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Biomedical subjects

Robert B Zipursky

Publications and source records attributed to Robert B Zipursky.

At least 19 recordsLinked to original sources
PubMed2006

The effect of antipsychotic treatment on Theory of Mind.

BACKGROUND: Deficits in a patient's 'theory of mind' (TOM) have been proposed to lead to psychosis. However, it remains unclear whether TOM deficits constitute a trait- or a state-related deficit and whether they respond to antipsychotic treatment, and also whether the change in TOM and change in psychosis are associated. METHOD: In the cross-sectional component of this study, 71 patients with psychotic disorders were included and TOM ability was measured using a hinting task in which subjects had to infer real intentions behind indirect speech. In the longitudinal study, a different cohort of 17 drug-free patients were included wherein they received antipsychotic treatment for 6 weeks and the effect on psychotic symptoms and TOM was measured every 2 weeks. Associations between TOM and psychopathology were assessed and a mixed effects model was used to investigate the rate of change over time. RESULTS: Positive and Negative Syndrome Scale (PANSS) total scores were significantly associated with TOM scores. The hinting task was not associated with positive symptoms but was significantly associated with negative and general symptoms. The longitudinal arm of the study showed that both PANSS positive scores and TOM improved after medication was started, particularly during the first 2 weeks of antipsychotic treatment, but these changes were not associated. The TOM response at 2 weeks of antipsychotic treatment reached similar values to those obtained in the cross-sectional sample. CONCLUSIONS: Although TOM and psychotic symptoms are related to each other, antipsychotic treatment impacts each independently, suggesting a dissimilar cognitive or neurobiological substrate for the two.

Adult↗
PubMed2006

Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response--a double-blind PET study in schizophrenia.

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.

Adolescent↗
PubMed2006

The selective effect of antipsychotics on the different dimensions of the experience of psychosis in schizophrenia spectrum disorders.

While most standard symptom scales regard the 'psychotic' or 'positive' dimension of schizophrenia as a single factor, several lines of evidence suggest that psychosis itself is a multidimensional phenomenon. The foregoing literature suggested at least five distinct dimensions to psychosis; to test this, we developed, validated and applied an instrument to measure these dimensions and then applied it to examine the effect of antipsychotics on the different dimensions of the psychotic experience. The Dimensions of Psychosis Instrument (DIPI) was administered to 91 psychotic patients with schizophrenia spectrum disorders and a confirmatory factor analyses (CFA) was carried out to examine the five dimensions: cognitive preoccupation (CP) with the psychotic experience; emotional involvement (EM); behavioural impact (BI) of the experience; conviction (CO) in it; emotional; and external perspective (EP) about the experience. In a separate cohort of 17 prospectively treated patients, the impact of antipsychotics on these dimensions was assessed. BI showed the greatest improvement (32%) at 2 weeks, while CP and emotional improved somewhat less (22% and 14%, respectively). Improvement in CO was limited (6%) while EP showed no change. These results suggest that over the first few weeks of treatment, antipsychotics rapidly reduce the behavioural impact of the principal psychotic symptom and decrease cognitive and emotional preoccupation with it, without greatly altering the patients' conviction in or perspective about their psychotic experience.

Adolescent↗
PubMed2006

A longitudinal study of neurocognitive function in individuals at-risk for psychosis.

INTRODUCTION: Clinically defined prodromal diagnostic criteria identify at-risk individuals with a 35-40% likelihood of developing a psychotic disorder within a year. The time course and predictive value of cognitive deficits in the development of psychosis has not been established. METHODS: A comprehensive neurocognitive battery and clinical assessments were administered to 37 subjects meeting Criteria of Prodromal States (COPS) criteria for being at risk for psychosis, and two comparison groups: 59 first episode and 47 healthy subjects. Subjects were also evaluated at 6-month and 1-year follow-up periods. Primary analyses used a neurocognitive composite score derived from individual neurocognitive measures, including measures of vigilance, verbal memory, working memory, and processing speed. RESULTS: At-risk subjects performed more poorly than healthy subjects (t=2.93, P=0.01), but better than first episode subjects (t=4.72, p<0.0001). At-risk subjects were particularly impaired on measures of vigilance and processing speed. Cognitive composite scores were significantly lower in at-risk subjects who progressed to psychosis (N=11; z=-1.2), while those at-risk subjects who did not progress to psychosis (N=17) performed better (z=-0.5), and not significantly different from controls. Poor CPT performance combined with better WAIS-R digit symbol performance predicted progression to psychosis. Severity of neurocognitive deficits was not related to duration of prodrome or to time to development of psychosis and neurocognitive function improved in all subjects except those who progressed to psychosis. CONCLUSION: Neurocognitive impairment emerges early in the course of psychotic illness. Performance on tests of neurocognition may prove to be an early risk predictor for subsequent development of psychotic disorders.

