Prefrontal cortical sulcal widening associated with poor treatment response to clozapine

Increased sulcal widening in the prefrontal cortex of patients with schizophrenia may be associated with a poor treatment response to clozapine. To further evaluate this, we examined data from patients treated with clozapine in our center. Patients with the greatest degree of improvement (n=26) and those with no improvement (n=10) were compared. Computerized tomography (CT) scans were rated blindly on a visual scale of prefrontal sulcal widening. Patients with the greatest degree of functional improvement had significantly less prefrontal sulcal widening than those whose symptoms remained unchanged. There was no relationship between clozapine response and general sulcal widening. These data support the link between the superior therapeutic efficacy of clozapine and the integrity of the prefrontal cortex.     

Subjective response to clozapine and risperidone treatment in outpatients with schizophrenia

The purpose of the present study was to compare the subjective response and attitude towards antipsychotic treatment between schizophrenic patients receiving clozapine and those receiving risperidone. Ninety-four outpatients who had been on a stable drug dosage were evaluated (clozapine group: n=57, mean dose=254.1 mg/day; risperidone group: n=37, mean dose=3.0 mg/day). Subjective response to antipsychotic treatment was assessed using the Drug Attitude Inventory (DAI). The two treatment groups had a positive total mean score, indicating that both groups had a positive subjective view of drug treatment. The proportion of subjects who had a positive total score was not different between the two groups. In subscale scores, multivariate analysis revealed that clozapine group tended to have a higher score on the subjective positive response subscale (P=0.06). The scores of subjective negative response or attitude to medication subscales were not different between groups. In conclusion, there was no marked difference between stabilized outpatients taking clozapine and risperidone in terms of subjective response and attitude towards antipsychotic treatment. Considering that subjects treated with clozapine were treatment resistant patients, equal DAI score might indicate a more favorable subjective experience of clozapine. Further prospective studies on subjective response to various atypical agents are required to obtain valuable insight into how best to use these drugs from the patient's perspective.     

Schizophrenic syndromes and clozapine response in treatment-resistant schizophrenia

Relationships between symptom profile and clozapine response were studied. Symptom scores on the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms were subjected to principal component analysis (PCA) in a group of 66 treatment-resistant schizophrenic patients, 49 of whom were treated with clozapine. Factor scores were compared among responders, non-responders and partial responders. The PCA yielded a four-factor solution, with positive symptoms, negative symptoms, cognitive disorganization and behavioral disorganization components. Cognitive and behavioral disorganization syndrome scores showed significant differences across groups. Cognitive disorganization was higher in non-responders, while behavioral disorganization was higher in partial responders. The results support the possibility of using clinical profiles to predict therapeutic response to clozapine.     

Smoking and therapeutic response to clozapine in patients with schizophrenia.

BACKGROUND: Of patients with schizophrenia, 70 to 80% smoke. Nicotine corrects certain information processing and cognitive psychomotor deficits seen in many patients with schizophrenia. Clozapine, but not conventional antipsychotics, has been shown to correct some of these deficits. METHODS: We assessed psychopathology and smoking in 70 patients with treatment refractory schizophrenia (55 smokers and 15 nonsmokers) at baseline when they were receiving conventional antipsychotics and again after they were switched to clozapine. RESULTS: Smokers showed significantly greater therapeutic response to clozapine than nonsmokers. Smokers smoked less when treated with clozapine than when treated with conventional antipsychotics. CONCLUSIONS: Certain patients with schizophrenia have contributing pathophysiologic mechanisms that respond favorably to either nicotine or clozapine.     

Clinical predictors of response to clozapine treatment in ambulatory patients with schizophrenia

BACKGROUND: Despite the advent of new atypical antipsychotics, clozapine remains an important option in the treatment of patients with poor response to conventional antipsychotics. Clinicians would be well served if clinical characteristics could be identified that predict a favorable response to clozapine. A few studies addressing this issue have reported inconsistent results. METHOD: The association of clinical characteristics with a sustained response was investigated in 37 partially treatment-refractory outpatients with a DSM-III-R diagnosis of chronic schizophrenia who had been assigned to clozapine treatment in a double-blind, haloperidol-controlled, long-term (29-week) study of clozapine. Response was defined as a 20% decrease of the Brief Psychiatric Rating Scale (BPRS) psychosis factor score sustained over 2 consecutive ratings. Differences between responders and nonresponders with regard to selected baseline variables were analyzed with t tests and chi2 tests. In addition, Cox regression analyses were performed to identify variables that best predicted a response to clozapine treatment. RESULTS: Clozapine responders were rated as less severely ill, showed a lesser degree of negative symptoms, and demonstrated fewer extrapyramidal side effects at baseline as compared with nonresponders. In addition, higher BPRS total scores--after controlling for the effects of the other variables--were associated with a response. CONCLUSION: In a cohort of partially treatment-refractory outpatients, a favorable response to clozapine was associated with characteristics describing less severely ill patients. The history of patients did not affect their response to clozapine.     

