Jeffrey A. Ali

Hippocampal dysfunction in Gulf War Syndrome. A proton MR spectroscopy study

The pathogenesis of Gulf War Syndrome (GWS) is not clearly understood. Data exist to suggest that GWS may originate from a combination of chronic fatigue and sensitivity to the exposure of exogenous agents. Since the head region of hippocampus is highly vascularized and thus vulnerable to toxic substances in circulation, we postulated that hippocampal impairment occurs in GWS. To test this, single volume localized in vivo proton MR spectroscopy (MRS) studies of the left and right hippocampi of consenting Gulf War veterans (N=15; 10 with GWS, and 5 without GWS) and control Vietnam veterans (N=6) were conducted in accordance with approved human study protocols. The N-acetyl aspartate (NAA) to creatine and choline to creatine ratios were computed from the spectra. The NAA/creatine ratio of the GWS group (N=10) was found to be significantly lower than that of the entire control group (N=11) or the unaffected GW control group (N=5). No laterality differences were observed among any of the three groups. The choline/creatine ratio of the GWS group was not different from that for either control group. To check the existence of any relationship between age and the NAA/creatine ratios, the entire study population was grouped into those below or above the median age (44.3 years). It was found that the NAA/Cre ratio of the younger group (only Gulf War veterans) was significantly lower than that of the older group. The lower NAA/creatine ratio for the GWS group points to the existence of hippocampal dysfunction.

Benzodiazepine-receptor ligands in humans: acute performance-impairing, subject-rated and observer-rated effects.

The study presented here compared the acute performance-impairing, subject-rated, and observer-rated effects of quazepam (15, 30, and 45 mg), triazolam (0.1875, 0.375, and 0.5625 mg), zolpidem (7.5, 15, and 22.5 mg), and placebo in nine healthy, non-drug-abusing humans. Quazepam, a trifluoroethylbenzodiazepine, was chosen for study because, when compared with triazolam, a triazolobenzodiazepine, it is a relatively weak benzodiazepine-receptor ligand, and it may bind selectively to the BZ1 benzodiazepine-receptor subtype. Zolpidem, an imidazopyridine, is the most commonly prescribed hypnotic and was chosen for study because it is biochemically distinct from benzodiazepine hypnotics and also purportedly binds selectively to the BZ1 benzodiazepine-receptor subtype. Triazolam was chosen as the reference compound because it binds nonselectively to BZ1 and BZ2 benzodiazepine-receptor subtypes. Triazolam, zolpidem, quazepam, and placebo were administered orally in a double-blind, crossover design. Triazolam and zolpidem produced orderly dose- and time-related impairment of learning, performance, and recall, and produced sedative-like subject- and observer-rated drug effects. The behavioral pharmacologic profile of zolpidem and triazolam was indistinguishable in that at peak effect, the absolute magnitude of drug effect was comparable across the various measures. Quazepam, by contrast, did not impair performance on any task to a statistically significant degree, nor did it produce significant sedation as measured by subject- and observer-rated drug-effect questionnaires. Whether these effects are a result of the unique benzodiazepine-receptor binding profile of quazepam or the testing of insufficient dosages is unknown. Future research could extend the findings presented here by testing higher dosages of quazepam.

Delusions of pregnancy associated with increased prolactin concentrations produced by antipsychotic treatment

Treatment of psychotic symptoms has traditionally involved conventional antipsychotics. While efficacious, their side-effects have been problematic and the approval by the Food and Drug Administration of the newer antipsychotics with improved side-effects profiles heralded important advances in treating psychoses. Prolactin elevation has been associated with all classical and some atypical antipsychotics. We present cases where elevation of prolactin concentrations secondary to antipsychotic treatment was associated with delusions of pregnancy. Risperidone was the antipsychotic employed and elevation of prolactin concentrations were noted each time. The delusions abated and prolactin concentrations decreased when the drug was discontinued. Rechallenge with risperidone resulted in re-elevation of prolactin levels along with recurrent delusions. Substituting risperidone with another antipsychotic (either olanzapine or quetiapine) also led to abatement of the delusions and lowering of prolactin. Although no direct psychotogenic effects of prolactin are known, it is contended that delusions of pregnancy reported during antipsychotic treatment might be associated with rising prolactin concentrations.

