Treatment-resistant depression.
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Antidepressive Agents↗
Biomedical subjects
G M Simpson
Publications and source records attributed to G M Simpson.
Pharmacokinetics of neuroleptics.
Older studies on neuroleptic pharmacokinetics had problems in methodology and laboratory techniques. High performance liquid chromatography (HPLC) and combinations of techniques are used now. Clozapine levels are related to dose, age, sex, and smoking. Fluphenazine decanoate gives more predictable levels than oral, and 25 mg/2 weeks is associated with the lowest relapse rate. A therapeutic window with haloperidol is not well established; increased side effects at higher doses may account for the worsening seen. Half-lives much longer than previously quoted are now described. Children and the elderly are more susceptible to side effects of neuroleptics. Studies of the neuroleptic threshold and brain imaging indicate that doses used today are excessive. Nonresponders can distort dose effect relationships. Plasma levels are not useful routinely; they are of use in ruling out pharmacokinetic factors in nonresponse and when side effects are severe.
Antipsychotic Agents↗
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.
Acute Disease↗
Acute dystonia during fixed-dose neuroleptic treatment.
Eighty-six patients with acute psychotic exacerbations were treated with fixed dosage regimens of oral fluphenazine up to 10-30 mg/day in randomized, double-blind studies. Dystonic reactions occurred in 33.8% of the subjects at risk. Of these, 58% occurred by the third day, 88% by the fourth day, and 100% by the ninth day of treatment; most occurred later in the interdose interval. Significant predictors of dystonic reactions were higher fluphenazine mg/kg dosage and younger age. There was a trend toward a lower risk of dystonia in patients who received amobarbital sodium for agitation. Results are discussed in relation to possible mechanisms of neuroleptic-induced dystonia.
Adult↗
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.
Adult↗
Gait disorders in tardive dyskinesia.
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Adult↗
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.
Adult↗
Neuroleptic withdrawal in patients meeting criteria for supersensitivity psychosis.
In an attempt to prospectively validate the existence of supersensitivity psychosis (SSP), five schizophrenic patients meeting Chouinard's criteria for SSP and five non-SSP schizophrenic controls had neuroleptic treatment withdrawn for 2 weeks under double-blind conditions. The sudden worsening of psychotic symptoms and tardive dyskinesia postulated in the SSP group was not observed on the Brief Psychiatric Rating Scale, the Clinical Global Impressions scale, and the Abbreviated Dyskinesia Rating Scale. In conclusion, the authors' pilot data do not seem to support the existence of SSP.
Adult↗
Pharmacologic treatment of major depression for elderly patients in residential care settings.
A significant drug-placebo difference was found in a double-blind, placebo-controlled study of nortriptyline for treatment of major depression among frail elderly patients living in an institutional setting. This finding confirms the validity of the DSM-III-R diagnosis of major depression and establishes the need for specific psychiatric services for the chronically ill elderly living in nursing homes and congregate housing facilities. The incidence of adverse events requiring early termination of treatment was 34%, demonstrating the vulnerability of these patients and their need for careful monitoring during treatment. High levels of self-care disability and low levels of serum albumin were both associated with decreased therapeutic responses, demonstrating the need for further research on psychopathology in these settings.
Age Factors↗
Steady state pharmacokinetics of nortriptyline in the frail elderly.
The frail elderly, for whom chronic disease and disability are essentially universal, are at high risk for depression and are specifically vulnerable to the adverse effects of antidepressant medication. There have, however, been few investigations of either the pharmacokinetics or the clinical investigations of either the pharmacokinetics or the clinical response to antidepressants in such patients. We report on the pharmacokinetics of nortriptyline at steady state in a group of 22 patients, average age 84, living within an institutional setting. Comparison of our findings with those previously reported for younger and healthier subjects suggests that there are no clinically significant group differences in nortriptyline kinetics. Plasma levels of nortriptyline and those of both the trans- and cishydroxylated metabolites are linear with daily dose. Mean (and SD) for the parameter (plasma level/dose) was 1.21 (0.63) ng/ml/mg/day for the parent compound, 1.41 (0.86) for the trans metabolite, and 0.30 (0.16) for the cis metabolite. There was no significant correlation across individuals between the accumulation of the parent compound and the metabolites. Based upon these data, the average dose of nortriptyline required to achieve a plasma level of 100 ng/ml is 80 mg/day. Dose requirements, however, vary between individuals by a factor of 20. Plasma levels measured 24 hours after a 25-mg test dose of nortriptyline can allow early identification of slow metabolizers. Twenty-four-hour plasma levels (mean 8.8 ng/ml, SD 3.2) were significantly correlated with steady state levels at 25 mg/day (r = 0.71), steady state levels at 50 mg/day (r = 0.73), and each individual's average (plasma level/dose) (r = 0.57).