Stability of psychopathology dimensions in chronic schizophrenia: response to clozapine treatment

Current models of schizophrenia postulate that different symptom complexes, including the positive and negative, may relate to fundamental underlying neurobiological distinctions. However, the premise of an underlying stability to the psychopathological profile has not been systematically investigated, particularly in response to pharmacological intervention. The present work aimed to study this issue in 14 chronic schizophrenic inpatients by comparing their symptom clusters before and after a 20-week course of clozapine treatment. The results indicated significant improvement on all eight symptom dimensions, as well as in severity of general psychopathology. Despite the clinical gains, most dimensions remained highly stable, with correlations between prestudy and clozapine week 20 ranging up to .91 (P less than .0001) for the positive-negative composite score. These findings of stability over time, even in response to potent treatment, support the validity and importance of schizophrenic psychopathology dimensions, which appeared to possess fundamental traitlike characteristics.     

Quantitative EEG in schizophrenia and in response to acute and chronic clozapine treatment

Topographic quantitative electroencephalographic (EEG) power and frequency indices were collected in 17 treatment refractory, DSM-III diagnosed schizophrenic patients, before and after acute (single dose) and chronic (six weeks) clozapine treatment, as well as in 17 healthy volunteers. Prior to treatment, patients exhibited greater overall absolute theta power, slower mean alpha frequency and elevated absolute delta and total power in anterior regions. Acute dosing increased total spectrum power globally, slow wave power posteriorally, mean alpha frequency and beta power anteriorally and decreased alpha power posteriorally. Six weeks of clozapine treatment significantly reduced clinical ratings of positive and negative symptoms as well as symptoms of global psychopathology. Chronic treatment resulted in EEG slowing as shown by decreases in relative alpha power, mean beta/total spectrum frequency and by widespread increases in absolute total and delta/theta power. The preliminary findings suggest that brain electric profiling may be a promising tool for assessing and understanding the central impact of pharmacotherapeutic interventions in schizophrenia.     

Prefrontal lobe dysfunction predicts treatment response in medication-naive first-episode schizophrenia

Dysfunction of the frontal lobe is considered to be central to the pathology of schizophrenia. However, the nature of these abnormalities is unclear, in particular whether they are affected by treatment. In an earlier functional MRI study of our group we found dorsolateral prefrontal lobe (DLPFC) dysfunction to be present in medication-naive first-episode patients. In this follow-up study, we investigated whether treatment with atypical antipsychotics had an effect on DLPFC functioning, and whether (change in) DLPFC functioning was related to treatment response. Twenty-three medication-naive, first-episode male schizophrenia patients and 33 matched healthy controls were scanned at baseline and were re-scanned after 10 weeks, while performing a modified Sternberg working-memory task. We specifically investigated the effect of practice on brain activation, defined as the signal change between a novel and practiced working-memory task. After the baseline scan, patients were treated with atypical antipsychotics. Based on their symptom change after ten weeks, patients were divided into responders and non-responders We found DLPFC function did not change after 10 weeks in healthy controls or in patients who received treatment. However, while patients who responded to treatment did not differ from controls, non-responders showed a reduced practice effect in the DLPFC that was present already at baseline, which did not change after treatment. A reduced practice effect in the DLFPC at baseline was found to be predictive of poor treatment response at 10 weeks. These results suggest that prefrontal lobe dysfunction reflects a distinct neuropathological substrate in a subgroup of treatment non-responsive schizophrenia patients.     

