose, albino Wistar rats of either sex were exposed to cuprizone (CPZ) in two different intoxication protocols: one group was intoxicated before weaning (CPZ-BW), from postnatal day 7 (P7) to P21, through maternal milk, whereas the other group was intoxicated after weaning (CPZ-AW), from P21 to P35. After treatment, rats were returned to a normal diet until P90 when behavioral studies were performed. Both treatments produced marked demyelination in the corpus callosum and retraction of cortical myelin fibers. The subsequent normal diet allowed for effective remyelination at P90. Interestingly, CPZ-AW correlated with significant behavioral and neurochemical changes in a gender-dependent manner. CPZ-AW treatment altered both the number of social activities and the latency to the first social interaction in males, while also highly compromising recognition-related activities. In addition, only P90 males treated AW showed a hyperdopaminergic striatum, confirmed by an increase in tyrosine hydroxylase expression and in dopamine levels. Our results suggest that the timing of demyelination significantly influences the development of altered behavior, particularly in adult males. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 51 | Eur Arch Psychiatry Clin Neurosci 2014 Mar 264: 121-9 |
| PMID | 23728937 |
| Title | Differential effects of antipsychotics on the development of rat oligodendrocyte precursor cells exposed to cuprizone. |
| Abstract | Cuprizone (CPZ) is a copper-chelating agent and has been shown to induce white matter damage in mice and rats. The compromised white matter and oligodendrocytes (OLs) respond to some antipsychotics in vivo. However, little is known about the effects of antipsychotics on cultured OLs in the presence of CPZ. The aim of this study was to examine effects of some antipsychotics on developing OLs in the presence of CPZ. Oligodendrocyte progenitor cells (OPCs) were prepared from rat embryos; OLs at different developing stages were labeled with specific antibodies; levels of CNP and MBP proteins in mature OLs were assessed by Western-blot analysis; malondialdehyde (MDA) levels and activity of catalase were evaluated as well for an assessment of oxidative stress and antioxidative status. In immunofluorescent staining, CPZ was shown to inhibit the differentiation of cultured OPCs into O4-positive cells, reduce the maturation of O4-positive cells into CNP- and MBP-positive cells, and decrease levels of CNP and MBP in mature OLs. These inhibitory effects of CPZ were ameliorated by clozapine and quetiapine (QUE), but not by haloperidol and olanzapine. Further experiments were performed to explore the mechanism of the protective effects of QUE. QUE attenuated the decreases in CNP and MBP in CPZ-treated OLs, and blocked the CPZ-induced increase in MDA and decrease in catalase activity in cultured OLs. These results are relevant to the pathophysiology and treatment of schizophrenia considering the aberrant white matter development and evidence suggesting the derangement of the oxidant and antioxidant defense system in some of the patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 52 | Eur. J. Pharmacol. 2014 Jul 735: 38-43 |
| PMID | 24755143 |
| Title | Chlorpromazine confers neuroprotection against brain ischemia by activating BKCa channel. |
| Abstract | Chlorpromazine (CPZ) is a well-known antipsychotic drug, still widely being used to treat symptoms of schizophrenia, psychotic depression and organic psychoses. We have previously reported that CPZ activates the BKCa (KCa1.1) channel at whole cell level. In the present study, we demonstrated that CPZ increased the single channel open probability of the BKCa channels without changing its single channel amplitude. As BKCa channel is one of the molecular targets of brain ischemia, we explored a possible new use of this old drug on ischemic brain injury. In middle cerebral artery occlusion (MCAO) focal cerebral ischemia, a single intraperitoneal injection of CPZ at several dosages (5mg/kg, 10mg/kg and 20mg/kg) could exert a significant neuroprotective effect on the brain damage in a dose- and time-dependent manner. Furthermore, blockade of BKCa channels abolished the neuroprotective effect of CPZ on MCAO, suggesting that the effect of CPZ is mediated by activation of the BKCa channel. These results demonstrate that CPZ could reduce focal cerebral ischemic damage through activating BKCa channels and merits exploration as a potential therapeutic agent for treating ischemic stroke. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 53 | Neurochem. Int. 2014 Apr 69: 20-7 |