Adolescent↗
PubMed2006

Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode.

BACKGROUND: Many patients recovering from a first psychotic episode will discontinue medication against medical advice, even before a 1-year treatment course is completed. Factors associated with treatment adherence in patients with chronic schizophrenia include beliefs about severity of illness and need for treatment, treatment with typical versus atypical antipsychotic and medication side effects. METHOD: In this 2-year prospective study of 254 patients recovering from a first episode of schizophrenia, schizophreniform, or schizoaffective disorder we examined the relationship between antipsychotic medication non-adherence and patient beliefs about: need for treatment, antipsychotic medication benefits, and negative aspects of antipsychotic medication treatment. We also examined the relationship between medication non-adherence and treatment with either haloperidol or olanzapine, and objective measures of symptom response and side effects. RESULTS: The likelihood of becoming medication non-adherent for 1 week or longer was greater in subjects whose belief in need for treatment was less (HR=1.75, 95% CI 1.16, 2.65, p=0.0077) or who believed medications were of low benefit (HR=2.88, 95 CI 1.79-4.65, p<0.0001). Subjects randomized to haloperidol were more likely to become medication non-adherent for >or=1 week than subjects randomized to olanzapine (HR-1.51, 95% CI 1.01, 2.27, p=0.045). CONCLUSION: Beliefs about need for treatment and the benefits of antipsychotic medication may be intervention targets to improve likelihood of long-term medication adherence in patients recovering from a first episode of schizophrenia, schizoaffective, or schizophreniform disorder.

Adult↗
PubMed2006

Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis.

OBJECTIVE: This study assessed the efficacy of olanzapine in delaying or preventing conversion to psychosis and reducing symptoms in people with prodromal symptoms of schizophrenia. METHOD: This randomized trial occurred at four North American clinics in the Prevention Through Risk Identification, Management, and Education project. Outpatients received olanzapine (5-15 mg/day, N=31) or placebo (N=29) during a 1-year double-blind treatment period and no treatment during a 1-year follow-up period. Efficacy measures included the conversion-to-psychosis rate and Scale of Prodromal Symptoms scores. RESULTS: During the treatment year, 16.1% of olanzapine patients and 37.9% of placebo patients experienced a conversion to psychosis, a nearly significant difference. The hazard of conversion among placebo patients was about 2.5 times that among olanzapine-treated patients, which also approached significance. In the follow-up year, the conversion rate did not differ significantly between groups. During treatment, the mean score for prodromal positive symptoms improved more in the olanzapine group than in the placebo group, and the mixed-model repeated-measures least-squares mean score showed significantly greater improvement between weeks 8 and 28 with olanzapine. The olanzapine patients gained significantly more weight (mean=8.79 kg, SD=9.05, versus mean=0.30 kg, SD=4.24). CONCLUSIONS: A significant treatment difference in the conversion-to-psychosis rate was not demonstrated. However, these results may be influenced by low power. The nearly significant differences suggest that olanzapine might reduce the conversion rate and delay onset of psychosis. Olanzapine was efficacious for positive prodromal symptoms but induced weight gain. Further treatment research in this phase of illness is warranted.

Adolescent↗
PubMed2006

Insulin resistance and adiponectin levels in drug-free patients with schizophrenia: A preliminary report.

OBJECTIVE: To compare the insulin sensitivity and adiponectin levels of medication-free patients suffering from schizophrenia or schizoaffective disorder with that of matched healthy volunteers. METHOD: We evaluated 9 nondiabetic patients aged 26.6 years (median 26 years, range 17 to 41 years) and matched volunteers, using the frequently sampled intravenous glucose tolerance test, minimal model analysis, and fasting adiponectin levels. RESULTS: The mean insulin sensitivity index of the patients was 42% lower than that of the healthy volunteers (P = 0.026), with inadequate compensation in insulin secretion. Patients with schizophrenia tended to have reduced adiponectin levels (P = 0.055). CONCLUSIONS: By direct measurement, this study provides evidence of insulin resistance and susceptibility to type 2 diabetes in patients with schizophrenia who are free of antipsychotic drugs.

Adiponectin↗
PubMed2005

How antipsychotics work: the patients' perspective.

