Cerebral metabolic changes induced by clozapine in schizophrenia and related to clinical improvement

Rationale The study of the different effects on brain metabolism between typical and atypical antipsychotics would aid in understanding their mechanisms of action. Clozapine is of special interest, since it is one of the most effective antipsychotic drugs and demonstrates a distinctive mechanism of action in pre-clinical studies with respect to typical neuroleptics.Objective To study the differences in cerebral activity induced by clozapine as compared to those produced by haloperidol.Methods [¹⁸F]Fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) scans were obtained in the resting condition before and after 6 months of treatment with clozapine in 22 treatment-resistant patients with schizophrenia. Before inclusion, patients had been chronically treated with classical drugs, and all of them received haloperidol during the last month. Data were analyzed with statistical parametric mapping (SPM99) methods, comparing pre-treatment and post-treatment conditions. The association between the changes in symptom scores and metabolism was also assessed to corroborate the functional relevance of possible metabolic changes.Results Clozapine decreased prefrontal and basal ganglia activity, and increased occipital metabolism, including primary and association visual areas. The change in negative symptoms was related with the decrease of basal ganglia activity; the improvement in disorganization related to the metabolic decrease in the motor area, and the change in positive symptoms was associated to the increase of activity in the visual area.Conclusions These results show that haloperidol and clozapine produce different patterns of metabolic changes in schizophrenia. Compared to the haloperidol baseline, clozapine inhibited the metabolic activity of the prefrontal and motor cortical regions and basal ganglia and induced a higher activation of the visual cortex. The improvement in disorganization, negative and positive syndromes with clozapìne may be respectively associated with metabolic changes in the motor area, basal ganglia, and visual cortex.     

Olanzapine-induced cerebral metabolic changes related to symptom improvement in schizophrenia

The pattern of brain metabolic changes produced by olanzapine has yet to be described, despite the theoretical and clinical interest of this new antipsychotic. We studied a group of 17 schizophrenic patients who underwent two fluoro-deoxyglucose-positron emission tomography (FDG-PET) studies under two different conditions: a baseline scan during treatment with either conventional antipsychotics (n=15) or risperidone (n=2) and a second scan performed 17-24 weeks after switching to olanzapine. PET scans were obtained while performing a standard cognitive paradigm (Continuous Performance Test) and analysed by means of Statistical Parametric Mapping. No significant metabolic changes were found in the comparison between pre- and post-olanzapine conditions. A brain map of the statistical power of our design showed that changes up to 3% in the frontal and up to 8% in the occipital region were not likely to exist (1-beta=0.8). The degree of improvement in positive symptoms was related to the amount of activity decrease in the right orbital region and to the amount of activity increase in the primary visual area. Improvement in negative symptoms was associated with an activity increase in the dorsal prefrontal cortex, and a higher baseline activity in both temporal poles. These correlation patterns suggest that the functional mechanism of action of olanzapine may share traits from both typical and atypical neuroleptics.     

Neuroleptic radioreceptor activity and clinical outcome in schizophrenia

The relationship between serum haloperidol concentration and clinical response was examined in 27 schizophrenic inpatients between the ages of 18 and 56 years. All patients were treated with haloperidol, 20 mg/day for the first 2 weeks. Dosage adjustment after 2 weeks of treatment was made in seven subjects based on poor clinical response or side effects. Haloperidol activity was determined by the radioreceptor assay for neuroleptics on weeks 2 and 4 serum samples. The results indicated that higher radioreceptor activity levels, particularly above 22 ng/ml, were associated with poorer clinical response. The data suggest that radioreceptor activity levels are not at a steady state after 2 weeks drug treatment. Additionally, problems secondary to low sensitivity of the radioreceptor assay may limit its utility at low serum concentrations.     

