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Background: Despite the demonstrated efficacy of clozapine in severely refractory schizophrenia, questions remain regarding its efficacy for primary negative symptoms, comparison with a moderate dose of a first-generation antipsychotic, and adverse effects during a longer-term trial. This study examined its efficacy in partially responsive, community-based patients, compared clozapine with moderate-dose haloperidol, and extended treatment to 6 months., Methods: Randomized, double-blind, 29-week trial comparing clozapine (n = 37) with haloperidol (n = 34). Subjects with schizophrenia who were being treated in community settings at 3 collaborating clinical facilities were enrolled., Results: Subjects treated with haloperidol were significantly more likely to discontinue treatment for lack of efficacy (51%) than were those treated with clozapine (12%). A higher proportion of clozapine-treated subjects met an a priori criterion of improvement (57%) compared with haloperidol-treated subjects (25%). Significantly greater improvement was seen in symptoms of psychosis, hostile-suspiciousness, anxiety-depression, thought disturbance, and total score measured on the Brief Psychiatric Rating Scale. No differences were detected in negative symptoms using the Brief Psychiatric Rating Scale or the Schedule for Assessment of Negative Symptoms. Subjects treated with clozapine experienced more excess salivation, dizziness, and sweating and less dry mouth and decreased appetite than those treated with haloperidol., Conclusions: Compared with a first-generation antipsychotic given in a moderate dose, clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are seen in a broad range of symptoms but do not extend to negative symptoms.

Background: We studied the effectiveness of treating patients with low doses of fluphenazine decanoate and supplementing them with oral fluphenazine when there was evidence of prodromal symptoms of psychotic exacerbations., Methods: Eighty schizophrenic patients who were receiving 5 to 10 mg of fluphenazine decanoate every 2 weeks were monitored for prodromal symptoms using an idiosyncratic prodromal rating scale. When patients met our criteria for a prodromal episode, they were randomly assigned to a double-blind comparison of oral fluphenazine hydrochloride (5 mg twice daily) or a placebo for the current and future prodromal episodes. We compared rates of psychotic exacerbations in the two treatment groups., Results: Thirty-six patients (45%) met the criteria for a prodrome at some point during the trial and were randomized to drug or placebo. Using survival analysis during the entire 2 years, we did not find a significant difference between fluphenazine and placebo in the likelihood that a prodrome would continue to an exacerbation. Survival analysis beginning at the start of the second year of treatment did indicate a significant reduction in exacerbation risk for patients receiving drug supplementation (P = .032). Similarly, there was no difference between the two groups in the proportion of time at risk spent in exacerbation during the first year, but patients receiving active drug supplementation spent less time in an exacerbated state in the second year (P = .05)., Conclusions: Our treatment strategy appeared to be effective for some patients, particularly those who were able to remain in the study beyond the first year. Although the occurrence of a prodrome was a fairly good marker that a patient was at high risk of ultimate exacerbation with our low-dose maintenance protocol, prodromes were not highly sensitive indicators of imminent exacerbation.

Eighty newly admitted or readmitted men with DSM-III schizophrenia were assigned to receive 5, 10, or 20 mg/d of haloperidol for 4 weeks. Staff were not "blind" to dose. By Clinical Global Impression Scale ratings, the 20-mg dose appeared to be superior to both the 5- and 10-mg doses for the first 2 weeks of treatment but not thereafter. On the Brief Psychiatric Rating Scale Schizophrenia factor, the 20-mg dose was superior to the 5-mg dose throughout the trial and tended to be marginally superior to the 10-mg dose after the first 2 weeks of treatment. By the second week of treatment, however, the group receiving the 20-mg dose deteriorated significantly with regard to Brief Psychiatric Rating Scale ratings of Withdrawal-Retardation (blunted affect, motor retardation, and emotional withdrawal) as well as akinesia and akathisia ratings. Furthermore, 35% of patients given 20 mg/d of haloperidol insisted on leaving the hospital against medical advice vs only 4% of those given 5 or 10 mg/d of haloperidol. A 20-mg/d dose of haloperidol, therefore, may have substantial "psychotoxic" effects by the second week of treatment.

Acute behavioral response to 20 mg of dextroamphetamine (intravenous) predicted fourth-week antipsychotic response to double-blind pimozide treatment. Patients whose psychotic condition improved with dextroamphetamine administration showed more antipsychotic response to pimozide therapy than those whose condition worsened or did not change. Multiple regression analysis indicated amphetamine-induced response predicted pimozide response after four weeks for fifth-week pimozide response was more accurately predicted by prepimozide psychosis ratings. Our study provides some evidence that mechanisms underlying early and late pimozide response are not necessarily identical. Because patients who did not respond to dextroamphetamine administration still improved with pimozide therapy, our data do not support the concept that schizophrenia can be divided into two groups (dopamine-sensitive or dopamine-insensitive) but, rather, that dopamine responsiveness changes over time. Clinical application is not warranted until studies with larger samples have replicated our findings.