| PMID | 24613425 |
| Title | Concurrent changes in ¹H MRS metabolites and antioxidant enzymes in the brain of C57BL/6 mouse short-termly exposed to cuprizone: possible implications for schizophrenia. |
| Abstract | Cuprizone (CPZ) is a copper chelating agent able to selectively insult mature oligodendrocytes (OLs) in brains of rodents. The CPZ-exposed mice show behavioral changes and have been employed to examine a putative role of altered OLs in the pathophysiology of schizophrenia. The aims of this study were to examine the brain metabolites in the CPZ-exposed mice during the early stage and to measure some antioxidant enzymes, lipid peroxidation and hydrogen peroxide (H2O2) in brain tissue. C57BL/6 mice were fed normal or CPZ-containing diet for 7 days. On days 7 and 8, mice were subjected to behavioral tests. On days 9 and 10, mice were subjected to (1)H MRS procedure. On day 10 mice were sacrificed and their brain tissue was processed for biochemical analyses. CPZ-exposure for 7 days caused an anxiety-like behavior, but had no effect on the social interaction and spatial working memory in C57BL/6 mice. The treatment significantly decreased levels of GPC+PCh, ml, NAA, NAA+NAAG, and PCr in the thalamus and hippocampus. It impaired the activities of some antioxidant enzymes, but did not increase levels of MDA and H2O2. This first (1)H MRS study with CPZ-exposed mice provided neurochemical evidence for mitochondrial dysfunction in brain cells of living mice during the early stage of CPZ-exposure. The results are of relevance to the pathophysiology of schizophrenia in which mitochondrial dysfunction of neural cells and altered OLs are two important players. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 54 | Psychiatry Res 2014 May 216: 438-45 |
| PMID | 24613202 |
| Title | Olanzapine ameliorates neuropathological changes and increases IGF-1 expression in frontal cortex of C57BL/6 mice exposed to cuprizone. |
| Abstract | Cuprizone (CPZ) induced demyelinating mouse has been used as an animal model to examine the assumed roles of altered oligodendrocytes in the pathophysiology and treatment of schizophrenia. The objectives of this study were to examine the effect of olanzapine, an atypical antipsychotic, on cuprizone-induced neuropathological changes in the frontal cortex of C57BL/6 mice, and to explore the underlying mechanism for the possible protective effects. The effects of six-week olanzapine (10 mg/kg/day) treatments on neuropathological changes were examined by immunohistochemistry and Western-blot analyses. Olanzapine treatment for six weeks effectively decreased the breakdown of myelin and oligodendrocytes loss of cuprizone-fed mice. Reactive cellular changes, including astrocyte gliosis, microglia accumulation and increased activation of oligodendrocyte progenitor cells, were also attenuated by olanzapine. However, the cortical expression level of insulin-like growth factor 1 (IGF-1) was significantly increased by olanzapine treatment in cuprizone-fed mice as measured by the quantitative real-time polymerase chain reaction (PCR) method. Olanzapine treatment in control mice consuming normal food had no effect on all above measures. These results provide the first in vivo evidence for the protective effects of olanzapine on cuprizone-induced neuropathological changes and suggest that up-regulated insulin-like growth factor 1 may contribute to the protective effects of this antipsychotic. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 55 | Neurochem. Res. 2014 Jan 39: 59-67 |
| PMID | 24190599 |
| Title | Geissoschizine methyl ether, an alkaloid from the Uncaria hook, improves remyelination after cuprizone-induced demyelination in medial prefrontal cortex of adult mice. |
| Abstract | Accumulating evidence indicates that the medial prefrontal cortex (mPFC) is a site of myelin and oligodendrocyte abnormalities that contribute to psychotic symptoms of schizophrenia. The development of therapeutic approaches to enhance remyelination, a regenerative process in which new myelin sheaths are formed on demyelinated axons, may be an attractive remedial strategy. Geissoschizine methyl ether (GM) in the Uncaria hook, a galenical constituent of the traditional Japanese medicine yokukansan (Yi-gan san), is one of the active components responsible for the psychotropic effects of yokukansan, though little is known about the mechanisms underlying the effects of either that