Early prediction of clinical and functional outcome in schizophrenia

The objective of this paper was to investigate the prognostic and predictive value of a small panel of independent and clinically important factors based on symptom improvement, baseline cognitive impairment, and weight change during the early treatment phase.MethodsThe study sample was based on a double-blind, 6-month continuation study of ziprasidone and olanzapine (N=94). We developed a parsimonious 6-month GAF prediction function using a logistic regression model, and evaluated its predictive accuracy and performance using bootstrap estimates of c-statistics and error in predicted probability.ResultsAt up to 6 months of follow-up, 52 (55%) of all subjects treated with ziprasidone or olanzapine met the responder criterion of ≥50% improvement in GAF. At Week 2 (acute phase), the majority of ziprasidone (75%) and olanzapine (70%) patients showed greater than 25% improvement in the BPRS psychotic symptom subscale score. These early psychotic symptom responders (Week 2) showed significantly greater improvement in global functioning than early non-responders at all time points (Week 6 and Month 6) (all p's<0.05), confirming early response as an indicator of continued responsiveness to treatment over at least 6 months. A multivariate prediction function based on baseline neurocognitive scores and GAF, early reduction of psychotic symptoms at 2 weeks, and percentage of weight change observed at 6 weeks (All p's <0.05), showed statistically acceptable predictive performance (boostrap c-statistics=0.8598).ConclusionsOur findings suggest that a parsimonious model incorporating a psychotic symptom assessment score, baseline neurocognitive performance, and risk of weight gain can be developed for predicting patients' likelihood of achieving favorable, long-term treatment outcomes.     

Brain membrane disordering related to acute ethanol administration in naive and short-term ethanol-intoxicated rats

Crude synaptic membrane fluidity (checked by fluorescence polarization) together with (Na+ + K+) ATPase activity were examined 18 hours after a single oral ethanol administration (5 g/kg bwt.) to naive rats and to rats previously intubated with ethanol repeatedly during 4 days. The sensibility of both parameters to different concentrations of ethanol added in vitro (0.175 M-1.400 M) was also determined. Although no changes in the basal intrinsic fluidity were found, (Na+ + K+)ATPase activity increased slightly in both conditions. The fluidizing as well as the ATPase inhibiting effects following the addition of ethanol in vitro were markedly increased 18 hours after ethanol administration to naive rats. This hypersensitization was no longer apparent in rats pretreated with ethanol during 4 days. The acute ethanol-induced hypersensitization found in naive rats appears not to be related to an unspecific stress or to changes in body temperature. The disappearance of this hypersensitization in short-term alcohol-intoxicated animals may represent the first stage of tolerance acquisition.     

Relationship between clinical improvement and functional gains with clozapine in schizophrenia

Impairment in psychosocial functioning is a key feature in schizophrenia, but few studies have examined the relationship between improvements in symptoms and functioning. We examined the relationship between change in symptoms and change in functioning in a group of patients with treatment-resistant schizophrenia after 6 and 12 weeks of clozapine treatment. Participants were assessed prior to clozapine and again at 6 and 12-week on the 18-item Brief Psychiatric Rating Scale (BPRS) and the Social and Occupational Functioning Scale (SOFAS). Change scores in BPRS and SOFAS at 6 and 12-week post-clozapine were calculated and the direct relationship was assessed via regression models. Forty-three participants were included in this study; age of sample was 42.1±12.7 years, with 31 (72.1%) male participants. At baseline, the mean BPRS total and SOFAS scores were 46.98±12.86 and 33.07±10.79, respectively. There were significant improvements in BPRS total and SOFAS scores at 6 weeks, but no significant differences between 6 and 12-week assessments. There was no significant change in negative symptoms at both follow-up assessments. At 6-week, change in symptoms was not correlated with change in functioning and while the relationship between change in symptoms and functioning was stronger at 12 weeks, none of the BPRS factors emerged as a significant predictor. The present study found that lower baseline SOFAS score was the most robust predictor for improvements in SOFAS at 6 and 12-weeks. There appears to be a “ceiling” for functional improvements on clozapine, but follow-up studies are needed to examine functional gains beyond 12 weeks.     

Haloperidol plasma levels and acute clinical change in schizophrenia

Twenty-five inpatients with acute exacerbations of schizophrenia (by Research Diagnostic Criteria) or schizoaffective disorder underwent a prospective haloperidol dosing procedure and were assigned fixed doses chosen to yield a distribution of haloperidol plasma levels above and below a hypothesized upper therapeutic limit of 18 ng/ml. Changes in Brief Psychiatric Rating Scale scores after 1 week of treatment were negatively correlated with haloperidol plasma levels, and the statistically optimum cutoff point fell near the predicted 18 ng/ml. Plasma level/response relationships over the subsequent 3 weeks were weaker but patients with higher plasma levels had consistently less improvement.     

Plasma flupentixol concentrations and clinical response in acute schizophrenia

Twenty-three acutely psychotic inpatients treated with flupentixol were included in the study. Steady-state plasma concentrations were compared with therapeutic outcome in a routine clinical setting. The threshold concentration for satisfactory antipsychotic effect appeared to be approximately 2 ng/ml. Controlled studies are needed to establish the existence and exact limits of a therapeutic window.     

