Elevated P-selectin on platelets in depression: response to bupropion.

Increased platelet activation has been suggested as a possible reason for the increased vulnerability of depressed patients to ischemic heart disease (IHD). Translocation of P-selectin, an integral alpha-granule membrane protein, to the platelet surface is a measure of platelet activation. Herein, western blots of platelet plasma membranes containing P-selectin were quantified in patients with major depression (n=19; mean age=39 +/- 2 years) and healthy comparison subjects (n=17; mean age=36 +/- 2 years). None evidenced clinical signs of IHD, and only two patients had a lifestyle IHD risk factor (smoking). Blood was obtained from all 19 depressed patients before treatment, and 15 returned after 6-8 weeks of open-label bupropion treatment. Bupropion was chosen as the antidepressant because it did not elevate plasma norepinephrine or serotonin, endogenous agonists that can induce platelet degranulation. Western blotting revealed more P-selectin immunoreactivity (75 kD band) in depressed patients compared to healthy controls (P=0.003). After bupropion treatment, P-selectin remained high in depressed patients. beta3-Integrin, a reference plasma membrane protein that does not translocate during activation, was of equivalent density in depressed patients and healthy control subjects, and was unchanged after treatment with bupropion. P-Selectin failed to correlate with severity of illness based on the Hamilton Depression scale, or with the post-treatment plasma concentration of bupropion. The results suggest an elevation in P-selectin on platelet plasma membranes might be a trait marker for depression.

Effect of bupropion on immunodensity of putative imidazoline receptors on platelets of depressed patients.

A substantial number of studies have demonstrated increased imidazoline receptors (I1 binding sites) on platelets of depressed patients and downregulation following antidepressant treatments. Herein, imidazoline receptor binding protein (IRBP) antiserum was used to quantify imidazoline receptors on platelets of depressed patients before and after treatment with the atypical aminoketone antidepressant, bupropion. Western blots revealed an increase in IRBP-immunodensity (p = 0.01, two-tailed) in a 33 kDa protein band in untreated depressed patients (n = 21) as compared with controls (n = 17). This band has been positively correlated with I1 binding sites on platelets. Following 6 weeks' treatment with bupropion, IRBP-immunodensity was downregulated in depressed patients (p = 0.03, paired t-test); predominantly in responders (p = 0.005). Patients non-responsive to bupropion (n = 5) were significantly different from responders (p = 0.05) by exhibiting no elevation in IRBP-immunodensity at pre-treatment and no downregulation of the 33 kDa band after treatment. IRBP-immunodensity was negatively correlated (r = -0.79, p = 0.01) with plasma concentrations of bupropion and its metabolites at week-4 of BUP treatment. Thus, a 33-kDa IRBP on platelet plasma membranes is elevated in depression and normalized in responders to bupropion.

Trazodone and triazolam: acute subject-rated and performance-impairing effects in healthy volunteers.

The present study compared the acute subject-rated and performance-impairing effects of trazodone and triazolam in seven healthy humans. Trazodone (50, 100 and 200 mg), triazolam (0.125, 0.25, 0.50 mg) and placebo were administered orally in a double-blind, crossover design. Drug effects were measured approximately 30 min before drug administration and repeatedly afterwards for 6 h. Trazodone and triazolam produced dose-related increases in subject-ratings of drug effect and sedation. The absolute magnitude of trazodone's and triazolam's effects was comparable across these measures, which suggests the doses tested were equivalent on some behavioral dimension. By contrast, triazolam, but not trazodone, increased subject ratings of "dizzy", "excited", "nervous", "restless", "stomach turning" and "itchy skin". Triazolam, but not trazodone, significantly impaired learning, recall and performance. The present findings suggest trazodone may be a viable alternative to benzodiazepine hypnotics like triazolam, especially when needing to minimize drug-induced impairment. Future research could extend the present findings by replicating them in a clinically relevant population such as individuals with histories of drug abuse.

