Towards a muscarinic hypothesis of schizophrenia.

Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including pre-clinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder.

Gender-specific effects in the treatment of acute schizophrenia with risperidone.

INTRODUCTION: Gender-related effects play a role in antipsychotic treatment. We recently published a study demonstrating the efficacy of the atypical antipsychotic risperidone in the management of acute psychotic decompensations. We have now reanalysed the clinical data to assess the effects of gender on treatment and outcome. METHODS: High-dose treatment with risperidone (6-8 mg/d) was administered to 23 male and 25 female acutely psychotic schizophrenic admissions. PANSS- and CGI-ratings were obtained for four weeks. RESULTS: Males and females did not differ significantly in age, duration of treatment, dose of risperidone or clinical ratings. Females were treated with a significantly higher maximum dose of risperidone per kg body-weight. Significantly more females (n=14) than males (n=8) discontinued the use of risperidone. CONCLUSION: Although the reasons for the lower drop-out rate in males are not clear, gender differences in the clinical presentation may have contributed. High-dose treatment with risperidone may be more beneficial in males for the treatment of acute schizophrenia.

White matter asymmetry in the human brain: a diffusion tensor MRI study.

Language ability and handedness are likely to be associated with asymmetry of the cerebral cortex (grey matter) and connectivity (white matter). Grey matter asymmetry, most likely linked to language has been identified with voxel-based morphometry (VBM) using T(1)-weighted images. Differences in white matter obtained with this technique are less consistent, probably due to the relative insensitivity of the T(1) contrast to the ultrastructure of white matter. Furthermore, previous VBM studies failed to find differences related to handedness in either grey or white matter. We revisited these issues and investigated two independent groups of subjects with diffusion-tensor imaging (DTI) for asymmetries in white matter composition. Using voxel-based statistical analyses an asymmetry of the arcuate fascicle was observed, with higher fractional anisotropy in the left hemisphere. In addition, we show differences related to handedness in the white matter underneath the precentral gyrus contralateral to the dominant hand. Remarkably, these findings were very robust, even when investigating small groups of subjects. This highlights the sensitivity of DTI for white matter tissue differences, making it an ideal tool to study small patient populations.

Involvement of plasma atrial natriuretic peptide in protracted alcohol withdrawal.

OBJECTIVE: Atrial natriuretic peptide (ANP) has been shown to inhibit the effects of corticotrophin releasing hormone, corticotrophin and cortisol, and to influence affective and anxiety symptoms in man. We tested the hypothesis of whether ANP is associated with endocrine and psychopathological disturbances during acute alcohol withdrawal. METHOD: ANP and cortisol plasma concentrations were studied in alcoholics during in-patient detoxification and in healthy controls. Additionally, craving, depressive mood and anxiety were assessed. RESULTS: Although mean ANP levels increased significantly in alcoholics between days 1 and 14, they remained diminished compared to controls. Separating a subgroup of alcoholics with a decrease of ANP levels during withdrawal, these individuals revealed significantly elevated scores for mean and maximum craving and a trend to an elevated self-rated anxiety on day 14. CONCLUSION: We suggest that a dysregulation of ANP plasma levels during alcohol withdrawal may contribute to symptoms of protracted withdrawal such as craving and anxiety.

Neuropharmacological studies with SPECT in neuropsychiatric disorders.

The last decade saw a rapid development of single photon emission computed tomography (SPECT) from a tool to assess cerebral blood flow to the study of specific neurotransmitter systems. Because of the relatively long half-life of SPECT radioisotopes, it is practical to measure the availability of neuroreceptors and transporters in conditions approaching equilibrium. The cost-efficiency of SPECT allowed studies in relatively large samples of patients with various neuropsychiatric disorders. We have applied this approach in studies of dopaminergic, serotonergic, and muscarinergic neurotransmission in patients with dementia, extrapyramidal disorders, schizophrenia, and alcoholism. No simple associations were observed between a single defect in one neurotransmitter system and a certain neuropsychiatric disease. Instead, complex dysfunction of several neurotransmitter systems in multiple, partially connected brain circuits have been implicated. Treatment effects also have been characterized. Microdialysis and neurotransmitter depletion studies showed that most radioligands and endogenous neurotransmitters compete for binding at receptors and transporters. Future research directions include the assessment of endogenous neurotransmitter concentrations measured by depletion studies and of genetic effects on neuroreceptor and transporter expression.