medicine or GM itself. In the present study, we employed a cuprizone (CPZ)-induced demyelination model and examined the cellular changes in response to GM administration during the remyelination phase in the mPFC of adult mice. Using the mitotic marker 5-bromo-2'-deoxyuridine (BrdU), we demonstrated that CPZ treatment significantly increased the number of BrdU-positive NG2 cells, as well as microglia and mature oligodendrocytes in the mPFC. Newly formed oligodendrocytes were increased by GM administration after CPZ exposure. In addition, GM attenuated a decrease in myelin basic protein immunoreactivity caused by CPZ administration. Taken together, our findings suggest that GM administration ameliorated the myelin deficit by mature oligodendrocyte formation and remyelination in the mPFC of CPZ-fed mice. The present findings provide experimental evidence supporting the role for GM and its possible use as a remedy for schizophrenia symptoms by promoting the differentiation of progenitor cells to and myelination by oligodendrocytes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 56 | Eur. J. Pharmacol. 2015 Oct 765: 249-57 |
| PMID | 26321148 |
| Title | Quetiapine mitigates the neuroinflammation and oligodendrocyte loss in the brain of C57BL/6 mouse following cuprizone exposure for one week. |
| Abstract | This study aimed at examining effects of quetiapine (QTP), an atypical antipsychotic, on the behaviors of mice which had consumed cuprizone (CPZ)-containing diet for one week and on inflammatory reactions and oligodendrocyte (OL) loss in brains of them. Young adult C57BL/6 mice, after fed CPZ-containing diet (0.2%, w/w) for one week, showed an increase in the locomotor activity in the open-field, and a decreased exploration time in the novel object recognition (NOR) test compared to controls. But, these changes were not seen in mice co-administered with QTP and CPZ. All mice in the four groups showed comparable performances in Y-maze test. After the behavioral tests, mice were killed and their brains were processed for immunohistochemical and immunofluorescence staining to examine OLs, astrocytes and microglia. The levels of proinflammatory cytokines TNF-? and IL-6 in certain brain regions were also evaluated by ELISA method. Mice in the NS+CPZ group showed fewer OLs, more activated astrocytes and microglia with higher immunofluorescence intensity in the examined brain regions of the corpus callosum, caudate putamen, cerebral cortex, and hippocampus. The levels of TNF-? and IL-6 in some of these brain regions were also increased. But these changes were completely blocked or effectively ameliorated in the QTP+CPZ group. These results demonstrated an anti-inflammatory effect of QTP in CPZ-exposed mice and this action may contribute to its protection on OLs and beneficial effects on the CPZ-induced behavioral changes in these mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 57 | Int. J. Biochem. Cell Biol. 2016 Jan 70: 82-91 |
| PMID | 26592196 |
| Title | Chlorpromazine inhibits mitochondrial apoptotic pathway via increasing expression of tissue factor. |
| Abstract | Chlorpromazine (CPZ) is a widely used antipsychotic drug with antagonistic effect on dopamine receptors. Accumulating evidence has shown that CPZ plays a neuroprotective role in various models of toxicity and apoptosis. However, the underlying mechanism contributing to this protective effect remains unclear. Here, we evaluate the effect of CPZ on mitochondrial apoptotic pathway in the neuron system. Higher levels of B-cell lymphoma-2 (Bcl-2) and tissue factor (TF) but lower apoptotic rate were found in hippocampus of CPZ-treated schizophrenic patients compared with non-antipsychotic treated controls. Additionally, both short-term and long-term treatment of CPZ in rats could up-regulate the levels of Bcl-2 and TF with no cytotoxic effects. In the in vitro experiment, expression of Bcl-2 was up-regulated in the C6 glioma cells transfected with pEGFP-N1-TF recombinant plasmid. Furthermore, in another independent rat model of apoptosis, compared with the group administrated with alcohol only, the brains of the CPZ-pretreated rats showed lower expression of cleaved caspase-3, cytochrome c and Bax, but higher expression of Bcl-2 and TF. Our data demonstrate that CPZ exerts its neuronal protective effects through inhibiting the activation of mitochondrial apoptotic pathway by up-regulating TF expression, thus providing new insight into CPZ function and application. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 58 | Chin J Physiol 2016 Feb 59: 21-32 |