Aged↗
Neuroleptic-induced dystonia.
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Antipsychotic Agents↗
Tyramine and new monoamine oxidase inhibitor drugs.
The hypertensive crisis induced by the ingestion of cheese in subjects undergoing treatment with monoamine oxidase inhibitors (MAOIs) led to their virtual disappearance in many parts of the world. Three strategies to try and diminish the risk of this reaction have been developed: the combination of current (irreversible and non-selective) MAOIs with tricyclic antidepressants, the use of new selective MAOIs, and the use of new reversible MAOIs. The relative effectiveness of these different approaches can be assessed by the tyramine pressor test. The introduction of reversible and selective monoamine oxidase-A (MAO-A) inhibitors looks especially promising clinically.
Antidepressive Agents, Tricyclic↗
Measurement of negative symptoms in schizophrenia.
This article focuses on the measurement of 'negative symptoms'. Standardized scales used to rate negative symptoms are reviewed and compared, as are the individual items which comprise them. The overlap of negative symptoms, akinesia, and depression is explored, and means are suggested to improve the precision of defining and measuring negative symptoms. Flat affect is the only item present in all negative symptom scales and may overlap with depression and akinesia. Inappropriate affect and attentional disturbance should not be considered negative symptoms. Poverty of speech and anhedonia lack unified definitions, and in some scales, they can also be confounded with depression and akinesia. The psychometric properties of most scales have not been sufficiently studied. The lack of long-term studies of stability of the supposedly enduring negative symptoms is especially worrisome. Carpenter's deficit syndrome consisting of non-secondary negative symptoms lasting more than one year is a promising new step to try and address some of these problems.
Humans↗
Neuroleptic plasma level may predict response in patients who meet a criterion for improvement.
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Fluphenazine↗
Antipsychotic use in the medically ill.
Antipsychotics are of use in a variety of medical settings. They can be used to treat organic mental disorders resulting from the medical illness and its therapy, as well as to control the symptoms of coexisting psychiatric conditions. Antipsychotics also have a variety of nonpsychiatric applications. This paper will review these uses of antipsychotic agents and how their administration must be modified in the medically ill.
Antipsychotic Agents↗
Neuroleptic-induced supersensitivity psychosis: retrospective study of schizophrenic inpatients.
Chouinard has suggested that a significant number of schizophrenic outpatients may rapidly relapse after discontinuing or abruptly reducing antipsychotic drugs, and he has hypothesized that this relapse reflects a supersensitivity psychosis related to mesolimbic postsynaptic dopamine supersensitivity caused by drug therapy. Using Chouinard's criteria, the authors found 12 probable but no definitive cases of this syndrome while conducting a chart review of 265 hospitalized schizophrenic patients. Six of the 12 patients were subsequently rediagnosed as schizoaffective. Four patients had tardive dyskinesia, but this condition did not worsen after the drug dosage was decreased. Although supersensitivity psychosis was not common among this population, further study of the syndrome is needed to determine if neuroleptics are causing a subgroup of patients to relapse early or if the early relapses are a manifestation of the natural course of illness in these patients.
Adult↗
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.
Adult↗
Tardive dyskinesia rating scales.
The authors review the history of the introduction of the concept of tardive dyskinesia (TD). They discuss the various ranges of prevalence of TD and also of senile dyskinesias and point out that these are two different entities. They critically discuss the use of various rating scales for measuring TD and then review the literature on the use of various other tools used for measuring TD. The issue of practical difficulties and flaws encountered in the assessment of TD is also addressed. Lastly, they suggest that various electromyographic or other gadgetry may very well identify neuromuscular abnormalities at an earlier point in time and this could lead to earlier detection and intervention as well as further the information about pathophysiology of this disorder.
Dyskinesia, Drug-Induced↗