Lamotrigine augmentation in patients with schizophrenia who show partial response to clozapine treatment

BackgroundSeveral placebo controlled studies investigating lamotrigine augmentation of clozapine in schizophrenia patients with partial response have shown varying results. The aim of this study was to further investigate the efficacy and safety of this augmentation strategy, and its effect on the glutamatergic system through utilizing mismatch negativity (MMN) component of auditory event related potentials.MethodsThe study was designed to evaluate the efficacy and safety of lamotrigine augmentation of clozapine in a 12-week, double-blind, placebo-controlled, prospective, randomized design. Thirty-four patients diagnosed according to DSM-IV schizophrenia criteria and with partial response to clozapine were included. Patients were randomized to 25 mg/day of lamotrigine or placebo, gradually increasing up to 200 mg/day on the 6th week. The change in psychopathology was assessed with Positive and Negative Syndrome (PANSS), Calgary Depression (CDS) and Clinical Global Impression-Severity (CGI-S) scales. A neuropsychological test battery was administered and MMN measurements were also obtained at baseline and endpoint. Safety evaluation included physical examination, UKU Side Effect Rating Scale (UKU) assessment and serum drug level measurements.ResultsNo significant differences were found between the two treatment groups in PANSS Positive and General Psychopathology, CDS, neurocognitive test and UKU scores, as well as MMN measurements. PANSS Total, Negative and CGI-S scores showed significant improvement compared to lamotrigine in the placebo group.ConclusionThis study did not show any benefit of augmentation of clozapine with lamotrigine in schizophrenia patients with partial response. The need for further investigation of other augmentation strategies of clozapine in partially responsive schizophrenia patients is evident.     

Double-blind study of clozapine dose response in chronic schizophrenia.

OBJECTIVE: This study explored the relative efficacy of three different doses of clozapine. METHOD: Fifty patients who met Kane et al.'s criteria for treatment-refractory schizophrenia or schizoaffective disorder were studied. All subjects were randomly assigned to 100, 300, or 600 mg/day of clozapine for 16 weeks of double-blind treatment. Forty-eight patients completed this first 16 weeks. Of the 50 patients, 36 went on to second and third 16-week trials of double-blind treatment at the remaining doses. RESULTS: Four subjects (8%) responded to the first 16-week condition, and one subject (2%) responded to the next 16-week crossover condition. A chi-square comparison of the response rates from the three dose groups failed to show a significant effect. An analysis of variance (ANOVA) comparison of Brief Psychiatric Rating Scale-Anchored (BPRS-A) total change scores from baseline to last observation carried forward showed a significant dose effect (600>300>100 mg/day) at 16 weeks of treatment. A crossover ANOVA of the BPRS-A total scores from the 48-week study also showed that the main effect for dose was highly significant; the 100-mg/day dose gave the higher (poorer) values, and the 300- and 600-mg/ day doses gave equal (better) values. Gender played a role in clinical response to treatment at 100 mg/day. CONCLUSIONS: Clozapine treatment at 100 mg/day was less effective than at 300 or 600 mg/day. At 100 mg/day, women responded better than did men. The 600 mg/day group had the best results, but an occasional patient required up to 900 mg/day. Overall response rates were lower than expected.     

氯氮平治疗精神分裂症及血药浓度研究

目的：探讨氯氮平治疗的适宜剂量及血药浓度与临床效应的关系。方法：氯氮平治疗精神分裂症６周共６２例（１５０ｍｇ／ｄ组２１例,３００ｍｇ／ｄ组２０例,４５０ｍｇ／ｄ组２１例）。用阳性和阴性症状量表（ＰＡＮＳＳ）和副反应量表（ＴＥＳＳ）评定疗效及副反应。在治疗第２、４、６周末晨服药前测血药浓度。结果：３种剂量组间有效率、ＰＡＮＳＳ减分值、ＴＥＳＳ增分值均无显著差异（Ｐ〉０．０５）,不同时段ＰＡＮＳＳ分值改变也无明显差异,提示３组间不仅疗效相当且起效快慢也无明显差异。完成血药浓度测定者４２例,有效血浓度低于以往研究推荐的３５０～４５０μｇ／Ｌ。提示氯氮平血浓度治疗窗尚有较大探讨余地。结论：在一定范围内低剂量氯氮平能取得与高剂量同样的疗效,对临床工作中避免盲目大剂量用药有指导意义,同时也有助于人们对氯氮平血浓度治疗窗有新     