Discriminative stimulus effects of zolpidem in pentobarbital-trained subjects: II. Comparison with triazolam and caffeine in humans.

In the present study, four non-drug-abusing humans were trained to discriminate between a hypnotic dose of pentobarbital, 100 mg, and placebo. After acquiring the pentobarbital-placebo discrimination, a range of doses of zolpidem, triazolam, pentobarbital and caffeine were tested to determine whether they shared discriminative stimulus effects with the training dose of pentobarbital, Zolpidem, a rapid-onset, short-duration, quickly eliminated imidazopyridine hypnotic agent, was tested because its discriminative stimulus effects have been shown to differ from those of classic sedative/hypnotic compounds in rodents, but not in nonhuman primates. Triazolam and caffeine were included as positive and negative controls, respectively. The subject-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital and caffeine were assessed concurrently. These four subjects met the discrimination criterion (> or = 80% correct drug identifications on four consecutive seasions) in 4 to 18 (mean = 8.5) sessions, and the pentobarbital-placebo discrimination was well maintained during a test-of-novel-doses and test-of-novel-drugs phase (i.e., placebo and 100 mg pentobarbital occasioned 0-35% [mean = 17%] and 75-100% [mean = 85%] drug-appropriate responding, respectively). Zolpidem, triazolam and pentobarbital generally produced dose-related increases in pentobarbital-appropriate responding and sedative-like, subject-rated drug effects. Caffeine on average produced low levels of pentobarbital-appropriate responding, although some doses of caffeine produced maximal pentobarbital-appropriate responding in some subjects. Caffeine produced some stimulant-like (e.g., jittery, motivated, nervous and stimulated) subject-rated drug effects. Zolpidem and triazolam, and to a much lesser extent pentobarbital, but not caffeine, impaired performance. These results suggest that humans can acquire and maintain a pentobarbital-placebo discrimination, and this discrimination is pharmacologically specific. These results also suggest that despite the somewhat unique biochemical profile of zolpidem, its discriminative stimulus, subject-rated and performance-pairing effects are similar to those of classic sedative/hypnotic compounds like the barbiturates and benzodiazepines. Finally, the results observed in the present study with zolpidem, triazolam and caffeine demonstrate that the discriminative stimulus effects of drugs observed with nonhuman primates can be systematically replicated in humans.

Evaluation and treatment of premature ejaculation: a critical review.

OBJECTIVE: Premature ejaculation is the most prevalent male sexual dysfunction. The present article is a comprehensive review of the literature on premature ejaculation. METHOD: This critical discussion of the literature evaluates the definitional issues, theoretical conceptualizations, assessment strategies, and treatment alternatives for premature ejaculation. RESULTS: The review integrates the most recent findings on the diagnosis and treatment of premature ejaculation updating an earlier review with the addition of more than fifty recent articles and adding sections on treatment generalization and maintenance, medical evaluation, pharmacological intervention, and a discussion of methodological issues in the literature. CONCLUSIONS: The pause-squeeze technique remains the current treatment of choice for the disorder. However, this unitary treatment recommendation disguises a multidimensional disorder which has yet to evolve an operational definition, psychometrically sound assessment procedures, or clearly articulated etiology.

Amoxapine-induced neuroleptic malignant syndrome.

Amoxapine is a second-generation antidepressant possessing significant dopamine-blocking activity and extra-pyramidal side effects. The occurrence of neuroleptic malignant syndrome is described in a patient treated with amoxapine. The syndrome resolved rapidly following discontinuation of the drug. Older patients may be particularly at risk for this adverse reaction with amoxapine.

Child custody and relitigation: trends in a rural setting.

Types of child custody awards made in 884 divorce cases in a rural North Carolina County were compared and rates of postdivorce litigation were examined for each type of custody. Findings suggest a low frequency of joint custody awards and do not reveal any advantage of joint versus other forms of custody with regard to relitigation experience.

Acute posttraumatic stress disorder in victims of a natural disaster.