Depressive symptoms in acute schizophrenia.

1. The incidence of psychopathological symptoms rated by the CPRS was compared in 54 English depressed patients and 52 Swedish depressed patients. 2. A new rating scale for depression was created from the 10 items shown to be most sensitive to treatment change. The Montgomery and Asberg Depression Rating Scale (MADRS) was found to be more sensitive to treatment change than the Hamilton Rating Scale (HRS). 3. The incidence of psychopathological symptoms was assessed using the full Comprehensive Psychopathological Rating Scale (CPRS) in 50 patients with unequivocal acute schizophrenia. 36 patients were rated again after treatment and a 12 item rating scale for schizophrenia was derived from the items best able to discriminate between responders and non responders. 4. The schizophrenia scale was found to be a more sensitive discriminator between responders and non responders than the Brief Psychiatric Rating Scale (BPRS) in the 25 patients rated on both scales simultaneously. 5. There was a relatively high incidence of depressive symptoms rated on the MADRS in acute schizophrenia suggesting that depressive symptoms are a commoner presenting feature of acute unequivocal schizophrenia than is normally acknowledged.     

Use of an acute challenge with d‐amphetamine to model cognitive improvement in chronic schizophrenia

There is general agreement that pharmacologic improvement of cognition in chronic schizophrenia is a worthwhile therapeutic goal. Accordingly, there has been careful consideration about how neuropsychological methods can be used to detect improvement in cognition in people with schizophrenia. However, little data are available on the nature and magnitude of cognitive improvement that can occur with adjunctive therapeutic interventions. This double‐blind, placebo‐controlled crossover study examined the nature and magnitude of cognitive enhancement associated with a single‐dose administration of d‐amphetamine in 32 adult men with schizophrenia using a set of tasks developed specifically for detecting treatment‐related change in cognitive function. Relative to placebo, acute d‐amphetamine administration was associated with clinically meaningful improvement on measures of executive function and visual attention and vigilance, and with modest improvements on a measure of speed of processing. These results suggest that a brief computerized cognitive test battery designed for repeat administration, in combination with a statistical approach that emphasizes individual‐level change, provides a sensitive approach to detecting the effect of cognitive‐enhancing medications in people with chronic schizophrenia. Copyright © 2010 John Wiley & Sons, Ltd.     

P300 and symptom improvement in schizophrenia

RATIONALE: A reduced amplitude of the auditory evoked P300 was interpreted as a trait marker of schizophrenia but reports about correlations between schizophrenic psychopathology and P300 amplitude indicate also a state character. OBJECTIVES: To shed light upon these trait and state aspects a longitudinal study was performed to investigate the influence of symptom improvement and atypical neuroleptics on the amplitudes of the P300 and their subcomponents. METHODS: P300 was recorded in 17 schizophrenic patients before and after 4 weeks under either clozapine or olanzapine in a double-blind controlled design. For comparison, 17 age- and sex-matched healthy subjects were investigated. Parietal and frontal P300 subcomponents were investigated separately using dipole source analysis. RESULTS: Schizophrenic patients had smaller parietal (temporo-basal dipole) but not frontal subcomponent amplitudes (temporo-superior dipole) than controls. For the whole sample subcomponent amplitudes did not change over 4 weeks despite clinical improvement but patients with a pronounced improvement of the PANSS positive score showed a slight enhancement of both subcomponents. This was not significant when the P300 amplitude was measured at a single electrode (Pz). No significant difference between clozapine and olanzapine concerning effects on P300 amplitudes were observed. CONCLUSIONS: The results indicate that P300 subcomponents are modulated by changes of positive but not by changes of negative symptoms or different neuroleptics. This result was obvious for P300 subcomponents but not for Pz electrode measurement, which may be due to a higher reliability of the dipole source activity. The results can be integrated into a hypothetical model containing two pathophysiological subgroups of schizophrenia.     