BACKGROUND: While much is known about the neuropharmacology and objective efficacy of antipsychotics, little is known about how these drugs act on psychosis from the patients' perspective. Most previous studies of the patient's perspective have focused on drug tolerability and acceptability-rather than their effects on psychosis per se. METHODS: The authors examined how antipsychotics work from a patient's perspective by analyzing their responses to a subjective questionnaire. Ninety-one patients with schizophrenia (cross-sectional component) and eight neuroleptic naïve patients (before and after treatment, longitudinal component) participated. The patients' responses to the questionnaire were analyzed using Principal Component Analysis (PCA) and general linear models. RESULTS: Analysis of the patients' responses showed that from their perspective the drugs were substantially more effective in: "help deal, help stop thinking, and make the symptoms not bother" rather than "take away" or "change my mind". This differentiation was clear in the raw data and was supported by a formal PCA. Two underlying factors-the first termed detachment and second eradication-explained 71% of the variance in the patients' perspective on how antipsychotics work for them. Neuroleptic naïve patients, who had no prior exposure, expected drugs to help with both detachment and eradication, but, changed their mind with just 6 weeks of experience with the medications. CONCLUSIONS: From the patients' perspective the action of antipsychotics is best characterized by a detachment from symptoms-rather than an eradication or elimination of symptoms. They have more wide-ranging expectations prior to antipsychotic exposure, but, even 6 weeks of exposure is sufficient to change their mind in favor of detachment. This finding is consistent with some of the very earliest ideas that antipsychotics produced a state of "indifference" and is also consistent with the more recent, neurobiologically informed notions that antipsychotics work by dampening the salience of psychotic symptoms.

Adolescent↗
PubMed2005

Treatment response to olanzapine and haloperidol and its association with dopamine D receptor occupancy in first-episode psychosis.

OBJECTIVE: Response to typical antipsychotic medication has been associated with achieving a level of striatal dopamine D2 receptor occupancy in the range of 65% to 70%. We undertook this study to determine whether response to the atypical antipsychotic olanzapine occurs at lower levels of D2 receptor occupancy. METHOD: Eighteen patients who presented with a first episode of psychosis were randomized to receive olanzapine 5 mg daily or haloperidol 2 mg daily in a double-blind design. We acquired positron emission tomography (PET) scans using the D2 ligand [11C]raclopride within the first 15 days of treatment to determine the percentage of D2 receptors occupied by the medication. According to response, dosage was then adjusted to a maximum dosage of 20 mg daily of either drug. PET scans were repeated after 10 to 12 weeks of treatment. RESULTS: At the first PET scan, the 8 olanzapine-treated patients had significantly lower D2 receptor occupancies (mean 63.4%, SD 7.3) than those observed in the 10 patients treated with haloperidol (mean 73.0%, SD 6.1). When patients were rescanned following dosage adjustment, mean D2 receptor occupancies were greater than 70% in both groups. D2 receptor occupancies did not differ significantly between the olanzapine-treated group (mean 72.0%, SD 5.7) and the haloperidol-treated group (mean 78.7%, SD 7.6). CONCLUSIONS: These results suggest that, in patients being treated for a first episode of psychosis, olanzapine has its antipsychotic effect at approximately the same levels of D2 receptor occupancy as are achieved with low dosages of haloperidol.

Acute Disease↗
PubMed2005

Neurobiology of early psychosis.

BACKGROUND: Neurobiological studies of the early course of psychoses, such as schizophrenia, allow investigation of pathophysiology without the confounds of illness chronicity and treatment. AIMS: To review the recent literature on the biology of the early course of psychoses. METHOD: We carried out a critical appraisal of the recent findings in the neurobiology of early psychoses, using structural, functional and neurochemical imaging techniques. RESULTS: Brain structural alterations are present early in the illness and may predate symptom onset. Some changes, notably those in frontal and temporal lobes, can progress during the early phases of the illness. Functional and neurochemical brain abnormalities can also be seen in the premorbid and the early phases of the illness. Some, although not all, changes can be trait-like whereas some others might progress during the early years. CONCLUSIONS: A better understanding of such changes, especially during the critical periods of the prodrome, around the transition to the psychotic phase and during the early phases of the illness is crucial for continued research into preventive intervention strategies.

Brain↗
PubMed2005

Course and predictors of weight gain in people with first-episode psychosis treated with olanzapine or haloperidol.

BACKGROUND: Substantial weight gain is common with many atypical antipsychotics. AIMS: To evaluate the extent, time course and predictors of weight gain and its effect on study retention among people with first-episode psychosis treated with olanzapine or haloperidol. METHOD: Survival analysis assessed time to potentially clinically significant weight gain (> or =7%) and the effect of weight gain on study retention. Weight gain during the 2-year study was summarised using last-observation-carried-forward (LOCF), observed cases and study completion approaches. RESULTS: After 2 years of treatment, LOCF mean weight gain was 10.2 kg (s.d.=10.1) for olanzapine (n=131) and 4.0 kg (s.d.=7.3) for haloperidol (n=132); observed cases mean weight gain was 15.4 kg (s.d.=10.0) for olanzapine and 7.5 kg (s.d.=9.2) for haloperidol. Change in body mass index was significantly predicted only by treatment group (P < 0.0001). CONCLUSIONS: Olanzapine was associated with significantly greater weight gain than haloperidol, with both leading to greater weight gain than previously described.

