Andrew Lautin

Metoclopramide: Antipsychotic efficacy of a drug lacking potency in receptor models

Metoclopramide is a substituted benzamide derivative, structurally similar to procainamide and sulpiride. In behavioral, biochemical, and neuroendocrine tests it displays classic neuroleptic dopamine (DA) antagonist properties; in contrast to other DA antagonists, it lacks potency in currently used DA receptor models. In clinical studies using low doses or dubious measures, it was considered not to be efficacious as an antipsychotic. We now find that it indeed has a clinical profile similar to known neuroleptics when used in a dose range predicted from animal models. The findings raise questions regarding the validity and universality of several predictive models, as well as hypotheses purporting to explain molecular mechanisms of action of neuroleptic agents. The drugs inactivity in receptor models suggests that an as yet unidentified DA receptor subpopulation may be important as the mediator of many DA dependent neurobiologic phenomena.

Lyme disease: point/counterpoint

Lyme disease represents a growing public health threat. The controversial science and politics of Lyme disease have created barriers to reliable diagnosis and effective treatment of this protean illness. Two major clinical hurdles are the absence of a therapeutic end point in treating Borrelia burgdorferi, the spirochetal agent of Lyme disease, and the presence of tickborne coinfections with organisms such as Babesia, Anaplasma, Ehrlichia and Bartonella that may complicate the course of the disease. From a pathophysiologic standpoint, the affinity of Borrelia burgdorferi for multiple cell types and the presence of nonreplicating forms of the Lyme disease spirochete have contributed to persistent infection and failure of simple antibiotic regimens. Newer approaches to the treatment of Lyme disease should take into account its clinical complexity in coinfected patients and the possible need for prolonged combination therapy in patients with persistent symptoms of this potentially debilitating illness. The optimal antibiotic regimen for chronic Lyme disease remains to be determined.

Lithium carbonate and weight gain

In order to evaluate weight gain in lithium-treated patients., a group of 21 bipolar patients on lithium were compared against a group of 12 bipolar patients on placebo over a 12-month period. During this time both groups exhibited euthymic mood. Eleven of the 21 patients on lithium gained greater than 10 lbs. whereas only 1 placebo patient gained more than 10 lbs. Thirteen of 21 lithium-treated patients showed a gain of 5% total body weight while only 2 of 12 placebo patients showed a gain of 5% total body weight. Both of these results were statistically significant (P less tha 0.05). The findings seem to indicate that weight gain is a direct effect of lithium treatment.

The dexamethasone suppression test and response to placebo

The predictive value of the dexamethasone suppression test (DST) was evaluated in two consecutive double-blind, placebo-controlled trials evaluating 61 depressed inpatients randomized to either one of two drugs, sertraline or oxaprotiline, or placebo over a 4-week clinical trial. For 30 patients who completed at least 3 weeks of double-blind treatment on either drug, the initial DST was not predictive of response to drug treatment. For the 17 patients who completed at least 3 weeks of double-blind treatment on placebo, the presence of a positive DST predicted a statistically significantly poorer response to placebo as opposed to a negative DST. These preliminary findings suggest that for depressed individuals who present with a positive DST, remission without active medication is less likely and somatic treatment should be considered.

TRH test abnormalities in psychiatric disorders

Blunted responses to thyrotropin-releasing hormone (TRH) stimulation have been found consistently in depressed patients, and have been reported in other affective disorders as well. In a smaller number of schizophrenic subjects, TRH tests have generally been normal. Thus, it has been suggested that this test may have diagnostic utility in distinguishing schizophrenia from affective disorders. In the present study the TRH test was performed upon a sample of 51 subjects that included 17 schizophrenics in order to further study the diagnostic or symptom specificity of this endocrine test. Abnormal TRH tests were present in both schizophrenic and affectively disturbed patients. There were no correlations with ratings of depression or other aspects of psychopathology. Factors which may have previously obscured abnormal TRH tests in schizophrenia are discussed.

Lyme disease: the quest for magic bullets.

Lyme disease represents a growing public health threat. Recent molecular and genetic studies have confirmed that Borrelia burgdorferi, the spirochetal agent of Lyme disease, is one of the most complex bacteria known to man. Affinity for multiple cell types and the presence of non-replicating forms of B. burgdorferi have contributed to persistent infection and failure of simple antibiotic regimens. The controversial clinical science of Lyme disease has impeded reliable diagnosis and effective treatment of this protean illness. Two major clinical hurdles are the absence of a therapeutic endpoint in treatingLyme disease and the presence of tick-borne coinfections that may complicate the course of the illness. New strategies for the diagnosis, treatment and prevention of Lyme disease are urgently needed.

Chronic treatment with metoclopramide induces behavioral supersensitivity to apomorphine and enhances specific binding of 3H-spiroperidol to rat striata

Abstract Metoclopramide is a dopamine (DA) antagonist with a potency and pharmacologic profile similar to chlorpromazine, but is paradoxical insofar as it is virtually inactive as an antagonist of DA-stimulated adenylate cyclase and has an extremely low affinity for DA/neuroleptic binding sites in membranes prepared from DA-rich brain regions. Chronic administration of metoclopramide to rats induced behavioral supersensitivity to apomorphine which was associated with enhanced specific binding of 3 H-spiroperidol to striatal membranes. These changes were seen when metoclopramide was administered to rats in their drinking water for 39 days, but not when it was given i.p. once daily for 14 days. These findings are discussed in terms of their implications regarding the validity of currently used receptor models as predictors of DA antagonism as well as the implicit assumption that DA/neuroleptic binding sites truly represent functionally relevant DA receptors.

A double-blind comparison of trebenzomine and thioridazine in the treatment of schizophrenia

Forty inpatient volunteers with diagnoses of schizophrenia were randomly assigned to treatment either with trebenzomine or thioridazine in a double-blind study of clinical antipsychotic efficacy following a 1-week placebo treatment. Psychopathology was rated using the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI). There was a significant difference in therapeutic response to the two drugs in that psychopathology decreased significantly for the thioridazine group, but not for the trebenzomine group. Serum prolactin was elevated during treatment with thioridazine, but not with trebenzomine. Side effects were more frequently reported for the thioridazine group. These results fail to confirm previous reports of clinical antipsychotic efficacy for trebenzomine.

Lithium prophylaxis of depression in unipolar, bipolar II, and cyclothymic patients

The authors assessed lithiums prophylactic effect against depression in unipolar (N = 43), bipolar II (N = 102), and cyclothymic (N = 69) patients using a longitudinal life-table analysis and calculated the probability of remaining free of a depressive episode. The probability of remaining free of one depressive episode after 2 years of taking lithium ranged from 42% to 55% for the bipolar II patients, 31% to 42% for the unipolar patients, and 26% to 36% for the cyclothymic patients. The average probability of suffering one depressive episode severe enough to require either pharmacologic intervention or hospitalization in a 2-year period was 51% for the bipolar II patients, 64% for the unipolar patients, and 69% for the cyclothymic patients.