ABSTRACT
BACKGROUND: Some clinical symptoms or cognitive functions have been related to the overall state of monoamine activity in patients with schizophrenia, (e.g. inverse correlation of the dopamine metabolite HVA with delusions or visual-masking performance). However, profiles (as presented here) of the relations of the activity of dopamine, noradrenaline and serotonin to neuropsychologic (dys)functions in major patient sub-groups with their very different symptomatic and cognitive characteristics have not been reported. METHODS: Serum measures of dopamine, noradrenaline and serotonin turnover were examined by regression analyses for the prediction of performance on 10 neuropsychological measures reflecting left- and right-hemispheric and frontal-, parietal- and temporal-lobe function in 108 patients with schizophrenia and 63 matched controls. The neuropsychological battery included tests of verbal fluency, Stroop interference, trail-making, block-design, Mooney faces recognition, picture-completion, immediate and delayed visual and verbal recall. Paranoid and nonparanoid subgroups were based on ratings from the Positive and Negative Syndrome Scale (PANSS). Groups with high and low ratings of ideas-of-reference and thought-disorder were formed from a median split on the Scale for Assessment of Positive Symptoms (SAPS). RESULTS: Verbal-fluency and Stroop-interference (left frontal and fronto-cingulate function) were negatively associated with noradrenergic turnover in nonparanoid and thought-disordered patients. High dopamine turnover related to speeded trail-making (frontal modulation of set switching) in those with many ideas-of-reference. In contrast, low dopamine turnover predicted poor recall in nonparanoid patients and those with little thought disorder. Serotonin metabolism did not independently contribute to the prediction any measure of cognitive performance. But, with regard to the relative activity between monoaminergic systems, increased HVA/5-HIAA ratios predicted visual-reproduction and Mooney's face-recognition performance (right-hemisphere functions) in highly symptomatic patients. Decreased HVA/MHPG predicted non-verbal recall. CONCLUSION: Clinical state and function are differentially sensitive to overall levels of monoamine activity. In particular, right-lateralised cerebral function was sensitive to the relative activities of the monoamines. Increased noradrenergic activity was associated with enhanced frontal but impaired temporal lobe function in nonparanoid syndromes. Low dopaminergic activity predicted poor attentional set control in those with ideas-of-reference, but poor recall in nonparanoid patients. These data, especially the HVA/5-HIAA ratios, provide a basis for planning the nature of antipsychotic treatment aimed at patient specific symptom dimensions and cognitive abilities.
ABSTRACT
BACKGROUND: Plasma and serum indices of monoaminergic activity reflect partly the illness of schizophrenia (e.g. HVA/deficit syndrome) and sometimes the symptoms (e.g. HVA/anhedonia). But, such studies have rarely taken both metabolites and parent amines or inter-amine activity ratios into account. We hypothesized that comparing the major symptom dimensions to measures of transmitter activity (with and without control for antipsychotic drug treatment) would show differential patterns of activity useful for the design of pharmacological treatments. METHODS: Dopamine (DA), noradrenaline (NA), serotonin (5-HT), their three major metabolites and prolactin were measured in the serum of 108 patients with schizophrenia and 63 matched controls: DA D2-receptor blocking-activity was estimated from a regression of butyrophenone displacement in striatum in vitro on to PET reports of drug-binding in vivo. Symptoms were factored into four dimensions (disorganized/thought disorder, nonparanoid/negative, ideas-of-reference and paranoid/positive symptoms). RESULTS: (1). Patients' DA activity did not differ from controls: but their 5-HT and NA turnovers increased/decreased, respectively, and the DA/5HT-metabolite ratio was lower. Increased DA-D2-receptor occupancy was predicted by decreased DA-metabolism and its ratio to 5-HT-metabolism. (2). Patients had higher levels of NA, DA-metabolites and DA-/5-HT-metabolite ratios on atypical vs typical drugs. (3). Increased D2-occupancy was associated with lower DA metabolism in paranoid patients but was unrelated to relative increases of DA/5-HT- and NA-metabolism in nonparanoid patients. (4). Low DA-/5-HT-metabolite ratios, high prolactin and low DA-metabolism characterized thought-disordered patients. (5). High DA-/5-HT-metabolite ratios paralleled many ideas-of-reference. The metabolites were sensitive, respectively, to control for D2-occupancy and prolactin. CONCLUSIONS: The role of DA in paranoid, and 5-HT in thought-disordered and ideas-of-reference dimensions point both to the mechanisms underlying the features typical of these subgroups and the type of medication appropriate.