A diagnostic system using broad categories with clinically relevant specifiers: lessons for ICD-11.

A diagnostic system for ICD-11 is proposed which commences with broad reorganization and simplification of the current categories and the use of clinically relevant specifiers. Such changes have implications for the positioning of diagnostic groups and lead to a range of possibilities for improving terminology and the juxtaposition of individual conditions. The development of ICD-11 provides the fi rst opportunity in almost two decades to improve the validity and reliability of the international classification system. Widespread change in broad categories and criteria cannot be justified by research that has emerged since the last revision. It would also be disruptive to clinical practice and might devalue past research work. However, the case for reorganization of the categories is stronger and has recently been made by an eminent international group of researchers (Andrews et al., 2009). A simpler, interlinked diagnostic system is proposed here which is likely to have fewer categories than its predecessor. There are major advantages of such a system for clinical practice and research and it could also produce much needed simplification for primary care (Gask et al., 2008) and the developing world (Wig, 1990; Kohn et al., 2004).

Behavioural and neuroendocrine responses to D-fenfluramine in rats treated with neurotoxic amphetamines.

The amphetamine derivatives p-chloroamphetamine (pCA), 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and D-fenfluramine can, if given repeatedly in high doses to rats, produce a degeneration of serotonergic nerve terminals which we have previously shown to result in a reduction in D-fenfluramine-evoked release of 5-HT in vivo. It is therefore possible that fenfluramine-evoked responses may have value as a probe of 5-HT neurodegeneration in man. The present study examined the effect of pre-treatment with these three agents (pCA 12 mg/kg×2; MDMA 20 mg/kg×8; D-fenfluramine 12.5 mg/kg×8, 14 days prior to testing) on behavioural (5-HT syndrome) and neuroendocrine [prolactin and adrenocorticotrophin (ACTH)] responses in rats to acute administration of D-fenfluramine and other serotonergic agonists. All three pre-treatments attenuated the D-fenfluramine-evoked behavioural syndrome, but did not affect the prolactin or ACTH responses to acute challenge with D-fenfluramine (apart from a small effect of pre-treatment with pCA on the ACTH response to D-fenfluramine). For comparison, the effect of pCA pre-treatment on the behavioural responses to acute administration of pCA and the 5-HT(1A) and 5-HT(2) receptor agonists 8-hydroxy-2-(di- n- propylamino)tetralin (8-OH-DPAT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), respectively, were also examined. pCA pre-treatment attenuated all components of the behavioural response to pCA but had little or no effect on the behavioural responses to 8-OH-DPAT or DOI, suggesting that there was no alteration in post-synaptic 5-HT(1A) or 5-HT(2) receptor function. While the loss of behavioural effect of D-fenfluramine on rats pre-treated with neurotoxic amphetamines can be understood in terms of the loss of D-fenfluramine's 5-HT-releasing action following 5-HT neurodegeneration, the lack of change in the neuroendocrine responses to D-fenfluramine is not easily explicable in this way. These results emphasise the need for further research into the actions of D-fenfluramine before carrying it forward as a probe of neurodegeneration in man.

p-Chloroamphetamine (PCA), 3,4-methylenedioxy-methamphetamine (MDMA) and d-fenfluramine pretreatment attenuates d-fenfluramine-evoked release of 5-HT in vivo.

Previous work has suggested that repeated treatment with substituted amphetamines including PCA, MDMA and d-fenfluramine produces a persistent neurodegeneration which is relatively selective for the fine serotoninergic terminals arising from the dorsal raphe nucleus. The aim of the present study was to investigate whether the acute releasing effect of d-fenfluramine might also be sensitive to lesions produced by PCA, MDMA and d-fenfluramine itself. Basal and 5-HT release evoked by d-fenfluramine or 100 mM KCl was measured by microdialysis in frontal or parietal cortex of rats 2 weeks after they had been treated with a neurodegenerative regime of PCA, MDMA, d-fenfluramine, or vehicle. In frontal cortex of vehicle controls, d-fenfluramine (10 mg/kg IP) and KCl (100 mM via microdialysis probe) evoked an increase in 5-HT of 1740% and 779% of basal, respectively. PCA pretreatment reduced d-fenfluramine-evoked 5-HT release by 90.9% while potassium-evoked release was reduced by only 66.8%. Similar results were obtained in parietal cortex. MDMA (20 mg/kg x 8) and d-fenfluramine (1.25 mg/kg x 8) pretreatment reduced d-fenfluramine-evoked release of 5-HT in frontal cortex by 45.2% and 72.0%, respectively. Overall, the present data are consistent with the hypothesis that the acute release of 5-HT evoked by d-fenfluramine occurs via those terminals destroyed by pretreatment with PCA, MDMA and d-fenfluramine, while KCl evokes release from both PCA-sensitive and PCA-insensitive terminals. The significance of these results for the interpretation of neuroendocrine data from d-fenfluramine challenge tests is discussed.