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.

In ten of 30 schizophrenic patients treated with pimozide for five weeks, 20 mg of dextroamphetamine sulfate induced an increase in psychosis. The number of patients becoming more psychotic with the dextroamphetamine challenge was not significantly different from the number who worsened after dextroamphetamine challenge when pretreated with placebo. Half of the patients who showed a psychotic response to dextroamphetamine during placebo pretreatment responded to dextroamphetamine with an increase in psychosis after pimozide treatment. Dextroamphetamine induced a worsening in patients who had improved with pimozide. The stability of the preinfusion condition is more important to the type of response to dextroamphetamine than long-term pretreatment with a dopamine receptor blocker. The activation-euphoria response to dextroamphetamine was unaffected by pimozide pretreatment, which suggests that the changes in psychosis and activation may be regulated by different mechanisms. These findings question the postulated relationship between the antipsychotic drug response and dopamine receptor blockade.

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.

Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, was measured in the CSF of 30 schizophrenic patients and 27 normal controls. The CSF DBH activity in the patients was not significantly different from that in controls. Levels of CSF DBH activity in individual patients were highly constant over time and were not influenced by clinical state or neuroleptic treatment. Low levels of DBH in CSF did significantly relate to good social and sexual functioning, good prognosis, less symptoms between hospitalizations, and excellent clinical response to neuroleptic treatment. We speculate from these data that low brain DBH activity may produce a type of vulnerability to psychotic decompensation and thereby influence the clinical course, although it does not cause schizophrenia, in general. Low CSF DBH activity may delineate a "reactive" subgroup from the heterogenous population of patients with diagnoses of schizophrenia.

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.

Thirty-six stabilized schizophrenic outpatients were randomly assigned to receive either 5 or 25 mg of fluphenazine decanoate biweekly and were followed up for two years. The best and worst outcomes were found in groups with good or poor information-processing abilities (as measured by a partial-report span-of-apprehension task) given the same 25-mg dose of fluphenazine decanoate. The 86% two-year survival rate of the patients with poor span performance was considerably better, while the 44% one-year and the 21% two-year survival rates of patients with good span performance were considerably lower than previously reported survival rates for schizophrenic patients receiving a conventional dose of fluphenazine. The significant correlations in a patient's span performance for periods up to one year were consistent with the hypothesis that this task taps processes associated with vulnerability to schizophrenic disorder.

In a sample of 22 psychotic schizophrenic patients, eight improved substantially during a 30-day drug-free period. The drug-free improver group differed from the nonimprover group in demonstrating a later age of onset, briefer psychotic episodes, shorter hospitalizations, and better prognostic scores on the Phillips Scale, Strauss-Carpenter Modified Prognostic Scale, and the Vaillant Scale. After drug withdrawal, drug-free improvers frequently demonstrated further improvement when treated with doses of neuroleptic drugs that were substantially lower than the clinically recommended doses. The authors raise the question as to whether the drug-free improvers may represent a subgroup of schizophrenic patients who are being overtreated presently by standard neuroleptic practice.

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.

The dopamine hypothesis of schizophrenia claims that increased dopamine activity underlies psychotic behavior. This hypothesis gets major support from the reported d-amphetamine-induced worsening of psychosis, because amphetamine increases dopamine activity in the brain. Dopamine receptor supersensitivity has been shown to be present in animals during the postneuroleptic period. In this study the postulated relationships between psychotic decompensation as observed after d-amphetamine infusion and the dopamine receptor supersensitivity expected to be present during the neuroleptic withdrawal period were examined. Twenty milligrams of d-amphetamine administered intravenously did not cause a stronger psychotogenic effect in 12 schizophrenic patients. One week after discontinuation of pimozide treatment, the d-amphetamine-induced change as indicated by the Brief Psychiatric Rating Scale (BPRS) paranoid disturbance cluster score, was not significantly different from the response to a similar infusion during the drug-free state. Unexpectedly, the increase in the BPRS mannerisms and posturing item and in the pulse rate response to d-amphetamine were decreased. These results raise questions about the role of dopamine in d-amphetamine effects and suggest postneuroleptic dopamine receptor subsensitivity. They challenge a simple dopamine hypothesis of schizophrenia.