The clinical use of antipsychotic agents may be enhanced by considering their dose-effect characteristics. In particular, assessment of immediate and later follow-up treatment of psychotic patients (1) indicates that moderate doses are adequate for most patients, (2) fails to support the utility of unusually high doses, and (3) even suggests the existence of a biphasic relationship of antipsychotic efficacy to dose of neuroleptics and possibly to plasma concentrations of the drugs as well. Trends toward lesser overall clinical benefits of high doses may reflect untoward extrapyramidal or other central nervous system effects leading to behavioral and cognitive symptoms. Thus, moderate doses of neuroleptics appear, on average, to be about as effective as, and probably safer than, the larger doses that have been popular in the United States in recent years.

Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses.

• It is possible that some "postpsychotic depressions" may be a toxic effect of antipsychotic drugs. Out of a total of 94 schizophrenic patients, 28 developed a mild akinesia and 32 never developed extrapyramidal symptoms. Those who developed akinesia became less psychotic, but they also experienced a significant, although modest, increase in depression ratings. Successful treatment of the akinesia resulted in significant improvements in depression, somatic concern, anxiety, emotional withdrawal, blunted affect, and motor retardation on both physicians' and nurses' ratings. A high association between akinesia and both objectively rated and subjectively experienced sedative effect indicates that an "akinetic depression" is not likely if the patient does not look or feel drowsy. The 32 nonakinetic patients also became less psychotic, but not more depressed.

"akinetic depression" in schizophrenia

We review evidence from randomized, placebo-controlled studies of patients with schizophrenia or schizoaffective disorder, which compared 2 or more doses of an antipsychotic to calculate the dose-response curve for each first-generation (typical) antipsychotic (FGA) or second-generation (atypical) antipsychotic (SGA) and as a group (based on dose equivalence). We identified the near-maximal effective dose (ED; ie, the threshold dose necessary to produce all or almost all the clinical responses for each drug). In randomized, fixed-dose studies of SGAs, the near-maximal efficacy dose for olanzapine may be greater than 16 mg; for risperidone, it is 4 mg; and for ziprasidone, it is 120 mg. Risperidone at 2 mg daily is 50% less efficacious than higher doses. Olanzapine at about 6 mg is approximately 33% less effective than higher doses. Aripiprazole at 10 mg daily was fully efficacious. Doses of clozapine well above 400 mg are necessary for optimal treatment of many schizophrenia patients. We found 3.3 to 10 mg haloperidol to be the near-maximal ED range. We find no evidence that doses higher than these are more effective. We failed to find that high doses of haloperidol (or all other first-generation comparison drugs converted to equivalent doses) were less effective than medium doses (3.3 to 10 mg). While high-dose FGAs are not less effective, we feel it is important not to avoid using high dose to avoid excessive toxicity.

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Dose response and dose equivalence of antipsychotics.

Adolescent sons of alcoholics and nonalcoholics were compared on a battery of intellectual, neuropsychological, personality, and behavioral measures. The former group demonstrated certain neuropsychological deficits in perceptual-motorability, memory, and language processing. They also had auditory and visual attertbonal impairments and a lower level of achievement in reading comprehension. In addition, the sons of alcoholics presented a more neurotic personality profile than sons of nonalcohoiics. They were, however, less impulsive than the comparison group. More developmental and familial problems were noted in the alcoholics' offspring as well. The implications of these findings for understanding the causes and consequences of alcoholism are discussed.

Adolescent sons of alcoholics: neuropsychological and personality characteristics.

Antipsychotic medication is the mainstay of treatment for the functional psychotic illnesses. Such drugs are also referred to as neuroleptics (meaning a drug with both antipsychotic effects and effects on movement) and major tranquillisers. The psychotic illnesses for which they are prescribed include schizophrenia, mania in the course of a bipolar mood disorder, and, more rarely, depression accompanied by psychotic symptoms. These are not uncommon illnesses. At some time during their lives approximately 1% of the population will suffer at least one episode of schizophrenia and a further 1% will suffer at least one episode of mania. During an episode some patients, but by no means all, suffer extreme changes in their thinking, mood and behaviour which can be very distressing to experience and which can make patients a danger to themselves or other people.

The use of high-dose antipsychotic medication.

• In a double-blind trial of six months' duration, a very high dose (VHD) regimen of fluphenazine decanoate (250 mg weekly) was compared with a standard dose (SD) regimen (12.5 mg weekly) in 50 chronic schizophrenic patients. The rating scales used included the Brief Psychiatric Rating Scale 1 and the Wing Ward Behavior Scale. 2 Both treatment groups improved during the trial, but there was no significant difference between them. The VHD regimen, however, exerted better control of the psychosis in that it had fewer patient dropouts and fewer "additional treatments" prescribed. Some of the patients receiving standard doses were probably not receiving adequate antipsychotic drug dosage. No predictors of clinical response could be defined. Extrapyramidal side effects were not significantly higher in the VHD group.

John A. Furness

Papers

Very high dose fluphenazine decanoate: a controlled trial in chronic schizophrenia.