Primary hypothyroidism associated with acute mania: case series and literature review.

In the evaluation of patients presenting with altered mental function searching for underlying medical conditions is necessary. Abnormal thyroid function has long been implicated in mood changes with the classic associations of depression occurring together with hypothyroidism and of mania along with hyperthyroidism. We here report 3 patients who presented with symptoms consistent with acute manic episode diagnosed using DSM IV-TR criteria and who were found to have primary hypothyroidism biochemically. This led to a review of the literature on this phenomenon resulting in the identification of 10 reports of mania and associated thyroid profiles consistent with primary hypothyroidism. All 3 of our patients improved clinically after use of levothyroxine and psychotropic medications, consistent with the literature reports. This illustrates that thyroid function abnormalities including primary hypothyroidism should be considered and screened for when evaluating patients with acute manic episodes.

Naltrexone does not attenuate the acute behavioral effects of ethanol or pentobarbital in humans.

The aim of the present study was to determine whether naltrexone, an opioid antagonist, attenuates the acute subject-rated, performance-impairing and physiological effects of ethanol or pentobarbital. To accomplish this aim, two separate experiments were conducted. In Experiment 1, eight volunteers (one female, seven males) received ethanol (0, 0.5 and 1.0 g/kg) alone and in combination with naltrexone (0, 50 and 100 mg). In Experiment 2, eight different volunteers (five females, three males) received pentobarbital (0, 150 and 300 mg), alone and in combination with naltrexone (0, 50 and 100 mg). Subjects received one of the nine possible drug-naltrexone combinations under double-blind conditions during each of nine experimental sessions. Order of drug administration was mixed, and at least 48 h separated all sessions. In Experiment 1, subjects orally ingested ethanol 1 h after naltrexone. In Experiment 2, subjects ingested naltrexone 1 h after pentobarbital. The timing of drug administration was arranged so that the peak behavioral effects of ethanol or pentobarbital occurred so that across peak plasma levels of naltrexone. Drug effects were assessed before drug administration and periodically afterwards for 5 h using a battery of subject-rated drug-effect questionnaires and performance measures previously shown to be sensitive to the acute effects of ethanol. Ethanol and pentobarbital produced prototypical subject-rated drug effects (e.g. increased subject ratings of Drunk, Drug Liking, Elated and Good Effects) and impaired performance. Naltrexone did not produce significant effects on these measures. In other words, naltrexone did not attenuate the acute subject-rated and performance-impairing effects of ethanol or pentobarbital. The mechanism by which naltrexone exerts its clinical effect in the treatment of alcohol abuse/dependence remains unclear.

A follow-up study of the acute behavioral effects of benzodiazepine-receptor ligands in humans: Comparison of quazepam and triazolam.

Quazepam, a trifluoroethylbenzodiazepine hypnotic, and triazolam, a triazolobenzodiazepine hypnotic, differ in terms of their benzodiazepine-receptor binding profile. Previous studies have suggested that quazepam produces less performance impairment than triazolam. Whether these effects are due to differences between quazepam and triazolam in terms of their benzodiazepine-receptor binding profile or to the testing of insufficient doses is unknown. The present study compared the acute behavioral effects of triazolam (0.1875, 0.3750, and 0.5625 mg), quazepam (30, 60, and 90 mg), and placebo in 12 healthy humans using a within-subjects, placebo-controlled, crossover design. Quazepam and triazolam produced comparable dose-dependent performance impairment and increased ratings of drug effect and drowsy. Quazepam, but not triazolam, increased ratings of dizzy/light-headed, performance impaired, and sleepy. Triazolam, but not quazepam, increased ratings of high. Thus, across a sufficient range of doses, the performance-impairing effects of quazepam were similar to those of triazolam. By contrast, quazepam and triazolam produced somewhat different constellations of participant-rated drug effects. These differential drug effects may be attributable to differences between quazepam and triazolam in terms of their benzodiazepine-receptor binding profile.