Adult↗
PubMed2005

Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study.

BACKGROUND: A substantial number of women of childbearing age suffer from schizophrenia and other mental illnesses that require the use of antipsychotic drugs. Atypical antipsychotics have been on the market since the mid-1990s, and to date there are no prospective comparative studies regarding use during pregnancy. OBJECTIVES: (1) To determine whether atypical antipsychotics increase the rate of major malformations above the 1% to 3% baseline risk seen in the general population. (2) To examine rates of spontaneous and therapeutic abortions, rates of stillbirths, birth weight, and gestational age at birth. METHOD: The cohort was composed of pregnant women who contacted the Motherisk Program in Canada or the Israeli Teratogen Information Service in Israel and women who were recruited from the Drug Safety Research Unit database in England. Women who had been exposed to atypical antipsychotics were matched to a comparison group of pregnant women who had not been exposed to these agents. RESULTS: Data were obtained on 151 pregnancy outcomes that included exposure to olanzapine (N= 60), risperidone (N = 49), quetiapine (N = 36), and clozapine (N = 6). Among women exposed to an atypical antipsychotic, there were 110 live births (72.8%), 22 spontaneous abortions (14.5%), 15 therapeutic abortions (9.9%), and 4 stillbirths (2.6%). Among babies of women in this group, there was 1 major malformation (0.9%), and the mean +/-SD birth weight was 3341 +/-685 g. There were no statistically significant differences in any of the pregnancy outcomes of interest between the exposed and comparison groups, with the exceptions of the rate of low birth weight, which was 10% in exposed babies compared with 2% in the comparison group (p = .05), and the rate of therapeutic abortions (p = .003). CONCLUSION: These results suggest that atypical antipsychotics do not appear to be associated with an increased risk for major malformations.

Abnormalities, Drug-Induced↗
PubMed2004

Volumetric MRI measurement of caudate nuclei in antipsychotic-naive patients suffering from a first episode of psychosis.

Magnetic resonance imaging (MRI) studies measuring basal ganglia volumes in first episode patients suggest that treatment with typical neuroleptics leads to alteration in these brain structures. However, caudate nuclei volumes (CNV) of untreated first-episode patients may even be smaller than in healthy controls. We investigated whether CNV of newly diagnosed neuroleptic-naive psychotic patients differ as compared to an age- and sex-matched healthy control group to detect possible treatment effects early in the course of this illness. Magnetic resonance images were acquired in 37 un-medicated psychotic patients and 37 healthy controls. Ten of the patients were re-examined after 12 weeks of treatment with the second generation antipsychotic quetiapine. Regions of interest (ROI) delineating the caudate nuclei bilaterally were drawn manually using Brain Image software. The neuroleptic-naive patients showed a mean CNV of 8.40 cc (SD=1.01) and the controls of 8.55 cc (SD=1.16). There was no significant difference between groups (F=.600; P=.441). In contrast to previous studies in patients treated with typical neuroleptics, this cross-sectional MRI study did not find significant differences in CNV of neuroleptic-naive first-episode patients compared to healthy controls.

Adult↗
PubMed2004

Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics.

OBJECTIVE: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics. METHOD: Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D(1) and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone. RESULTS: Mean striatal D(1) occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31). CONCLUSIONS: Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.

Adolescent↗
PubMed2003

Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome.

BACKGROUND: The prodromal phase of schizophrenic disorders has been described prospectively. The present study aimed to determine the short-term efficacy and safety of olanzapine treatment of prodromal symptoms compared with placebo. METHODS: This was a double-blind, randomized, parallel-groups, placebo-controlled trial with fixed-flexible dosing conducted at four sites. Sixty patients met prodromal diagnostic criteria, including attenuated psychotic symptoms, as determined by structured interviews. Olanzapine 5-15 mg daily or placebo was prescribed for 8 weeks. RESULTS: In the mixed-effects, repeated-measures analysis, the treatment x time interaction for the change from baseline on the Scale of Prodromal Symptoms total score was statistically significant, and post hoc analyses revealed that the olanzapine-placebo difference reached p<.10 by week 6 and p<.05 at week 8. Ratings of extrapyramidal symptoms remained low in each group and were not significantly different. Olanzapine patients gained 9.9 lb versus.7 lb for placebo patients (p<.001). CONCLUSIONS: This short-term analysis suggests olanzapine is associated with significantly greater symptomatic improvement but significantly greater weight gain than is placebo in prodromal patients. Extrapyramidal symptoms with olanzapine were minimal and similar to those with placebo. Future research over the longer term with more patients will be needed before recommendations can be made regarding routine treatment.

Adolescent↗