Brian Sheitman

Neurochemical sensitization in the pathophysiology of schizophrenia: Deficits and dysfunction in neuronal regulation and plasticity

Existing pathophysiological models of schizophrenia are limited in their ability to account for all the clinical dimensions of the disorder. The purpose of this article is to describe a comprehensive hypothesis of the pathophysiology of schizophrenia and specifically how a deficit in neural regulation of developmental origin can lead to a pathologic form of neuroplasticity, i.e., neurochemical sensitization, which causes the onset and psychotic symptoms of the illness. We propose that the symptoms of schizophrenia may be caused by deficits in neural regulation resulting in a pathologic condition of neurochemical sensitization analogous to the preclinical model of pharmacologically-induced behavioral sensitization. This condition, if sustained, can lead to potential neurotoxic effects which produce structural neuronal alterations and persistent morbidity. Several lines of indirect and direct clinical evidence are consistent with this hypothesis. These include the ability of stimulant and psychotomimetic drugs to induce psychosis in normal subjects, the development of apparent sensitization to psychosis-inducing effects of stimulants in chronic stimulant abusers and the increased susceptibility of patients with schizophrenia to the psychotogenic effects of Dopamine (DA) agonists. This hypothesis integrates and extends the work of other investigators and is consistent with specific aspects of the longitudinal course of schizophrenia. The association of longer duration and more episodes of psychosis, with poor treatment response and outcome, are also consistent with this model. From this hypothesis, specific predictions about the illness course, treatment interventions, and pathophysiologic features of schizophrenia can be derived and tested through clinical investigation.

A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: A double-blind, randomized, 8-week trial

This pilot study was undertaken to estimate the acute antipsychotic effect size and side effect propensity of risperidone and olanzapine in the pediatric population, in comparison to haloperidol, a conventional antipsychotic with established efficacy. Risperidone and olanzapine are widely used as first-line treatments to ameliorate psychotic symptoms in youth, but their abilities to specifically treat children and adolescents presenting due to psychotic symptoms have not been rigorously studied. Subjects, selected because of prominent positive psychotic symptoms, were randomly assigned to double-blind, parallel treatment with risperidone, olanzapine, or haloperidol for 8 weeks. The primary outcome was reduction in the Brief Psychiatric Rating Scale for Children total score from baseline to termination. An exploratory, descriptive analysis was done to compare the three treatments. A total of 50 patients, 8–19 years, participated. All treatments reduced symptoms significantly with p-values (corrected for multiple comparisons) of 0.0018 for each of the atypical agents and 0.012 for haloperidol. In all, 88% of subjects treated with olanzapine, 74% treated with risperidone, and 53% treated with haloperidol met response criteria. The primary side effects observed in all patients were mild to moderate sedation, extrapyramidal symptoms, and weight gain. Risperidone and olanzapine acutely reduced psychotic symptoms in this pediatric sample. Exploratory comparisons indicate the magnitude of the antipsychotic response with these atypical agents is comparable to that observed with haloperidol. However, youth treated with risperidone and olanzapine experienced weight gain and extrapyramidal effects that appear more prevalent and severe than reported in adults.

Antipsychotic-induced weight gain and therapeutic response: A differential association

This study investigated the association between antipsychotic-induced weight gain and therapeutic response to haloperidol and three commonly used atypical neuroleptic medications in schizophrenia and schizoaffective disorder. The subjects were 151 patients enrolled in a double-blind experiment with a duration of 14 weeks comparing the therapeutic efficacy of haloperidol (n = 36), clozapine (n = 38), olanzapine (n = 38), and risperidone (n = 39). Absolute and relative (%) gain in body weight and body mass index (BMI) was determined for the entire duration of the double-blind treatment period; therapeutic response was assessed by the total score and the individual subscales of the Positive and Negative Symptom Scale. Compared with the pretreatment baseline, results indicated that for olanzapine and clozapine, therapeutic response was closely related to an absolute and relative gain in weight and to a gain in BMI. No association between weight gain and therapeutic response was found for risperidone and haloperidol. These findings suggest that patients who are likely to have the maximal benefits of olanzapine or clozapine treatment for symptom alleviation are at the highest risk of a clinically significant increase in weight gain.

