Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic outpatients.

BACKGROUND: Nearly one third of patients suffering from schizophrenia do not fully respond to antipsychotic medication. Safe, effective, and cost-efficient methods to reduce symptoms are clearly needed; therefore, lithium as an adjunct to fluphenazine decanoate was tested in a placebo-controlled trial in outpatients who were part of the Treatment Strategies of Schizophrenia (TSS) study. METHOD: Forty-one patients with DSM-III schizophrenia or schizoaffective disorder were assigned to either adjunctive lithium or placebo after at least 6 months of fluphenazine decanoate treatment to stabilize symptoms had failed. The trial was designed for 8 weeks of treatment, and patients assigned to placebo could afterward be administered lithium in an 8-week, open-label study. RESULTS: Assessment of the intent-to-treat analysis revealed no significant differences in demographic variables between the lithium and placebo groups. Although both groups showed significant (p = .00135) improvement as measured by total scores on the Brief Psychiatric Rating Scale (BPRS), there were no significant differences in response between the lithium and placebo groups. Patients originally treated with placebo added to neuroleptic did not have significantly greater improvement when receiving open-label adjunctive lithium. CONCLUSION: Although success with lithium augmentation therapy for persistent psychosis has been reported in the past, this study of well-characterized patients showed no benefit for this common strategy, thus indicating that care be used in utilizing lithium augmentation.

Fluphenazine plasma levels, dosage, efficacy, and side effects.

OBJECTIVE: The authors sought to determine whether fluphenazine dose or plasma level predicts clinical improvement or side effects during acute treatment. METHOD: Oral fluphenazine was given in fixed, randomized, double-blind doses (10, 20, or 30 mg/day) for 4 weeks to 72 inpatients with acute schizophrenic exacerbations. Outcome measures included percentage improvement in ratings of positive symptoms (hallucinations, delusions, and thought disorder), percentage improvement in negative symptoms, and maximum score for extrapyramidal symptoms. Response was defined as an improvement in positive symptoms of 40% or more. RESULTS: The 42 responders had a shorter duration of illness, less chronic course, and lower rate of akathisia. Plasma level and dose did not differentiate responders and nonresponders, but they did predict percentage improvement in positive symptoms within the responder subgroup. Akathisia was more common and extrapyramidal symptoms were more severe at higher plasma levels. CONCLUSIONS: Responders showed the greatest improvement at fluphenazine plasma levels above 1.0 ng/ml and doses above 0.20-0.25 mg/kg per day. Since the literature suggests that optimal plasma levels are similar during acute and maintenance treatment, monitoring of plasma levels may thus be useful. Conditions for applying the "responder-only" analytic strategy in future studies are discussed.

Single-dose pharmacokinetics of fluphenazine after fluphenazine decanoate administration.

Fluphenazine decanoate is commonly used as part of maintenance treatment of schizophrenia, but its pharmacokinetics are poorly understood. We administered a single intramuscular dose of fluphenazine decanoate to nine patients and found that plasma fluphenazine level did not decline to 50% of the peak level by day 26 in any of the patients. This means that it has a long half-life measurable in months rather than weeks.

Fluphenazine dose, clinical response, and extrapyramidal symptoms during acute treatment.

Fifty-three patients with acute exacerbations of Research Diagnostic Criteria schizophrenic, schizoaffective (mainly schizophrenic), and other nonaffective psychoses completed 24 or 28 days of treatment with randomized, fixed, double-blind doses of 10, 20, or 30 mg of oral fluphenazine hydrochloride daily. In the sample as a whole, improvement was not predicted by dose but was negatively related to duration of illness and of lifetime hospitalization, and to the presence of akathisia during the study (which was unrelated to chronicity). But among patients showing 40% or greater improvement in positive symptoms, percent improvement was predicted by dose and dose per kilogram of body weight; this was not the case for negative symptoms. Severity of acute extrapyramidal symptoms (excluding acute dystonia, dyskinesia, and akathisia) was significantly correlated with dosage per kilogram. Doses greater than 0.2 mg/kg per day were associated with greater clinical improvement but also with a high incidence of extrapyramidal symptoms; doses over 0.3 mg/kg per day were associated with more severe extrapyramidal symptoms. These preliminary results suggest that there is a linear relationship between fluphenazine dosage and acute outcome, and that this relationship is observed in patients whose conditions improve to a criterion level. It is suggested that the nonresponder group may include many patients in whom dose is not relevant because they are unable (for a variety of reasons) to respond to the study treatment conditions; excluding them from analysis may allow a significant dose-response relationship to be observed. Akathisia deserves further study as a possible predictor of nonresponse.