Self-face recognition in schizophrenia is related to insight

A core feature of schizophrenia is the breakdown of the sense of self. A widespread clinical consequence of impaired self-awareness is a lack of insight. Self-face recognition is regarded as one aspect of self-awareness; how this relates to other self-referential processes such as insight into the disorder is as yet unknown. Nineteen patients with schizophrenia performed a facial recognition task using video morphings during which an average face gradually transformed into one’s own, a famous or an unfamiliar face (and vice versa). Reaction times to detect faces during the transitions were compared between patients and a matched control group. In the patient group, we also examined correlations between face recognition and insight, psychopathology, and self-evaluation. Both patients with schizophrenia and controls recognised their own faces faster than unfamiliar faces. Whereas healthy subjects recognised a famous face at an intermediate speed that did not differ significantly from the recognition of one’s own and unfamiliar faces, schizophrenia patients recognised the famous face, similar to their own face, significantly faster than an unfamiliar face. Moreover, in the patient group, higher insight correlated with faster reaction times in distinguishing one’s own from famous faces. Patients with schizophrenia seem to distinguish less than controls between their own and a famous face relative to an unfamiliar face. Patients with good insight into the disorder, however, were better able to differentiate between their own and a famous face. This study supports the view that self-face recognition is an indicator for higher-order self-awareness.     

Refractory symptomatic schizophrenia resulting from frontal lobe lesion: response to clozapine

A 34-year-old man with a 10-year history of persistent auditory hallucinations and passivity delusions had failed to respond to a variety of conventional antipsychotic medications. He had a history of head trauma 8 years before the onset of psychiatric symptoms. Recent investigations revealed a post-traumatic infarct, situated in the left frontal lobe, on a magnetic resonance imaging scan. Treatment with clozapine for more than 2 years resulted in a marked improvement in his psychotic symptoms. The localization of the brain lesion may be related to the etiology of his symptoms and to the clinical response to clozapine.     

Gap junction intercellular communication in gliomas is inversely related to cell motility

Gliomas are lethal because of local invasion into brain parenchyma. Glioma cells were isolated from different regions (white matter, gray matter and tumor core) of a glioma-bearing dog brain. Individual clonal cell lines were established from each area, and characterized for growth, migration and gap junctions. The regional clonal cell lines differed in rates and preferred substrate for migration. Cell lines generated from invaded white matter showed stimulated migration on collagen and variable migration on merosin, whereas migration of cell lines derived from invaded gray matter showed the reciprocal responses: stimulation on merosin and inhibition on collagen. Gap junctional communication showed significant degrees of variation between the different clones. A direct inverse relationship between the number of cells demonstrating gap junctional communication and migration rate of cells away from multicellular spheroids was evident. Glioma cells which have a reduced capacity to connect to each other have an accelerated migration rate onto autologous, glioma-derived matrix. These results suggest that invasive glioma cells suppress autologous cell-to-cell cohesion, partly evident as reduced formation of gap junctions. In addition, glioma cells were stimulated to migrate in a dose-dependant manner in response to epidermal growth factor (EGF) coincident with the reduction of Cx43 levels and increased serine phosphorylation. We speculate that in order for glioma cells to invade locally into brain parenchyma they must first detach from neighboring cells ("let go...let's go" paradigm of invasion).     

How long to wait for a response to clozapine: a comparison of time course of response to clozapine and conventional antipsychotic medication in refractory schizophrenia

This study compared the time course to clinical improvement with clozapine and with conventional antipsychotic medications. A double-blind trial compared clozapine and haloperidol in patients with schizophrenia who were refractory to conventional antipsychotic medication and were hospitalized for 30 to 364 days at 15 Veteran Affairs medical centers during the year before study entry. Patients in the original study were randomly assigned to haloperidol or clozapine and followed for 12 months, at maximum tolerable doses. Patients who completed a full year of treatment with clozapine (n = 122), or with either haloperidol or another conventional antipsychotic medication (n = 123) and who also completed the 9- or 12-month assessment were included. Response to treatment was defined as 20 percent improvement on standard scales of symptoms and quality of life at the latter of the 9- or 12-month interviews. More patients assigned to clozapine achieved 20 percent improvement in symptoms at each followup. Among patients who did not improve at 6 weeks, 3 months, or 6 months, there were no significant differences between clozapine and comparison patients in outcomes at 1 year. Among patients who did improve, maintenance of that improvement also did not differ between the groups at 1 year on symptom measures. Maintenance of improvement in quality of life at 1 year was significantly greater for clozapine patients who had improved at 6 months (p < 0.04). Significant differential symptom response to clozapine occurred exclusively during the first 6 weeks of treatment.     

