John M. Herrera

Ethnicity and Antipsychotic Response

OBJECTIVE: To review the data generated by studies examining interethnic/racial differences in response to antipsychotics. DATA SOURCES: A MEDLINE search (1966-19%) identified all articles examining differences in antipsychotic response among Caucasians, Asians, Hispanics, and African-Americans, as well as articles evaluating postulated mechanisms for these differences. STUDY SELECTION: All abstracts, studies, and review articles were evaluated. DATA SYNTHESIS: Ethnic/racial differences in response to antipsychotic medications have been reported and may be due to genetics, kinetic variations, dietary or environmental factors, or variations in the prescribing practices of clinicians. Studies suggest that Asians may respond to lower doses of antipsychotics due to pharmacokinetic and pharmacodynamic differences. Research relevant to African-Americans is limited, but some studies suggest that differences in this group may be due to clinician biases and prescribing practices, rather than to pharmacokinetic or pharmacodynamic variability. CONCLUSIONS: Future research directed at validating the hypotheses that different ethnic/racial groups show variations in response to antipsychotics should focus on homogenous ethnic groups, use recent advances in pharmacogenetic testing, and control for such variables as observer bias, gender, disease chronicity, dietary and environmental factors, and exposure to enzyme-inducing and -inhibiting agents. Clinicians should be aware that potential interethnic/racial differences in pharmacodynamics and pharmacokinetics may exist that can alter response to antipsychotics.

The continuous performance test, identical pairs version (CPT-IP): III. Brain functioning during performance of numbers and shapes subtasks.

The numbers and shapes subtasks of the CPT-IP are difficulty-matched measures of independent aspects of attentional skill that have been used to differentiate the impairments of schizophrenics and major depressives. Previous studies suggest that they tap into lateralized aspects of attentional performance. To investigate this hypothesis, seven subjects free of psychiatric illness were presented with these CPT-IP subtasks during a SPECT procedure. Subtasks--4-digit number strings and nonsense shapes--were administered on successive weeks, in counterbalanced order, simultaneous with administration of 10 mCi 99mTc HMPAO. Scanning took place after 10 min of test performance. Quantitative data were extracted from each scan via a semi-automated region of interest (ROI) analysis which defined eight cortical and four subcortical ROI on each of five transverse slices. Data for each ROI were normalized and compared between task conditions. Results indicate that the two tasks produce different patterns of functioning within two general areas of the brain. First, during Numbers task performance, left-sided activity was increased on multiple transverse slices in an anterior subcortical region that incorporated the anterior cingulate, frontal white matter, and much of the basal ganglia. Left-sided activity was also increased in a posterior subcortical region including the left side of the thalamus. Lateralization of function, defined as relative activity on the left and right sides, changed within these regions across tasks, but primarily as a result of the contribution of increased or decreased activity on the left side alone. Second, relative perfusion to occipital regions, bilaterally, was more extensive during the Shapes task. These results suggest that subtle alterations in stimulus parameters can affect activation patterns in regions that are critically associated with task performance. They also suggest that the Numbers task may provide more robust activation of anterior attention systems, that may better discriminate the functioning of these systems in normal and psychopathological groups.

Neuroleptic-induced hypothermia associated with amelioration of psychosis in schizophrenia

Body temperature is a regulatory function of the hypothalamus. Recently, DeMet et al. (Society for Neuroscience Abstracts Vol 12, 1986) reported that apomorphine stimulation of dopamine autoreceptors caused a significant decrease in metabolic rate in the posterior heat-conserving area of the hypothalamus. The logical hypothesis to follow is that apomorphine administration should induce a decrement in body temperature; this in fact was demonstrated by Cutler et al. (Commun Psychopharmacol 3:375-382, 1979) in humans. It is well known that neuroleptics also disrupt thermoregulation (Clark: Neurosci Biobehav Rev 3:179-231, 1979) and affect dopamine autoreceptors. Therefore, eight chronic treatment-resistant schizophrenics underwent a 6-week single-blind trial of haloperidol and then a subsequent 6-week double-blind trial of clozapine. Both haloperidol and clozapine significantly lowered oral body temperatures relative to baseline washout temperatures. More interestingly, clozapine relative to haloperidol was found to induce a greater decrement in body temperature and was associated with greater clinical improvement. Possible confounding variables are discussed, as is the possible neurochemical basis for the amelioration of psychosis associated with hypothermia.