Prevalence of substance abuse in schizophrenia: demographic and clinical correlates.

Methodological issues involved in assessing the prevalence of substance abuse in schizophrenia are discussed, and previous research in this area is comprehensively reviewed. Many studies suffer from methodological shortcomings, including the lack of diagnostic rigor, adequate sample sizes, and simultaneous assessment of different types of substance abuse (e.g., stimulants, sedatives). In general, the evidence suggests that the prevalence of substance abuse in schizophrenia is comparable to that in the general population, with the possible exceptions of stimulant and hallucinogen abuse, which may be greater in patients with schizophrenia. Data are presented on the association of substance abuse with demographics, diagnosis, history of illness, and symptoms in 149 recently hospitalized DSM-III-R schizophrenic, schizophreniform, and schizoaffective disorder patients. Demographic characteristics were strong predictors of substance abuse, with gender, age, race, and socioeconomic status being most important. Stimulant abusers tended to have their first hospitalization at an earlier age and were more often diagnosed as having schizophrenia, but did not differ in their symptoms from nonabusers. A history of cannabis abuse was related to fewer symptoms and previous hospitalizations, suggesting that more socially competent patients were prone to cannabis use. The findings show that environmental factors may be important determinants of substance abuse among schizophrenic-spectrum patients and that clinical differences related to abuse vary with different types of drugs.

Tardive dystonia: four case histories.

Tardive dystonia is an uncommon, disabling side effect of antipsychotic medication that is generally believed to be resistant to treatment. On the basis of a literature review and their experience, the authors propose treatment strategies and report the results of treatment in four patients.

Changing from oral to depot fluphenazine.

Many of the problems that occur when patients are changed from oral to depot fluphenazine are caused by the high dosages resulting from the formulas used for dose conversion. The authors propose a new method based on recent information on the pharmacokinetics of fluphenazine decanoate, low-dose treatment strategies in schizophrenia, and their own clinical experience.

Double-blind carbidopa/levodopa and placebo study in tardive dyskinesia.

The receptor sensitivity modification theory proposed as a potential treatment for tardive dyskinesia states that dopamine sensitivity can be down-regulated by temporarily increasing dopamine levels. We present a preliminary report of a double-blind carbidopa/levodopa-placebo study based on this hypothesis. Fifteen patients completed this 20-week trial. Based on the total tardive dyskinesia scores (using the Abnormal Involuntary Movement Scale) in the beginning and end of the study, patients were grouped as improved, same or worse. The six placebo-treated patients were equally represented in all three groups, but the distribution in the carbidopa/levodopa group was bimodal: five improved, four worsened, and none remained the same. This observation lends some support to the above theory.

Mania in two sisters with similar cerebellar disturbance.

The authors describe two sisters who presented with a clinical picture consistent with mania. On further investigation, both had marked vermian and cerebellar cortical atrophy on CAT scans. Their mother also had a history suggestive of cerebellar disease. To the authors' knowledge, this is the first report of familial cerebellar disease with a clinical presentation of mania.

Blood levels of neuroleptics: state of the art.

Difficulties in developing techniques to measure plasma levels of neuroleptic drugs have included the presence of metabolites, as well as cross-reactivity not only between these metabolites and the parent compound but between drugs (e.g., a phenothiazine and a tricyclic). Although newer techniques have minimized some of these problems, interpretation of published data must also recognize such design limitations as variable dose, small sample size, etc. The literature is reviewed on the relationship between therapeutic response and plasma levels of chlorpromazine, thioridazine, thiothixene, fluphenazine, butaperazine, and haloperidol. It is suggested that additional studies, carefully designed, on dosage and plasma levels could help in achieving the lowest possible therapeutic dosage and thus in minimizing side effects.