Subjects, healthy antipsychotic drugs

On the basis of studies with healthy subjects and observations in psychotic patients, Degkwitz (1967, p. 108) distinguished between three phases of action of antipsychotic drugs ... 

Table 3.5 Effects of antipsychotic drugs in healthy subjects...

Antipsychotic drugs with strong sedative clinical effects (e.g. chlorpromazine. clozapine, olanzapine) produce subjective and objective sedation and impair most areas of performance in healthy volunteers, usually at doses far below those typically used in patients. Antipsychotic drugs with little sedative clinical action (e.g. pimozide, sulpiride, amisulpride) produce few subjective and objective effects in healthy... 

An aspect of neuroleptic therapy that has been puzzling is the delay of three or more weeks before subjective improvement is noted, even though it can be shown that the drugs block D2 receptors at the beginning of therapy. It has been known for some time that schizophrenics have much higher levels of homovanillic acid (HVA), which is the major DA metabolite, than do healthy controls. The fact that HVA concentrations parallel alterations in DA turnover in the brain has also been understood. It was demonstrated that fluphenazine steadily decreased HVA levels after several weeks and can ultimately reach normal values. Moreover, in patients that were evaluated, improvement correlates well with the HVA levels. This delayed effectiveness, then, may indicate that decreased DA turnover is the important factor rather than the immediate DA receptor blockade. It should be realized that in humans antipsychotics may have increased HVA levels in the CSF over the first few weeks, apparently because of DA blockade, which likely increases DA synthesis as a compensatory mechanism in the presynaptic neuron. After that initial 3-week period, however, DA turnover decreases to normal levels while the drug is continuing. 

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