Subjective response as a predictor of outcome in pharmacotherapy: the consumer has a point.

Forty-two newly admitted patients with a schizophrenic illness were given a test dose of chlorpromazine, and their subjective response was graded on a euphoric-dysphoric continuum. Subjective response at 4, 24, and 48 hours after the test dose was significantly correlated with the subsequent outcome of a therapeutic course of treatment with chlorpromazine, as measured by the Brief Psychiatric Rating Scale, the Global Assessment Scale, and a write-in symptom scale. An early dysphoric response to chlorpromazine seemed to augur a poor prognosis for further treatment with the drug. These findings suggest that the subjective response to a test dose of chlorpromazine may be a useful predictor of short-term symptomatic outcome.

Plasma levels of chlorpromazine in schizophrenia; a critical review of the literature.

Measurment of chloropromazine and metabolite levels in the blood has not yet developed such that it can help the clinician. Apart from their chemistry, the clinical aspects of the experimentql design of most studies leave much to be desired, so that it is not possible to draw any overall conclusions about the relationship between chlorpromazine blood levels and clinical outcome from the data currently available. Measurement of response to a single test dose may prove potentially more fruitful in predicting outcome and in establishing drug and dosage choice for a given patient than simple attempts to correlate sustained dosage levels with clinical response. For chlorpromazine, indeed for any drug, it would seem wise in the first instance to focus clinically well-designed studies on the parent substance, rather than launching into more costly, but clinically unsophisticated, studies of its metabolites.

Schizophrenia--a follow-up study of results of treatment. I. Design and other problems.

This is the first of a series of articles on a follow-up study of the results of treatment of schizophrenia, studied over a period of two to five years after first admission and first release. The study compares the follow-up outcome of five different treatment methods given to first-admission male and female schizophrenic patients in the hospital. The design of the study is used as a basis for description and discussion of the practical, ethical, and statistical problems involved. A distinction is made between follow-up and continued treatment design, and it is concluded that both pose massive problems in execution, analysis, presentation, and interpretation.

Therapist characteristics and the outcome of treatment in schizophrenia.

The broad task of identifying and characterizing specific components of personality and behaviours of therapists that may be differentially helpful in the treatment of schizophrenia still remains to be addressed. This report presents data systematically collected in the course of a controlled study of the outcome of five different treatment methods in schizophrenia. Therapists seem to play a significant role in determining the outcome of the treatment of schizophrenia by drugs and by psychotherapy plus drugs. The salient therapist behaviors that seem to make a difference in outcome are yet to be identified and studied. The A-B dimension as customarily defined seems of little value for this task. The findings show a distinct need to identify cognitive and affective personality characteristics of the therapist relevant to eliciting patient cooperation, and the degree of knowledge and sophistication in the use of particular methods of treatment necessary for good results.

Akathisia with haloperidol and thiothixene.

We studied the incidence of akathisia in two populations of newly admitted schizophrenic patients: one group was treated with haloperidol and the other group was treated with thiothixene hydrochloride. Within six hours after taking a 5-mg test dose of haloperidol, 40% of the patients experienced akathisia; during maintenance treatment with 10 mg of haloperidol taken at bedtime, 75% of the patients experienced akathisia by the seventh day. With thiothixene hydrochloride (0.22-mg/kg test dose; 0.44-mg/kg maintenance dose), the respective percentages were 20% and 46%. The akathisia experienced after administration of the test of haloperidol dose was not mild or inconsequential; 28% of the patients experienced moderate, 17% of the patients experienced severe, and 22% of the patients experienced very severe akathisia. Akathisia with haloperidol could not be suppressed completely in half of the patients. Treatment-resistant akathisia was experienced as anxiety and depression. We believe these tallies to be important because akathisia causes much misery and often goes undiagnosed.

Schizophrenia--a follow-up study of results of treatment.

This is the second article from a study of the outcome of five different methods of treatment for schizophrenia; patients were followed up over a period of two to five years after first admission and the first release. Patients who had been originally treated in hospital with psychotherapy alone stayed longer in hospital over the follow-up period than those who had received electroconvulsive therapy (ECT), drug alone, or drug plus psychotherapy. Those who had been treated with milieu therapy also had a longer stay dated from the time of admission. Patients treated initially with drugs or ECT showed a trend toward spending less time in hospital after their release.

Low- and conventional-dose maintenance therapy with fluphenazine decanoate. Two-year outcome.

We evaluated the effectiveness and the side effects of what we defined as low (5-mg) and conventional (25-mg) doses of fluphenazine decanoate administered every two weeks in a double-blind comparison. Subjects were 66 patients who fulfilled DSM-III criteria for schizophrenic disorder. Evaluation of the survival with each dose revealed no significant difference at one year, but significantly better survival was seen with the 25-mg dose (64%) than the 5-mg dose (31%) at two years. There was no significant difference in survival when the clinician was permitted to make a dosage adjustment up to 10 mg in the low-dose group and 50 mg in the higher-dose group when the patient demonstrated evidence of a symptomatic exacerbation. Patients assigned to the higher dose appeared to feel more uncomfortable during the early months of the study, as indicated by significantly higher scores on subscales of the Hopkins Symptom Checklist-90R and higher side effect scores for retardation and akathisia. Implications for clinical practice are discussed.