Five months after a tornado devastated a rural community in eastern North Carolina, the authors surveyed the mental health status of 116 disaster victims, using the Hopkins Symptom Checklist (HSCL) expanded to include most of DSM-III criteria for posttraumatic stress disorder (PTSD). A total of 69 (59%) victims met the criteria for acute PTSD, 19 of whom had a severe form. Although an inadequate degree of social support was more often noted in victims with severe PTSD, other demographic factors and degree of injury or property damage did not appear to be related to the presence of PTSD. Severity or presence of PTSD was supported by high scores on all HSCL subscale factors. These findings suggest a high incidence of acute PTSD in victims of natural disasters and the potential value of HSCL in screening for PTSD in large populations.

Cardiac antiarrhythmic effect of nortriptyline.

With a quinidine-like cardiac action, the tricyclic antidepressant drugs, imipramine in particular, have been proposed as potentially antiarrhythmic agents. The antiarrhythmic activity of nortriptyline is described in a depressed patient with premature ventricular complexes, and the basis for this activity is discussed.

Misuse of the dexamethasone suppression test as a diagnostic tool.

The diagnostic reliability and appropriateness of use of the Dexamethasone Suppression Test (DST) were assessed by a retrospective chart survey of ninety-nine psychiatric admissions to a community hospital. A change in psychiatric diagnosis between admission and discharge occurred in one-third of the patients. The diagnostic change appeared to be associated with the DST result more than the clinical findings. Such reliance on the test was not justified as the observed diagnostic confidence of the DST in supporting a diagnosis of major depression was only 38 percent. These findings suggest a misuse of the test as a diagnostic tool in routine practice.

Reliability of amitriptyline dose prediction based on single-dose plasma levels.

To assess prospectively the predictability of therapeutic dosage based on tricyclic antidepressant (TCA) concentrations after a single dose, 30 subjects were given amitriptyline. In the first 11 subjects maintained on a fixed amitriptyline dose regimen, predictive capacities of 18- and 24-hr single-dose levels were assessed and confirmed in relation to steady-state levels. For the other 19 subjects, the dose that would achieve a therapeutic steady-state concentration of 200 ng/ml was predicted from the 18-hr single-dose level and was rapidly instituted. Subjects achieved a mean steady-state TCA level of 204 ng/ml, with approximately 90% of the levels falling within the therapeutic range. There was clinical improvement within 2 wk in 84% of the subjects. Our results suggest that dose prediction based on TCA levels after a single dose is reliable and useful.

Monitoring tricyclic antidepressant plasma levels.

Patients receiving tricyclic antidepressants exhibit extreme variability in steady-state plasma concentrations because of differences in metabolism. At routine dosages, rapid metabolizers may have suboptimal concentrations while slow metabolizers can suffer from adverse effects due to inappropriately high concentrations. Neither may benefit from the drug therapy. Through analysis of plasma levels of tricyclic antidepressants, an optimal therapeutic response can be achieved, and the risk of serious side effects can be reduced.

Single-dose single-point method in amitriptyline therapy.

Twenty-one depressed patients participated in a study that assessed the predictability of amitriptyline (AT) dosage based on plasma drug concentrations after a single dose. In 11 patients maintained on a fixed dose regimen, the 18-h single-dose level was confirmed to be predictive of steady-state levels. The dose for the next 10 patients was derived from their 18-h level aiming to attain steady-state levels of 200 ng/ml. The patients achieved a mean steady-state level of 213 ng/ml with 80% attaining therapeutic levels. All the patients improved within 2 weeks. These preliminary results suggest that dose prediction based on a single-dose TCA level is reliable and beneficial.

Capgras syndrome in a patient with myxedema.

The authors describe what may be the first reported case of Capgras syndrome associate with, or precipitated by, myxedema. The patient's mental status dramatically returned to normal with gradual thyroid replacement. The authors suggest that tests for organicity be done routinely on patients manifesting Capgras features.