Limited Eye Movement Patterns in Chronic Schizophrenic Patients

Eye movements of 29 chronic schizophrenic patients and 23 normal control subjects were measured by an eye mark recorder during viewing of stationary geometric figures. The results suggested that the eye movements of schizophrenic patients were more limited than those of normal control subjects and that the abnormal eye movement inspection patterns in schizophrenic patients may reflect a lack of visual investigation of novel stimuli in the environment. Our findings, together with Moriyas (1979) observation of similar eye movement pattern abnormalities in the relatives of schizophrenic patients, support the hypothesis that the limited eye movement patterns may be a biological marker for schizophrenia.

Efficacy of Adjunctive Carbamazepine in the Treatment of Chronic Schizophrenia

Six treatment-resistant schizophrenic patients were given a ten-week single-blind trial of carbamazepine. Treatment resistance was determined on the basis of documented failure to respond to treatment with at least three neuroleptic drugs from two different chemical classes. The adjunctive use of carbamazepine resulted in a significant improvement of the negative symptoms of schizophrenia. These symptoms are often poorly responsive to conventional antipsychotic drugs. Therefore, controlled studies should be performed to further assess the possible efficacy of carbamazepine in schizophrenia.

Patterns of neuroleptic usage in continuously hospitalized chronic schizophrenic patients: evidence for development of drug tolerance.

A retrospective review of neuroleptic dosages over a five-year period in 19 chronic schizophrenic patients revealed that the majority (85 percent) had either consistent yearly increases or decreases in dosage, although clinical status remained unchanged. The authors present differences in adverse effects between the two groups and discuss the implications of their findings for the concepts of neuroleptic drug tolerance and supersensitivity psychosis.

Effect of Molindone on Weight Change in Hospitalized Schizophrenic Patients

A retrospective review was conducted to assess the effect of molindone on weight. Monthly weights and neuroleptic dosages during the first three months of psychiatric hospitalization were compared between matched groups of patients receiving molindone, a combination of molindone and other neuroleptics, or other neuroleptic drugs. We found no significant differences in weight gain among the three groups. Our results challenge the common opinion that molindone can be associated with a lack of weight gain compared to other antipsychotics.

Pharmacy-based screening program for tardive dyskinesia

An ongoing screening program using pharmacists to detect tardive dyskinesia (TD) was developed, and a pharmacy-based prevalence survey of TD in chronic hospitalized psychiatric patients was undertaken to determine the extent of abnormal involuntary movements. The results show that older patients and women in particular are at higher risk for developing abnormal movements. Higher doses of neuroleptics were used in non-TD patients, indicating a possible masking effect caused by these drugs. By using a standardized rating method such as the Abnormal Involuntary Movement Scale, pharmacists can and should be utilized in the surveillance of TD.

Subjective neuroleptic response and treatment outcome under open and double-blind conditions — A preliminary report

1. A patients early subjective response to a neuroleptic was recorded in 17 schizophrenic patients following a fixed dose of neuroleptic under both open and double-blind placebo-controlled conditions. 2. High correlations were found between a patients subjective response at 2.5, 24 and 48 hours after the initial dose, suggesting that the timing of the initial subjective response rating is not critical. 3. The relationship between the psychiatric improvement and subjective response was not significant under double-blind conditions (r = 0.004), while the relationship under the open condition showed a trend towards significance comparable to earlier reports (r = 0.32). 4. The findings question the usefulness of applying early subjective response to a neuroleptic to predict clinical improvement.

Serum homovanillic acid concentrations in carbamazepine-treated chronic schizophrenics

Carbamazepine (CBZ) is clinically efficacious for the treatment of acute mania (Ballenger and Post 1980)) schizoaffective and schizophreniform disorders (Placidi et al. 1986), and excited psychotic states, including violent and aggressive schizophrenic patients (Hakola and Laulumaa 1982; Klein et al. 1984). However, there have been no well-controlled studies investigating the clinical efficacy of CBZ as the sole antipsychotic for the treatment of chronic schizophrenia. We report a preliminary, singleblind, 4-week trial of carbamazepine in a group of nonviolent chronic schizophrenic patients. In addition to the performance of routine clinical ratings, serum homovanillic acid (HVA) concentrations were measured to examine the presynaptic dopaminergic effects of CBZ.