| PMID | 26875559 |
| Title | Involvement of TRPV1 in the Olfactory Bulb in Rimonabant-Induced Olfactory Discrimination Deficit. |
| Abstract | Rimonabant is well recognized as a cannabinoid CB? receptor antagonist/inverse agonist. Rimonabant not only antagonizes the effects induced by exogenous cannabinoids and endocannabinoids at CB? receptors, it also exerts several pharmacological and behavioral effects independent of CB? receptor inactivation. For example, rimonabant can function as a low-potency mixed agonist/antagonist of the transient receptor potential vanilloid receptor 1 (TRPV1). Hence, it is important to explain the underlying mechanisms of the diverse physiological effects induced by rimonabant with caution. Interestingly, CB? receptor has recently been suggested to play a role in olfactory functions. Olfaction not only is involved in food intake, visual perception and social interaction, but also is proposed as a putative marker for schizophrenia and autism. Therefore, the present study aimed to investigate whether CB? receptor and TRPV1 played a role in olfactory functions. We first used the genetic disruption approach to examine the role of CB? receptor in olfactory functions and found that CB? knockout mice exhibited olfactory discrimination deficit. However, it is important to point out that these CB? knockout mice, despite their normal locomotivity, displayed deficiencies in the olfactory foraging and novel object exploration tasks. These results imply that general exploratory behaviors toward odorant and odorless objects are compromised in CB? knockout mice. We next turned to the pharmacological approach to examine the role of CB? receptor and TRPV1 in olfactory functions. We found that the short-term administration of rimonabant, injected systemically or directly into the olfactory bulb (OB), impaired olfactory discrimination that was rescued by the TRPV1 antagonist capsazepine (CPZ), via the same route of rimonabant, in wild-type mice. These results suggest that TRPV1 in the OB is involved in rimonabant-induced olfactory discrimination deficit. However, the rimonabant and/or CPZ treatments neither affected locomotivity nor general exploratory behaviors in wild-type mice. Finally, the acute systemic administration of rimonabant, unlike the short-term administration regimen, did not affect olfactory discrimination. Taken together, this study not only is the first one, to the best of our knowledge, suggests that the olfactory TRPV1 plays a role in olfactory functions, but also provides a possible mechanism for the olfactory discrimination deficit induced by rimonabant. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 59 | Schizophr Bull 2016 Mar -1: -1 |
| PMID | 26955982 |
| Title | Psychoeducation Improves Compliance and Outcome in Schizophrenia Without an Increase of Adverse Side Effects: A 7-Year Follow-up of the Munich PIP-Study. |
| Abstract | Psychoeducation improves adherence and motivates patients to accept a maintenance therapy as recommended by the guidelines. This would mean a daily consumption of at least 300 chlorpromazine (CPZ) units in the long run and should lead to an increase of the antipsychotic dosage in comparison to patients with treatment as usual (TAU). This raises 2 important questions: whether more side effects are provoked and do the patients have a corresponding benefit with a better outcome. A total of 41 patients with a diagnosis of schizophrenic or schizoaffective disorder were randomized at study entry, either to bifocal psychoeducation (21), or to standard treatment (20). They were compared concerning compliance, type of medication, dosage (CPZ equivalents), motor side effects and number of days in hospital. The average daily antipsychotic medication 2 and 7 years after index discharge was 365 and 354 CPZ-units respectively in the intervention group (IG), but 247 and 279, respectively in the control group (CG). The extent of motor side effects was slightly smaller in the IG, but they showed a small and statistically not significant increase in the rate of tardive dyskinesia (TD) after 7 years. At the 7-year follow-up the patients in the IG had spent 74.7 days in hospital compared to 243.4 days for the patients in the CG (P < .05). The course of illness was significantly better in the IG without increasing motor side-effects. Therefore, psychoeducation should be integrated more systematically into the routine treatment. These data are part of a previous study, published 2007, with a sample size of 48 patients. Seven patients-3 of the IG and 4 of the CG-could not be included, because they were not able to complete the very complex "Computer-based kinematic analysis of motor performance." In this article all conclusions are referred to the new sample size, therefore some results are slightly different in comparison to the previous data. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 60 | Schizophr Bull 2016 Mar -1: -1 |