Overt Aggression and Psychotic Symptoms in Patients with Schizophrenia Treated with Clozapine, Olanzapine, Risperidone, or Haloperidol

Abstract: The subjects were 157 treatment-resistant inpatients diagnosed with chronic schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week, double-blind trial. Incidents of overt aggression were recorded and their severity was scored. The Positive and Negative Syndrome Scale was administered. Atypical antipsychotics showed an overall superiority over haloperidol, particularly after the first 24 days of the study when the dose escalation of clozapine was completed. Once an adequate therapeutic dose of clozapine was reached, it was superior to haloperidol in reducing the number and severity of aggressive incidents. Patients exhibiting persistent aggressive behavior showed less improvement of psychotic symptoms than the other patients. There was an interaction between aggressiveness, medication type, and antipsychotic response: risperidone and olanzapine showed better antipsychotic efficacy in patients exhibiting less aggressive behavior; the opposite was true for clozapine. Clozapine appears to have superior antiaggresive effects in treatment-resistant patients; this superiority develops after the patient has been exposed to an adequate dose regimen.

A pilot study of social cognition and interaction training (SCIT) for schizophrenia

A pilot study of social cognition and interaction training (SCIT) for schizophrenia Dear Editors, There has been growing interest in the role of social cognition in schizophrenia (Penn et al., 1997). Much of the enthusiasm is due to the functional significance of social cognition; social cognition contributes variance beyond neurocognition to social functioning in schizophrenia (Brune, 2005; Vauth et al., 2004). Such findings have led to the measurement of social cognition in the MATRICS neurocognitive battery (Nuechterlein et al., 2004). The importance of social cognition has also led to interventions that seek to improve social cognitive functioning. These interventions can be conceptualized as either btargeted,Q that focus on a specific social cognitive ability (e.g., emotion perception; Silver et al., 2004), or bbroad-based,Q that typically include cognitive remediation (e.g., Hogarty et al., 2004). Targeted interventions ignore the range of social cognitive deficits in schizophrenia, while broad-based interventions raise questions about whether cognitive remediation is a necessary first step. These issues led us to develop an intervention that focuses specifically on the key domains of social cognition that are impaired in schizophrenia: emotion perception , attributional style, and theory of mind (Green et al., in press). Below, we report pilot data on this new intervention, Social Cognition and Interaction Training (SCIT). SCIT is a manual-based, group intervention designed for individuals with schizophrenia spectrum disorders, particularly individuals with paranoia. Three phases comprise SCIT: (1) Understanding emotions (6 sessions); (2) Social cognitive biases (7 sessions); and (3) Integration (5 sessions). In phase one, we introduce social cognition by asking participants to discuss times when they have gotten social situations bwrongQ (e.g., thinking someone was mad at them when they were not). The remainder of phase one is devoted to defining basic emotions, including suspiciousness, and linking facial expressions to emotions. This latter task is conducted in part with the Emotion Trainer, a computer program which has been shown to improve emotion perception in schizophrenia (Silver et al., 2004). Phase two is devoted to strategies for avoiding the pitfalls associated with bjumping to conclusions ,Q a common problem for clients with paranoia. This concept is illustrated via videotaped interactions of actors who draw conclusions from events without having adequate information. We tell clients that our goal is to make them better social detectives, so as not to bconvictQ based on initial evidence. To achieve this goal, clients are taught to brainstorm multiple possible explanations, first …

Clomipramine ameliorates adventitious movements and compulsions in prepubertal boys with autistic disorder and severe mental retardation

In an open, nonblind clinical trial, clomipramine reduced adventitious movements and compulsions in five previously medicated prepubertal boys with autistic disorder and severe mental retardation. Poorly adapted rating scales, interrater variability, subject heterogeneity, different treatment histories, and environmental stresses confounded the assessment of treatment effects.