In vivo olanzapine occupancy of muscarinic acetylcholine receptors in patients with schizophrenia.

Olanzapine is an atypical antipsychotic with potent antimuscarinic properties in vitro (K(i) = 2-25 nM). We studied in vivo muscarinic receptor occupancy by olanzapine at both low dose (5 mg/dy) and high dose (20 mg/dy) in several regions of cortex, striatum, thalamus and pons by analyzing [I-123]IQNB SPECT images of seven schizophrenia patients. Both low-dose and high-dose olanzapine studies revealed significantly lower [I-123]IQNB binding than that of drug-free schizophrenia patients (N = 12) in all regions except striatum. [I-123]IQNB binding was significantly lower at high-dose than low-dose in the same regions. Muscarinic occupancy by olanzapine ranged from 13% to 57% at 5 mg/dy and 26% to 79% at 20 mg/dy with an anatomical pattern indicating M(2) subtype selectivity. The [I-123]IQNB data indicate that olanzapine is a potent and subtype-selective muscarinic antagonist in vivo, perhaps explaining its low extrapyramidal side effect profile and low incidence of anticholinergic side effects.

In vivo determination of striatal dopamine D2 receptor occupancy in patients treated with olanzapine.

In vivo studies of dopamine D2 receptor occupancy with atypical antipsychotics have suggested good clinical efficacy at occupancy rates less than those observed with typical neuroleptics, and few extrapyramidal side effects (EPS), possibly even at high levels of D2 occupancy. We used [123I]IBZM-SPECT to investigate striatal D2 receptor occupancy in 10 schizophrenic patients who were treated with both a low (5 mg) and a high dose (20 mg) of the novel antipsychotic olanzapine without concomitant medications. The mean D2 occupancy at 5 mg was 59.8% (range 33-81%); the mean D2 occupancy at 20 mg was 82.8% (range 56-97%). Although the D2 occupancy rates on 5 and 20 mg olanzapine were significantly different (P < 0.001), there were no significant differences in clinical ratings for psychiatric symptoms or extrapyramidal side effects between the two doses of olanzapine. These data suggest that: (1) olanzapine doses below those used routinely occupy D2 receptors at levels approaching those associated with therapeutic response; (2) higher doses produce relatively high levels of D2 occupancy rates; and (3) EPS are mild even at relatively high levels of D2 occupancy.

Schizophrenia as a developmental disorder of the cerebral cortex.

The hypothesis that schizophrenia results from a developmental, as opposed to a degenerative, process affecting the cerebral cortex has become popular in current thinking about the disorder. While many of the data gathered in support of this hypothesis do not in themselves represent conclusive proof, an intriguing picture is emerging from a variety of research approaches. These approaches include the observation of minor physical anomalies, premorbid neuropsychological and social deficits, obstetrical complications, and exposure to adverse intrauterine events. Morphometric brain measurement techniques and neuropathological studies have perhaps provided more substantial support.

Extrapyramidal side effects with risperidone and haloperidol at comparable D2 receptor occupancy levels.

Risperidone is an antipsychotic drug with high affinity at dopamine D2 and serotonin 5-HT2 receptors. Previous clinical studies have proposed that risperidone's pharmacologic profile may produce improved efficacy for negative psychotic symptoms and decreased propensity for extrapyramidal side effects; features shared by so-called 'atypical' neuroleptics. To determine if routine risperidone treatment is associated with a unique degree of D2 receptor occupancy and pattern of clinical effects, we used [123I]IBZM SPECT to determine D2 occupancy in subjects treated with routine clinical doses of risperidone (n = 12) or haloperidol (n = 7). Both risperidone and haloperidol produced D2 occupancy levels between approximately 60 and 90% at standard clinical doses. There was no significant difference between occupancy levels obtained with haloperidol or risperidone. Drug-induced parkinsonism was observed in subjects treated with risperidone (42%) and haloperidol (29%) and was observed at occupancy levels above 60%. Based on these observations, it is concluded that 5-HT2 blockade obtained with risperidone at D2 occupancy rates of 60% and above does not appear to protect against the risk for extrapyramidal side effects.