| PMID | 26955982 |
| Title | Psychoeducation Improves Compliance and Outcome in Schizophrenia Without an Increase of Adverse Side Effects: A 7-Year Follow-up of the Munich PIP-Study. |
| Abstract | Psychoeducation improves adherence and motivates patients to accept a maintenance therapy as recommended by the guidelines. This would mean a daily consumption of at least 300 chlorpromazine (CPZ) units in the long run and should lead to an increase of the antipsychotic dosage in comparison to patients with treatment as usual (TAU). This raises 2 important questions: whether more side effects are provoked and do the patients have a corresponding benefit with a better outcome. A total of 41 patients with a diagnosis of schizophrenic or schizoaffective disorder were randomized at study entry, either to bifocal psychoeducation (21), or to standard treatment (20). They were compared concerning compliance, type of medication, dosage (CPZ equivalents), motor side effects and number of days in hospital. The average daily antipsychotic medication 2 and 7 years after index discharge was 365 and 354 CPZ-units respectively in the intervention group (IG), but 247 and 279, respectively in the control group (CG). The extent of motor side effects was slightly smaller in the IG, but they showed a small and statistically not significant increase in the rate of tardive dyskinesia (TD) after 7 years. At the 7-year follow-up the patients in the IG had spent 74.7 days in hospital compared to 243.4 days for the patients in the CG (P < .05). The course of illness was significantly better in the IG without increasing motor side-effects. Therefore, psychoeducation should be integrated more systematically into the routine treatment. These data are part of a previous study, published 2007, with a sample size of 48 patients. Seven patients-3 of the IG and 4 of the CG-could not be included, because they were not able to complete the very complex "Computer-based kinematic analysis of motor performance." In this article all conclusions are referred to the new sample size, therefore some results are slightly different in comparison to the previous data. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 61 | J Basic Clin Physiol Pharmacol 2016 Apr -1: -1 |
| PMID | 27089413 |
| Title | Histamine H3 receptor antagonists display antischizophrenic activities in rats treated with MK-801. |
| Abstract | Animal models based on N-methyl-d-aspartate receptor blockade have been extensively used for schizophrenia. Ketamine and MK-801 produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia, which led to the use of PCP (phencyclidine)- and MK-801 (dizocilpine)-treated animals as models for schizophrenia. The study investigated the effect of subchronic dosing (once daily, 7 days) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i.p.), and clobenpropit (CBP) (15 mg/kg, i.p.) on MK-801 (0.2 mg/kg, i.p.)-induced locomotor activity and also measured dopamine and histamine levels in rat's brain homogenates. The study also included clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively. Atypical and typical antipsychotic was used to serve as clinically relevant reference agents to compare the effects of the H3R antagonists. MK-801 significantly increased horizontal locomotor activity, which was reduced with CPX and CBP. MK-801-induced locomotor hyperactivity attenuated by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised striatal dopamine level, which was reduced in rats pretreated with CPX and CBP. CPZ also significantly lowered striatal dopamine levels, although the decrease was less robust compared to CLZ, CPX, and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increased histamine levels in the hypothalamus compared to MK-801 treatment alone. Histamine H3 receptor agonist, R-? methylhistamine (10 mg/kg, i.p.), counteracted the effect of CPX and CBP. The present study shows the positive effects of CPX and CBP on MK-801-induced schizophrenia-like behaviors in rodents. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |