David B. Menkes

Acute tryptophan depletion aggravates premenstrual syndrome.

The dietary technique of acute tryptophan depletion was used to suppress brain serotonin synthesis in 16 women with documented premenstrual syndrome. Each subject was tested at distinct phases of each of two menstrual cycles. Baseline amino acid levels did not vary across the menstrual cycle, except for tyrosine which showed a significant premenstrual decrement. Compared to a sham procedure, actual tryptophan depletion caused a significant aggravation of premenstrual symptoms, particularly irritability. Symptom magnitude was correlated with diminution of tryptophan relative to other amino acids. This result supports other evidence implicating serotonin in premenstrual syndrome.

Salivary THC following cannabis smoking correlates with subjective intoxication and heart rate

A cannabis smoking trial was conducted using paid volunteers. Subjective intoxication, measured using a visual analogue scale, was compared with heart rate and with salivary delta-9-tetrahydrocannabinol (THC) levels at various times after smoking a cigarette containing 11 mg THC. Subjective intoxication and heart rate elevation were significantly correlated with the log of salivary THC. Salivary THC levels are a sensitive index of recent cannabis smoking, and appear more closely linked with the effects of intoxication than do either blood or urine cannabinoid levels.

Interferons, serotonin and neurotoxicity

BACKGROUND Interferons are a class of cytokines profoundly affecting immune function. Several interferons are now synthesized and used clinically, notably for viral diseases and cancer. In addition to their desired immune effects, interferons cause a number of toxicities, including prominent effects on the nervous system. METHODS This literature review focused on the incidence of depression associated with interferon treatment. Possible neurochemical mechanisms and remedial strategies were also considered. RESULTS Interferon treatment, particularly with the alpha subtype, is unquestionably linked with depression, but the strength of association is uncertain because of erratic ascertainment and pretreatment co-morbidity. A likely pathogenic mechanism has been described, involving interferon suppression of serotonin synthesis. Controlled treatment trials of interferon-induced depression are not yet available. CONCLUSIONS Neurotoxicity substantially limits the use of interferons. At least some of the risk of depression appears to derive from their anti-serotonergic effects, consistent with the large body of evidence pointing to a general link between serotonin and affective illness. Vigilant detection and aggressive treatment of depression is necessary to optimize interferon treatment of many patients.

Fluoxetine's spectrum of action in premenstrual syndrome

This study extends our previous report of the efficacy and tolerability of fluoxetine in severe premenstrual syndrome (PMS), describes which aspects of the disorder are responsive to such treatment, and assesses the relationship between steady-state drug level and clinical outcome. Twenty-one women with documented PMS satisfied criteria for late luteal phase dysphoric disorder (DSM-III-R) and accepted the offer of a double-blind, randomized crossover trial of fluoxetine hydrochloride 20 mg/day vs placebo. Symptom severity was measured with daily self-rating, monthly premenstrual assessment forms and psychiatric interviews after 3 months each of baseline, placebo and fluoxetine treatment. Compared with an inconsistent placebo response, fluoxetine produced marked improvement in 15 of 16 women completing the trial, eight showing virtually complete remission of PMS symptoms. Fluoxetines efficacy extended over a range of affective, physical and behavioural symptoms; its superiority obtained whether it preceded or followed placebo. Three women withdrew due to adverse effects of fluoxetine, and 10 of 16 completing the trial reported at least one adverse effect of this agent. Compared with placebo, fluoxetine produced more (but usually transient) insomnia, sweating, gastrointestinal and menstrual disturbance. Plasma levels of fluoxetine and its active metabolite were not reliably associated with efficacy nor with side effects. Serotonergic agents appear to have considerable promise in treating a range of symptoms in women with severe PMS.

Are the newer antidepressant drugs as effective as established physical treatments? Results from an Australasian clinical panel review

Objective: The aim of this study was to determine, in a clinical panel sample, the extent to which patients with depression (and melancholic and non-melancholic subtypes) judged the effectiveness of previously received antidepressant treatments, particularly the comparative effectiveness of the older and newer antidepressant drugs. Method: Twenty-seven Australasian psychiatrists assessed 341 non-psychotic depressed patients and rated the extent to which previous antidepressant treatments had been effective. Patients were assigned to ‘melancholic’ and residual ‘non-melancholic’ categories by two processes (DSM-IV decision rules, and a cluster analysis-derived allocation) and treatment effectiveness examined within each category. Results: Electroconvulsive therapy (both bilateral and unilateral) was judged as highly effective by both melancholic and non-melancholic patients. Antipsychotic medication similarly rated highly (but was judged as more effective by the non-melancholic than melancholic patients). The tricyclics and irreversible monoamine oxidase inhibitors (MAOIs) were rated as more effective by the whole sample than several newer antidepressant classes (including the selective serotonin re-uptake inhibitors [SSRIs], venlafaxine, mianserin and moclobemide), whether effectiveness was examined dimensionally or categorically. Comparison of the overall tricyclic and SSRI classes indicated that any superior tricyclic effectiveness was specific to the melancholic subjects. Conclusions: Despite methodological limitations intrinsic to such clinical panel data, the judged greater effectiveness of the older antidepressants (tricyclics and irreversible MAOIs) for melancholic depression is of importance. If valid, such data are of intrinsic clinical relevance but also have the potential to inform us about the neurobiological determinants of ‘melancholia’ and pharmacological actions which contribute to its effective treatment.