Subjective response to antipsychotic drugs.

Sixty-three newly admitted schizophrenic patients were given a test dose of thiothixene and their subjective response was recorded by a technician blind to clinical ratings. All patients were then treated wih thiothixene in an active milieu setting. Patients varied widely in their subjective responses. An initial dysphoric response was a powerful predictor of both immediate and eventual drug refusal. Before treatment, dysphoric responders tended to be less symptomatic and did significantly better on the Continuous Performance Test. Dysphoric responders experienced significantly more extrapyramidal symptoms following the test dose. Some dysphoric responders did have a good outcome when treated with very low doses. We recommend that patients with a history of dysphoric response be given a very low dose initially.

Chlorpromazine levels and the outcome of treatment in schizophrenic patients.

Plasma and saliva levels of chlorpromazine hydrochloride were measured by gas chromatography-mass spectrometry, after a standard dosage had been administered to 48 newly admitted schizophrenic patients over 28 days. Other treatments were rigorously controlled. Saliva chlorpromazine concentrations were higher than plasma concentrations generally by about four to 50 times. Saliva and plasma chlorpromazine levels were significantly related. There was great variability in individuals between plasma and saliva peaks and values over time, in plasma/saliva ratios, and in change in plasma/saliva ratio over time. Chlorpromazine plasma and saliva levels at the end of fixed, sustained dosage treatment did not correlate with the amount of improvement as measured by ten criteria from the Brief Psychiatric Rating Scale and the Mobility, Affects Cooperation, and Communication Scale. Yet levels obtained in the 24 hours after the first dose did seen related to outcome, more strongly for saliva chlorpromazine than for plasma chlorpromazine levels. A reexamination is in order of our concepts of the relationships between levels of antipsychotic drugs in the body and treatment effect.

Schizophrenia. A follow-up study of the results of five forms of treatment.

Two hundred twenty-eight first-admission schizophrenic patients were randomly assigned to the following five treatments: psychotherapy alone, drug alone, psychotherapy plus drug, electroconvulsive therapy (ECT, and milieu. A there- to five-year follow-up examined their course after release from the hospital. The drug alone and ECT groups tended to have the best outcome and the psychotherapy alone group the worst. The positive effect from prior drug treatment began to dissipate after three years postadmission. For the in-hospital treatment successes, the advantage from drug treatment and the disadvantage from psychotherapy were less apparent. Overall, the follow-up outcome is far from reassuring, whatever the type of treatment. Even though a few patients may do well, much remains to be done in and out of the hospital.

Test dose response in schizophrenia: chlorpromazine blood and saliva levels.

A gas chromatographic/mass spectrometric method for measuring chlorpromazine using 2H6--labeled chlorpromazine as an internal standard has the potential for considerable precision and specificity. Results are reported of chlorpromazine levels in plasma and saliva after administration of a single test dose to 13 schizophrenic patients in a tightly designed experiment. There was a clear and substantive relationship between blood and saliva levels of chlorpromazine, both following a typical decay curve. Saliva and plasma levels were strongly associated for a particular patient, and there was even a strong consistency in saliva-plasma ratios between patients, with an overall statistically significant correlation between plasma and saliva levels for all measurement on all 13 patients. In general, it seems that saliva sampling has great potential as a simple noninvasive technique for investigation of chlorpromazine and other antipsychotic drugs in psychotic patients. Nevertheless, for the moment, it should be regarded as strictly experimental and not suitable for immediate clinical application.

Drug and family therapy in the aftercare of acute schizophrenics.

After a brief inpatient hospitalization, 104 acute, young schizophrenics, stratified by premorbid adjustment, were randomly assigned to one of four aftercare conditions for a six-week controlled trial. Conditions involved one of two dose levels of fluphenazine enanthate (1 ml or 0.25 ml) and presence or absence of crisis-oriented family therapy. Relapses during the six-week period and at six-month follow-up were least in patients who received both high-dose and family therapy (0%) and greatest (48%) in the low-dose-no therapy group. Brief Psychiatric Rating Scale symptom ratings disclosed a significant family therapy effect at six weeks that was sustained at six months only for therapy patients originally receiving the high drug dose. Numerous interactions were found between premorbid adjustment status and response to the two treatment conditions.

Costs and benefits of two doses of fluphenazine.