Clinical correlates of sulcal widening in chronic schizophrenia

Fifty-five chronic schizophrenic males who consented to have a computed Tomographic (CT) brain scan were divided into those with cerebral atrophy evidenced by sulcal widening (n=22) and those with normal sulci (n=33). The two groups were compared on several clinical variables obtained from medical records by psychiatrists who were unaware of the CT results. Schizophrenic men with sulcal enlargement were significantly less likely to show agitation as a clinical symptom during an acute relapse and had significantly worse cognitive test scores on admission to the hospital. The implications of these findings are compared to the literature on ventricular enlargement and their clinical applications are discussed.     

Age at first intercourse is inversely related to female cortisol stress reactivity

The relationship between age at first sexual intercourse and salivary cortisol stress reactivity (to the Trier Social Stress Test; TSST; consisting of public speaking and mental arithmetic) was examined in healthy subjects (43 females and 36 males; ages 19–38). Women reporting earlier first intercourse had less intense cortisol increases in response to the stressor (a non-significant trend was observed for males), and faster recovery from the stressor. Results were not confounded by age, oral contraceptive use, depression scores, smoking status, or body mass index. It is concluded that earlier first intercourse is associated with less reactivity to and faster recovery from stress as indexed by this endocrine measure. Results are discussed in terms of genetic and psychological influences on first intercourse and implications for coping with interpersonal stress.     

Effectiveness of clozapine in neuroleptic-resistant schizophrenia: clinical response and plasma concentrations

OBJECTIVE: To assess the relation between plasma concentrations of clozapine and its 2 main metabolites desmethyl clozapine and clozapine N-oxide, and clinical change in a sample of inpatients with schizophrenia who were resistant to conventional neuroleptics. METHOD: Thirty-seven patients (27 men and 10 women, mean age 34.8 yr) with treatment-resistant schizophrenia were treated with clozapine for 18 weeks; dosage was adjusted according to clinical response, and plasma concentrations of clozapine and of its metabolites were measured weekly by high-performance liquid chromatography. Clinical status was also assessed weekly with the Positive and Negative Syndrome Scale (PANSS). Patients were considered "responsive" if they showed at least a 20% improvement over their baseline PANSS ratings. RESULTS: The mean endpoint clozapine dosage was 486.5 mg/day. There was a significant correlation between the daily dosage of clozapine and the plasma levels of clozapine and of its metabolites (p < 0.05). There was no correlation between the clozapine plasma level and the percent improvement on the PANSS. Clozapine plasma levels were not significantly different between those who responded to clozapine (n = 19) and those who did not (n = 18) and were not significantly different between patients who smoked (n = 28) and those who did not (n = 9). Receiver operating characteristic (ROC) curve analysis determined the plasma level threshold (above which a better clinical response was obtained) to be 550 ng/mL. Using the total of plasma levels of clozapine and its metabolites did not lead to a better sensitivity and specificity. CONCLUSIONS: Our calculated plasma clozapine threshold was higher than that reported by others, but this may be related to the severity of symptoms of our patient sample. Monitoring plasma rates remains a useful tool, together with clinical evaluation, to establish the clozapine dosage for an optimum benefit-risk ratio.     

Placebo-controlled trial of glycine added to clozapine in schizophrenia

OBJECTIVE: The purpose of this study was to evaluate the effects of high-dose oral glycine on positive and negative symptoms and cognitive function when added to clozapine in adults with schizophrenia. METHOD: The authors conducted a double-blind, placebo-controlled, parallel-group trial of 60 g/day of glycine added to clozapine for 8 weeks in 30 adults with schizophrenia. Clinical ratings were performed every 2 weeks. RESULTS: Twenty-seven patients completed the trial. Glycine augmentation of clozapine produced no statistically significant change in positive or negative symptoms or cognitive functioning. No subjects showed clinically significant worsening of clinical ratings. CONCLUSIONS: These data, combined with data from previous trials with D-cycloserine and glycine, suggest that agonists at the glycine site may be less effective when combined with clozapine than they are when combined with conventional antipsychotics.