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Background: Selective action at limbic cortical dopamine D(2)-like receptors could mediate atypical antipsychotic efficacy with few extrapyramidal side-effects., Aims: To test the hypothesis that quetiapine has 'limbic selective' D(2)/D(3) receptor occupancy in vivo., Method: The high-affinity D(2)/D(3) ligand [(123)I]-epidepride and single photon emission tomography were used to estimate D(2)/D(3) specific binding and an index of relative percentage D(2)/D(3) occupancy in striatal and temporal cortical regions for quetiapine-treated patients (n=6). Quetiapine-, and previously studied typical-antipsychotic- and clozapine-treated patients were compared., Results: Mean (s.d.) relative percentage D(2)/D(3) receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300-700 mg/day). Quetiapine treatment resulted in limbic selective D(2)/D(3) blockade similar to clozapine and significantly higher than typical antipsychotics., Conclusions: Preliminary data suggest that limbic selective D(2)/D(3) receptor blockade is important for atypical drug action.

Background: The dopamine hypothesis proposes that antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade., Aim: To evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride., Method: [123I]-epidepride SPET scans were performed on 12 patients with schizophrenia treated with antipsychotics and II age-matched healthy controls. [123I]-epidepride 'specific binding' to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by typical antipsychotic drugs determined., Results: Mean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively., Conclusions: Typical antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.

Background: 5-HT2A receptor antagonism may be crucial to the action of atypical antipsychotics. Previous work has related 5-HT2A receptor blockade to clinical efficacy and protection from extrapyramidal side-effects., Method: We developed a SPET imaging protocol for assessing 5-HT2A receptor binding using the selective ligand 123I-5-I-R91150. Six healthy volunteers, five clozapine- and five risperidone-treated subjects with DSM-IV schizophrenia were studied. Multi-slice SPET was performed on each subject., Results: Cortex:cerebellum ratios were significantly lower in both clozapine- and risperidone-treated subjects compared with the healthy volunteers in all cortical regions. There was no difference in occupancy between the two drug-treated groups. No correlation was found between the percentage change in the Global Assessment Scale (GAS) and 5-HT2A receptor binding indices in the drug-treated groups., Conclusions: Clozapine and risperidone potently block 5-HT2A receptors in vivo. The lack of relationship between receptor binding indices and change in GAS suggests that 5-HT2A receptor blockade may be unrelated to clinical improvement. Future studies will substantiate this finding by studying 5-HT2A receptor binding in large groups of patients treated with both typical and novel atypical antipsychotics.

Background: We tested the hypothesis that reduced levels of the GABA-benzodiazepine receptor occur in alcohol dependency using single photon emission tomography (SPET) and the specific GABA-benzodiazepine ligand, 123I-iomazenil., Method: Neurologically and cognitively unimpaired abstinent alcohol-dependent (n = 12) and non-alcohol-dependent male subject (n = 14) underwent a 123I-iomazenil SPET scan. SPET and magnetic resonance images were co-registered and voxel-based statistical tests performed. Subjects' clinical and alcohol history were obtained with standard questionnaires. The relationships between clinical and alcohol variables and the regional level of GABA-benzodiazepine receptors were investigated using multiple regression analysis., Results: Abstinent alcohol-dependent subjects had decreased levels of GABA-benzodiazepine receptor compared with non-alcohol-dependent subjects within the frontal, parietal and temporal cortices, including regions in which grey matter atrophy was absent., Conclusions: Alcohol dependency is associated with reduced GABA-benzodiazepine receptor levels in the absence of grey matter atrophy in some cortical regions, such as within the parietal lobe. Regional variability of reduction in GABA-benzodiazepine receptors demonstrates that alcohol does not have a global, toxic effect on the brain.

Background: We compared regional cerebral blood flow (rCBF) in three groups of patients with DSM-III-R anxiety disorders., Method: Fifteen patients with obsessive -compulsive disorder (OCD), 15 with panic disorder with agoraphobia (PA), and 16 with post-traumatic stress disorder (PTSD) and a similar group of healthy controls were assessed on brain-dedicated high-resolution SPET., Results: MANOVA revealed significant rCBF differences between diagnostic groups (F = 4.4; d.f. = 3, 57; P = 0.007) and between cerebral regions (F = 6.4; d.f. = 1, 57; P = 0.01) in OCD and PTSD compared with PA and healthy controls, limited to bilateral superior frontal cortices and right caudate nuclei. Whole brain blood flow correlated positively with anxiety (r = 0.24, n = 46, P = 0.05). Beck depression scores correlated significantly negatively with left caudate rCBF (r = -0.24, n = 46, P = 0.05) and right caudate rCBF (r = -0.31, n = 46, P = 0.02). PTSD syndrome severity correlated significantly negatively with the left caudate (r = -0.49, n = 16, P = 0.03) and with right caudate rCBF (r = -0.7, n = 16, P = 0.001)., Conclusions: Functional rCBF differences in anxiety disorders could relate to repetitive, intrusive, distressing mental activity, prominent in both OCD and PTSD.