The relative costs and benefits of low- and conventional-dose neuroleptic maintenance therapy were evaluated in a double-blind comparison of 5 and 25 mg of fluphenazine decanoate administered every two weeks. Subjects were 50 patients fulfilling DSM-III criteria for schizophrenic disorder who had been successfully maintained with 25 mg or less of fluphenazine decanoate. A one-year survival analysis disclosed that there were no statistically significant differences between the two doses insofar as preventing relapse. Patients receiving the higher dose appeared to feel more uncomfortable, as indicated by higher scores on subscales of the Hopkins Symptom Checklist-90. In addition, patients receiving the higher dose had higher side-effect scores. These findings suggest that a substantial proportion of patients who are presently maintained with 25 mg or less of fluphenazine decanoate every two weeks will do just as well with as little as 5 mg.

Rational treatment for an irrational disorder: what does the schizophrenic patient need?

The author discusses the results of a review of controlled studies of treatment approaches to schizophrenia. Although the research evidence strongly supports the efficacy of pharmacotherapy, this finding should not be interpreted as meaning that all schizophrenic patients should receive antipsychotic drugs or that other forms of treatment are unnecessary. The author cautions against doctrinaire attitudes and advocates thoughtful adjustment of goals and methods to meet the needs of the various parties and situations involved in the treatment of the schizophrenic patient.

Diagnosing schizophrenia: Professor Kraepelin and the research diagnostic criteria.

The authors applied current diagnostic criteria (the Research Diagnostic Criteria developed by Spitzer and associates and DSM-III) to Kraepelin's descriptions of his own patients and compared Kraepelin's diagnoses of "functional" psychoses related to schizophrenia with those of today. Thirty-two case histories were selected from Kraepelin's textbook of psychiatry. Two psychiatrists screened out any comments from the case histories that might have revealed Kraepelin's original diagnoses.The screened case histories were then diagnosed by one of the authors. A high degree of agreement was found between Kraepelin's diagnoses and the diagnoses of present-day systems.

Predicting outcome of antipsychotic drug treatment from early response.

The authors gave 48 newly admitted schizophrenic patients an initial test dose (2.2 mg/kg) of chlorpromazine hydrochloride and additional doses at 24 and 36 hours. Clinical response was measured at 48 hours and at the end of subsequent treatment with a fixed dose (6.6 mg/kg) of chlorpromazine. There was a consistent correlation between 48-hour change and the eventual amount of improvement by the end of drug treatment for all 10 outcome criteria. The authors conclude that change early on in drug treatment is a useful predictor of outcome.

Importance of akinesia: plasma chlorpromazine and prolactin levels.

Akinesia, a common side effect of antipsychotic drugs, often goes unrecognized by physician and patient. Akinetic apathy and lack of spontaneity can be mistaken for the negative symptoms of schizophrenia and add to the well-known social and emotional disability of schizophrenic patients on maintenance therapy. The authors attempted to identify a measure that might distinguish between akinesia and the negative symptoms of schizophrenia but found no relationship between plasma and saliva chlorpromazine levels or prolactin levels and akinesia. The fact that all of the akinetic but only 31% of the nonakinetic patients rated themselves as drowsy 12 hours after their bedtime dose indicates that drowsiness is a fairly accurate correlate of akinesia.

Response to antipsychotic medication: the doctor's and the consumer's view.

The subjective response to antipsychotic medication was systematically evaluated in two samples of schizophrenic patients, one treated with haloperidol, the other with thiothixene. For both groups, a dysphoric response to the first dose was found to be a powerful predictor of noncompliance. A persisting dysphoric response was associated with a poor clinical outcome. Dysphoric responses were powerfully associated with akathisia. Patients' subjective responses were consistent throughout therapy, and there was moderate agreement between the patients' evaluation of the medication and the staff's ratings of improvement. The authors suggest that the subjective response to antipsychotic medication should not be dismissed and that dysphoric responses should be acknowledged.

Plasma and saliva levels of chlorpromazine and subjective response.

Newly admitted schizophrenic patients (N=48) were given a test does of 2.2 mg/kg of chlorpromazine hydrochloride by mouth. Chlorpromazine was measured in plasma and saliva at 1, 2, 3 (saliva only), 4, 6, 8, 12 (saliva only), and 24 hours by gas chromatography-mass spectography. Subjective response at 4 and 24 hours after test dose was not significantly related to either plasma or saliva level even for dysphoric responders. Dyschoric responses to chlorpromazine appear to be idiosyncratic--rooted perhaps in altered recepter sensitivity or in a patient's very personal interpretation of drug effect.

Woodpecker drilling behavior. An endorsement of the rotational theory of impact brain injury.

High-speed cinematograph films of a drilling woodpecker were examined by direct visual inspection and by a microdensitometer and computer-imaging technique. These showed (1) that the drilling trajectory is essentially linear, with very little, if any, rotation of the head; (2) that there is minimal movement after impact; (3) that the impact velocity is of the order of 600 to 700 cm/s; and (4) that the impact deceleration is of the order of 1,000 g. Dynamic and morphologic findings in the woodpecker may be highly relevant to the prevention of concussion and brain injury in man. Taken in the context of modern packaging technology and other animal and mathematical modelling research, they suggest that brain injury preventive systems could be greatly improved over those now in common use.