Hazardous drugs in developing countries.

The international pharmaceutical market shows substantial regional differences in availability and promotion of drugs.1 This variation depends on affluence, health requirements, capacity for local manufacture, and the restrictions which countries may impose to control dangerous or inappropriate use of drugs.2 3 Because of their limited industrial base, most developing countries import most of their drugs, and transnational corporations are adept at exploiting variations in such markets.1 Commercial interests may conflict with public health needs in developing countries,4 5 6 particularly when people are poisoned due to inadequate restriction of pharmaceutical use, misleading advertising or labelling, or frankly bogus products. Promotion of unsafe drugs in the developing world has long attracted criticism, particularly when products have been banned or restricted in the country of manufacture.3 5 Pharmaceutical adverts, labelling, and package inserts in developing countries often show the twin problems of exaggerated indications and minimised adverse effects.1 5 6 Drug exports from the United States to developing …

Triazolam-induced Nocturnal Bingeing with Amnesia

A combination of behavioural and cognitive adverse effects is illustrated in this case report of a recurrent triazolam-induced eating disorder. The co-occurrence of bingeing, irritability and anterograde amnesia is suggestive of a drug-induced Kleine-Levin Syndrome.

Subtyping depression by clinical features : the Australasian database

Objective: To distinguish psychotic, melancholic and a residual non‐melancholic class on the basis of clinical features alone. Previous studies at our Mood Disorders Unit (MDU) favour a hierarchical model, with the classes able to be distinguished by two specific clinical features, but any such intramural study risks rater bias and requires external replication. Method: This replication study involved 27 Australasian psychiatrist raters, thus extending the sample and raters beyond the MDU facility. They collected clinical feature data using a standardized assessment with precoded rating options. A psychotic depression (PD) class was derived by respecting DSM‐IV decision rules while a cluster analysis distinguished melancholic (MEL) and non‐melancholic classes. Results: The MELs were distinguished virtually entirely by the presence of significant psychomotor disturbance (PMD), as rated by the observationally based CORE measure, with over‐representation on only three of an extensive set of ‘endogeneity symptoms’. Conclusion: In comparison to PMD, endogeneity symptoms appear to be poor indicators of ‘melancholic’ type, confounding typology with severity. Results again support the hierarchical model.

How long does it take for antidepressant therapies to act

Objective: To review the proposition that antidepressants have a delayed onset of action by employing measurement and analytic strategies that overcome problems confounding interpretation of many efficacy studies. Method: A subset of patients was recruited to the longitudinal component of the Australasian database study, was assessed at baseline, and then completed measures of depression and anxiety when treatment commenced, and every 3 days over the next 4 weeks. The trajectories of defined 4-week outcome responders and non-responders were compared. Results: Both groups showed a similar decrease in depression (and anxiety) over the first 3 days. A clear trend break then occurred, with little further improvement in the non-responders, as against distinct and progressive improvement in the responders. Ongoing early improvement (across days 3–6) was a strong predictor of responder status. Conclusions: The small sample size limits firm interpretation, although distinct interpretive advantages to the study design are evident. Findings are compatible with a number of recent studies arguing against any extensive delayed onset of action for the antidepressant drugs, but argue for caution in interpreting immediate improvement as predicting likely responder status, and more for examining early and sustained improvement as such a marker.

A Double Blind Trial of Moclobemide versus Amltrlptyllne in the Treatment of Depressive Disorders

The antidepressant efficacy and side-effect profile of amitriptyline were compared to those of moclobemide, a reversible monoamine oxidase inhibitor with selectivity for the type A isozyme. Forty nine patients with DSM-Ill major depression were randomly assigned to receive either amitriptyline or moclobemide. Thirty seven patients (amitriptyline n=l6, moclobemide n=21) completed the six week protocol, which was conducted under double blind conditions. The results indicated a comparable antidepressant time course and efficacy for the two treatments. Amitriptyline produced significantly more sedation and antimuscarinic side-eff ects. Moclobemide appears to be a well tolerated antidepressant without the liability to produce significant postural hypotension and without the need for a tyramine-poor diet.