Background: Schizophrenia is highly expensive in calculable and incalculable costs. Measures which impact the cost in the most severely affected are likely to produce the greatest cost reductions. Studies regarding clozapine in the USA have demonstrated clear cost-effectiveness, despite the high prescription costs. There are no prior UK studies., Method: We performed a cost-effectiveness analysis comparing the three years prior to commencing clozapine to the period following establishment of clozapine treatment (mean 36.4 months) for 26 patients with chronic schizophrenia or schizoaffective disorder., Results: There was a significant improvement in all clinical ratings applied (and a mean net saving of ponds 3768 per annum). The cost-effectiveness of clozapine was double that of conventional neuroleptics (15.2 pre-, 33.0 post-clozapine, P < 0.005)., Conclusions: As a naturalistic study our data provide valuable information on the cost-effectiveness of clozapine in the UK. Our methodology could be applied in a community setting or in the study of another atypical neuroleptic.

Background: We tested whether cortical and subcortical regional cerebral blood flow (rCBF) differs between patients with obsessive-compulsive disorder (OCD) and healthy controls. We then explored the relationship between rCBF and OCD mental state., Method: Thirty out-patients from the Maudsley Hospital with OCD as defined in DSM-III-R were scanned at rest using brain-dedicated, high-resolution, single photon emission tomography. RCBF was measured as uptake of 99mTc-HMPAO in 15 regions of interest and compared with rCBF data in 30 healthy people matched for age, sex and handedness. Symptom ratings were obtained using standard measures on the scanning day. Principal components factor analysis identified two distinct clinical dimensions: obsessive-compulsive (OC) and anxious-avoidant (AA). These were correlated with patients' rCBF measurements, using Spearman's rank correlation coefficient, and multiple regression coefficients calculated., Results: We found significant reductions in rCBF measurements of OCD patients compared with resting, healthy controls (F = 1.92, P = 0.04) in seven brain regions: the right and left superior frontal cortex, right inferior frontal cortex, left temporal cortex, left parietal cortex, right caudate nucleus and right thalamus. Regional differences were not secondary to generalised reduction in patients' brain perfusion. Reduced blood flow to the right inferior frontal cortex correlated significantly with illness severity (r = 0.37, P = 0.02). There was no relationship with age, age-of-onset, sex, handedness, depression or medication status. OC clinical dimension, concerning obsessions, compulsions and low mood, was significantly negatively correlated with left inferior frontal, medial frontal and right parietal rCBF. AA dimension, concerning anxiety and avoidance, was significantly positively associated with left and right superior frontal, right inferior frontal, medial frontal cortical, and right and left caudate and thalamic rCBF., Conclusions: rCBF differs significantly between resting OCD patients and healthy controls, and separate clinical dimensions are associated with functionally distinct rCBF patterns.

We used SPECT to examine striatal D2 receptor binding in 20 antipsychotic-free DSM-III-R schizophrenic patients and 20 age- and sex-matched normal controls. Dynamic single-slice SPECT, at a slice chosen to include the basal ganglia, began immediately following intravenous injection of 185 MBq of 123I-IBZM. A semiquantitative approach was used to generate indices of specific D2 receptor binding in the basal ganglia. There was no overall elevation of D2 receptor binding between patients and controls. A male sex-specific left lateralised asymmetry of striatal D2 receptor binding was found in the patient group. Age-dependent decline of striatal D2 receptors was confirmed in controls, but not in patients. These results suggest that alterations in striatal D2 receptor distribution and density do occur in schizophrenia, and possibly reflect wider disruptions in prefrontal-striatal-limbic circuits.

In the search for neurobiological factors in the aetiology of autism, interest has focused on the temporal lobes. We present a case of Asperger's syndrome in an otherwise healthy adult with direct evidence of left temporal lobe damage on computerised tomography.