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The dopamine hypothesis proposes that antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade.
To evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride.
[123I]-epidepride SPETscans were performed on 12 patients with schizophrenia treated with antipsychotics and 11 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.
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.
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.
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.
We developed a SPET imaging protocol for assessing 5-HT2A receptor binding using the selective ligand 1231-5-1-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.
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.
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.
We compared regional cerebral blood flow (rCBF) in three groups of patients with DSM–III–R anxiety disorders.
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.
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)
Functional rCBF differences in anxiety disorders could relate to repetitive, intrusive, distressing mental activity, prominent in both OCD and PTSD.
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.
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.
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.
rCBF differs significantly between resting OCD patients and healthy controls, and separate clinical dimensions are associated with functionally distinct rCBF patterns.
Functional brain imaging with technetium-99m d,l-hexamethyl propyleneamine oxime (HMPAO) Single Photon Emission Tomography (SPET) allows us to explore the cerebral pathophysiology of Gilles de la Tourette's Syndrome (GTS).
Fifty patients and 20 controls were examined. Patients were rated for tic severity and mood. Scans were analysed quantitatively using internal ratios to the occipital cortex.
Patients differed from controls on measures of relative blood flow to the left caudate, anterior cingulate cortex and the left dorsolateral prefrontal cortex. Severity of tics was related to hypoperfusion of the left caudate and cingulate and a left medial temporal region. Hypoperfusion in the left dorsolateral prefrontal region was related to mood.
The areas found to be hypoperfused in this study are consistent with known functions of fronto-striatal circuits. A wide range of perfusion patterns is seen, however, and no characteristic patterns for behavioural subgroups has been documented with this technique.
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