Suggestive association between the C825T polymorphism of the G-protein β3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia

G-proteins are composed of alpha, beta and gamma subunits. Once activated, these subunits play a major role in the conversion of external receptor activation into intracellular signals. The functional C825T polymorphism of the beta3 subunit gene (GNB3) has recently been shown to modulate antidepressant response, with the T-allele conferring an increased signaling and being associated with favorable antidepressant response. We hypothesized that this polymorphism may be associated with response to antipsychotics in a population of 145 chronic schizophrenic patients deriving from two study-samples and being mainly treated with clozapine for up to 6 months. Overall, the C/C genotype was significantly associated with relative clinical improvement as measured by Brief Psychiatric Rating Scale (BPRS) change scores after 6 and 12 weeks (p<0.01 and p=0.03, respectively), with estimated effect sizes ranging from 4.8 to 7%. Our results further suggest that this effect is only attributable to Caucasians when compared to African-Americans. Moreover, our findings point to the role of intracellular mechanisms in antipsychotic response.

The development of treatment resistance in patients with schizophrenia: A clinical and pathophysiologic perspective

&NA; The pathophysiologic process and clinical factors that contribute to the development of treatment resistance in schizophrenia are not well defined. This article describes data indicating that treatment resistance may evolve over the course of the patients’ illness and maturational development. Data from multiepisode patients suggest that early effective intervention with clozapine can prevent treatment resistance. Early identification of patients with signs of treatment resistance is vital. Treatments must be effective and prevent relapse. At the first indication that a patient may be developing resistance (e.g., the emergence of extrapyramidal symptoms or increases in negative symptomatology) or may not be complying with treatment, clozapine therapy should be considered.

COMT158 polymorphism and hostility

The main study was designed primarily to compare the clinical effects of four antipsychotics in 157 patients with schizophrenia or schizoaffective disorder. The secondary genetic study, reported here, is based on a subset of 60 patients who consented to genotyping assays. Based on previous work with the catechol‐O‐methyltransferase (COMT) 158 polymorphism, we hypothesized that the Met–Met homozygotes would be more hostile than the heterozygotes and the Val–Val homozygotes. Hostility ratings at baseline were used to test this hypothesis. The Met–Met homozygotes (N = 7) were found to have significantly higher levels of hostility than the other patients (N = 53). The hypothesis was thus supported. The finding should be replicated in a larger sample.

Olanzapine for schizophrenia refractory to typical and atypical antipsychotics: an open-label, prospective trial.

The role of olanzapine in treatment-resistant schizophrenia is still unresolved. This article presents an open-label, prospective, 14-week trial with olanzapine in patients with schizophrenia and schizoaffective disorder selected for unambiguous resistance to either clozapine or risperidone and to typical antipsychotics. Forty-three inpatients (mean age, 41.6 years; mean duration of illness, 21.7 years) were enrolled and treated after cross-titration from their previous antipsychotic treatment with olanzapine 10 to 40 mg daily without any concomitant antipsychotic medication. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale, and the Extrapyramidal Symptom Rating Scale. The change with olanzapine treatment was associated with a PANSS total score improvement of 3.7 (SD = 15.6; not significant). There was a significant improvement for the PANSS cognitive and depression/anxiety factors, whereas the PANSS excitement factor worsened. The improvement rate was superior in patients receiving olanzapine doses higher than 20 mg. A total of 16.7% of patients reached response criteria set forth by a previous study. There was a significant decrease in extrapyramidal side effects (t = 2.04;p < 0.05) and statistically significant, yet modest, weight gain. These results indicate that olanzapine is only modestly effective in these severely treatment-resistant patients with schizophrenia. However, a trial with olanzapine can be recommended in these patients before moving to augmentation strategies, given the lack of proven alternatives and the observation that 16.7% of patients reached the response criteria.