Reduced haloperidol plasma concentration and clinical response in acute exacerbations of schizophrenia

Twenty-nine hospitalized patients suffering acute exacerbations of schizophrenia were treated for 2 weeks with fixed daily oral doses of haloperidol prospectively calculated to achieve a haloperidol plasma concentration of either 8–18 ng/ml or 25–35 ng/ml. Reduced haloperidol as well as haloperidol concentrations were assayed to determine if the former enhanced the predictability of response. Week 2 haloperidol plasma concentrations were negatively correlated to clinical response as measured by the percentage change in the BPRS score from baseline (r=–0.43,P<0.05). In contrast, week 2 plasma concentrations of reduced haloperidol, total haloperidol (haloperidol+reduced haloperidol), and reduced haloperidol/haloperidol ratio did not correlate with the change in the BPRS score. Chi-square analysis concluded that patients with ratios greater than one were no less likely to be treatment responders (<25% improvement in BPRS from baseline and week 2 BPRS <55) than those with ratios less than one. Although these data lend additional support to reports of a curvilinear relationship between haloperidol plasma concentration and clinical response, they also suggest that reduced haloperidol plasma concentrations are of no value in predicting treatment response.From the Mental Health Research Center — Major Psychoses, funded in part by NIMH Grant #5 P50 MH43271     

Behavioral response to methylphenidate and treatment outcome in first episode schizophrenia

In order to examine the relationship of behavioral response to psychostimulants and acute treatment response, we administered methylphenidate (0.5 mg/kg i.v.), an indirect dopamine (DA) agonist, to 38 patients who met Research Diagnostic Criteria (RDC) for definite or probable schizophrenia or schizoaffective disorder, were experiencing their first acute episode of psychosis, and had received less than 12 weeks or no prior lifetime neuroleptic exposure. Following baseline methylphenidate infusions, patients received a standardized regimen of acute neuroleptic treatment. Methylphenidate produced an increase in psychopathology reflected by a worsening of both positive and negative symptoms. Using a priori criteria, 61 percent of patients exhibited psychotic symptom activation, and 39 percent showed no change. Activation during methylphenidate infusion during the initial acute phase of illness was not correlated with time to achieve antipsychotic treatment response but was associated with side-effect vulnerability.     

SheaFlex70: cosmetic marker effects rather than clinical outcome improvement

Cheras PA, Myers SP, Paul‐Brent PA, Outerbridge KH, Nielsen GV. Randomized double‐blind placebo‐controlled trial on the potential modes of action of SheaFlex70^TM in osteoarthritis. Phytother Res 2010; 24: 1126–31.     

颅内压监测对创伤性脑损伤患者短期预后及急性肾损伤发生的影响

摘要：目的 探讨颅内压监测（ICP）对创伤性脑损伤（TBI）患者短期预后及急性肾损伤（AKI）发生的影响。方法 选取天津医科大学总医院神经外科创伤性脑损伤患者351例,其中ICP监测患者101例,无ICP监测患者250例。回顾性观察2组患者短期预后改善、呼吸机使用时间、重症监护病房（ICU）住院时间、住院时长、急性肾损伤发生率、20%甘露醇使用总量和临床生化检验结果的差异。进一步分析中型（n=160）和重型TBI（n=189）患者中应用和未应用ICP监测的临床特征。结果 ICP监测组患者AKI发生率及20%甘露醇使用量、血红蛋白、总蛋白和白蛋白水平低于无ICP监测组,呼吸机使用时间、ICU住院时间长于无ICP监测组（P＜0.05）;2组短期预后改善率及住院时间、球蛋白、肌酐和尿素氮水平差异无统计学意义。在重型TBI亚组中,ICP监测组（n=55）AKI发生率显著低于无ICP监测组（n=134）,呼吸机使用时间及尿素氮水平高于无ICP监测组（P＜0.05）;在中型TBI亚组中,ICP监测组（n=44）住院时间、ICU住院时间和呼吸机使用时间均长于无ICP监测组（n=116,P＜0.05）。结论 ICP监测可减少患者AKI发生率及20%甘露醇使用量,有助于TBI患者出入量平衡得到更精确控制。     

Trauma and short-term outcome for women in detoxification

The present study documents short-term outcomes for women receiving inpatient detoxification. We also aimed to determine the association between trauma history and these outcomes. One hundred and one randomly selected inner-city women completed a structured questionnaire covering demographic, treatment, and trauma history. All received follow-ups to trace postdischarge disposition; 59.4% (n = 60) were classified with positive short-term outcome. Statistically significant relationships were found between positive outcome and both number of previous detox hospitalizations (R = .20, p < .05) and attendance at outpatient programs (R = .35, p <.05). No significant relationships were demonstrated between outcome and histories of violence, use of drugs, or any demographic characteristics. Identifying histories of trauma did not interfere with treatment completion or further treatment seeking. Our results suggest that for women with heavy drug and alcohol problems, the capacity to accept and utilize help may be developed over repeated treatment exposures rather than related to intrinsic character traits.