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Biomedical subjects

G M Simpson

Publications and source records attributed to G M Simpson.

At least 19 recordsLinked to original sources
PubMed1992

The treatment and management of neuroleptic malignant syndrome.

1. The neuroleptic malignant syndrome was initially described as a disorder specifically related to neuroleptic usage with frequent fatal outcome. The observations of variant or mild cases of this syndrome as well as case reports on neuroleptic-malignant-like syndromes in the absence of neuroleptics raises the issue of the usefulness of this terminology and highlights the potential for inappropriate management of this "malignant" syndrome. It has been suggested that hypothalamic thermoregulatory responses may involve an interplay among noradrenergic, cholinergic and serotonergic pathways. Out treatment strategy is based on the pharmacology of neuroleptics and empirical data, verified in our own clinical practice and considers that it is often difficult to determine whether certain physiologic states are a consequence to or specific triggering factors. 2. If a patient's temperature is less than 101, we emphasize vigorous treatment with anticholinergic agents, while simultaneously assessing the psychiatric need for neuroleptics versus medical risks. Given that the severe rigidity of NMS represents severe extrapyramidal effects of dopamine blockade, there is no reason to withhold anticholinergics in the absence of higher temperatures. Neuroleptics can be stopped at the discretion of the clinician even during circumstances when there is fever below 101. 3. In cases of severe EPS with fever greater than or equal to 101, we recommend stopping neuroleptics, treating with anticholinergics and starting with dopamine agonists. In the event of a poor response to dopamine agonists, a brief trial of dantrolene and/or benzodiazepines is recommended. Dantrolene should not be introduced for prolonged periods, since abnormal liver function studies have been observed in approximately 1.8% of patients. 4. In cases of extreme hyperpyrexia (fever greater than 103), clinicians should consider transfer to an ICU or another medical support. Extreme temperatures have been associated with potentially irreversible cerebellar or other brain damage, if not aggressively treated. If neuroleptics are later indicated, a 2 week interval after resolution of symptoms should be maintained before reinstituting neuroleptics. 5. In patients with severe EPS without fever, we emphasize aggressive use of anticholinergic therapy, while simultaneously considering the psychiatric need for neuroleptics versus medical risks. In all cases where a patient's swallowing, respirations or physical mobility is severely compromised, we suggest stopping neuroleptics. Anticholinergic agents should be continued for 7 days after neuroleptics are stopped. If anticholinergic agents are unsuccessful after 2-3 dosages, dopamine agonists may be added, while simultaneously monitoring vital signs. It should be emphasized that severe EPS sometimes takes days to improve even after neuroleptic cessation and the addition of anticholinergics.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗
PubMed1992

Comparison of the pressor effect of tyramine after treatment with phenelzine and moclobemide in healthy male volunteers.

This study was conducted to establish the safety, tolerability, side effects, and pressor effects of tyramine on subjects treated with moclobemide, a short-acting reversible and preferential monoamine oxidase inhibitor, and to compare these responses with the responses of subjects treated with phenelzine. Twelve healthy male volunteers participated. An oral tyramine sensitivity test was performed on all subjects 24 hours before the start of a 28-day open-label treatment with phenelzine or moclobemide. A tyramine challenge was performed on day 28 on four subjects treated with phenelzine. The mean dose of oral tyramine required to increase systolic blood pressure by 30 mm Hg was 15 mg. The mean dose of tyramine that produced a clinical response (day 28) in subjects treated with moclobemide was 240 mg. No subject receiving moclobemide responded clinically on day 31 after receiving hourly doses of 20, 40, 80, 160, and 320 mg, respectively. These findings suggest that moclobemide may be used without stringent dietary precautions.

Administration, Oral↗
PubMed1992

Timing of acute clinical response to fluphenazine.

The time course of clinical improvement was studied in 41 schizophrenic and schizoaffective acute in-patients treated for 28 days with 10, 20 or 30 mg/day of oral fluphenazine hydrochloride in a double-blind, randomised study. Significant improvement was seen in the four BPRS factors: thinking disturbance, hostile-suspiciousness, withdrawal-retardation and anxious depression. The first two of these factors were improved by day 5. Significant improvement was seen up to day 22 for three of the four factors, but without significant improvement during the last week (although scores continued to drop). The half of the sample showing greater overall improvement did not improve faster than the sample as a whole. These more improved subjects did not differ significantly from the less improved subjects in the thinking disturbance factor until day 15, suggesting that at least a two-week neuroleptic trial would be necessary to begin to differentiate more and less responsive patients. The longer-term course of improvement cannot be determined from these data. The withdrawal-retardation and anxious depression factors showed their greatest improvement later than the 'positive' symptom factors, suggesting that the former may improve as a result of change in the latter.

Acute Disease↗
PubMed1992

Neurotoxicity related to lithium and neuroleptic combinations? A retrospective review.

The question of toxic interactions resulting from combinations of lithium and neuroleptic drugs is largely based on anecdotal reports. We replicated the methods of Miller and Menninger (1987) who reported that 27% of manic patients on treatment with lithium and neuroleptics developed toxicity. We found no cases of neurotoxicity as defined in the earlier report. Pharmacologic mechanisms and differences in the clinical findings of the two studies are discussed.

Antipsychotic Agents↗
PubMed1991

Negative symptoms, defect state and Huber's basic symptoms: a comparison of the concepts.

Comparing Crow's schizophrenia model with the defect state and Huber's basic symptoms shows that this model is an oversimplification of the complex reality of schizophrenic outcomes. The concept of negative symptoms is undermined by several factors, such as differing definitions, other confounding cross-sectional variables (e.g., akinesia and depression), short follow-ups and lack of confirmation by factorial analysis. The longitudinal concept of a defect state, which has been used in long-term follow-up studies, includes enduring symptoms currently classified as positive and negative. Huber's conceptualization of basic symptoms describes prodromal and enduring residual symptoms of schizophrenia associated with structural brain abnormalities. The overlap and lack of equivalence of these concepts and the limited empirical evidence does not allow firm conclusions. New longitudinal studies using clinical, psychosocial, and neuropsychological measures are needed to understand the natural history and etiology of the defect state.

Cross-Sectional Studies↗
PubMed1991

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1989

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↗