Immunocytochemical evidence for serotonergic neurotoxicity of N-ethyl-methylenedioxyamphetamine (MDE).

N-ethyl-3,4-methylenedioxyamphetamine (MDE) is one of a group of substituted amphetamines which have effects on several serotonergic markers such as tissue levels of serotonin and activity of tryptophan hydroxylase. In this study we have compared its effects on the rat brain with those of p-chloroamphetamine (PCA) using serotonin immunocytochemistry with a primary 5-HT antibody and a secondary avidin-biotin-HRP antibody. Two weeks after multiple (40 mg/kg x 8), but not single, injections of MDE there was a pronounced reduction in the number of serotonin-immunoreactive axons seen. This reduction was most marked in areas innervated extensively by serotonergic axons with varicosities of the fine type (e.g., posterior cerebral cortex and area CA1 of hippocampus). The reduction was quantitatively less than but qualitatively similar to that produced by a single dose of PCA (10 mg/kg). In material from short (3 day) survival animals, a large number of morphologically highly abnormal forms could be seen, suggestive of degenerating axons. A parallel series of sections prepared using tyrosine hydroxylase immunocytochemistry showed no differences between saline controls and PCA- or MDE-treated animals. We conclude that multiple systemic injections of MDE reduce the number of serotonin-immunoreactive fibers in the rat brain 2 weeks after treatment.

Psychiatric complications of 'Ecstasy' use.

Two case reports are presented of significant psychiatric disorders associated with ingestion of 'Ecstasy' (3,4-methylenedioxymethamphetamine), a recreational drug whose use appears to be increasing. In one case, the patient developed a brief paranoid psychosis which recurred and persisted for at least a month after he took a second dose of the drug. In the other, the patient experienced persistent symptoms of anxiety and depression for > 8 weeks after taking the drug.

Drug treatment of depression in medically ill patients.

Depressive symptoms are common in medically ill patients although depressive disorders are considerably underdiagnosed and undertreated. Drug treatments for depression are reviewed in terms of a risk/benefit analysis. The main benefit is approximately to double the chance of recovery (from about 30 to 65%), with possible associated improvements in physical condition. The risks of treatment are considerable and include overdose, unwanted effects at therapeutic dose and interaction with other drugs. Among the risks associated with specific medical conditions are orthostatic hypotension, cardiotoxicity, deterioration of seizure control in epileptic patients and increased side effects in patients with renal and hepatic impairment. The available data suggest that there is relatively little to choose between antidepressants in terms of efficacy (although the quantity and quality of these data vary). It is therefore primarily the risks which should determine the choice of antidepressant, and these must be separately evaluated for each patient.

Protective effect of BCG in Ahmednagar, India.

As part of a series of investigations to determine the effect of sensitisation by environmental mycobacteria on the efficacy of BCG vaccination in India, this study was carried out in Ahmednagar in Maharashtra. A preliminary skin test survey showed that the rate of sensitisation with age was much lower than in Agra, the site of a previous study, and BCG vaccination scars were associated with considerable enhancement in sensitisation to Tuberculin and other reagents. It was possible to set up prospective BCG vaccination studies in pre-school and primary and secondary school children. Follow up with skin tests were carried out 1 and 2 years later. By the second year, results were obtained almost identical with those 10 years after BCG administration in the UK. On this basis it is proposed that the vaccine is likely to provide a considerable level of protection in Ahmednagar. The results of this study also resemble those obtained in the very youngest age group studied in Agra. The marked differences between Indian towns strongly suggest the influence of exposure to mycobacteria in the environment.

HPLC-EC analysis of catechols and indoles in rat brain dialysates.

This short article reviews HPLC-EC methodology that we are currently applying to measure DA, 5-HT and their acid metabolites in rat brain dialysates collected in vivo. HPLC-EC systems based on standard-bore HPLC columns are described which are sufficiently sensitive to allow detection of the monoamine transmitters and their metabolites in regional brain dialysates collected at 10-20 min intervals. A large reduction in sample requirement was achieved by "down-scaling" the conventional HPLC-EC assay to incorporate small-bore HPLC columns. The small-bore systems allowed monoamines to be detected in samples collected over 1 to a few minutes.

A prospective study of BCG given to young children in Agra, India--a region of high contact with environmental mycobacteria.

A multiple skin test survey of school children (aged 5-15 years) living in Agra, India showed very high levels of sensitisation to numerous species of mycobacteria and little difference in tuberculin positivity between those with and without BCG scars. A total of 136 children aged 3 months to 8 years, living in Agra, were skin tested with Tuberculin and Leprosin A and examined for scars of previous BCG vaccination. Of those who had not previously received BCG and who had responses to Tuberculin of zero or less than 5 mm induration, 109 were offered BCG vaccination: 107 accepted and as many of them as possible were followed up with repeat skin testing 1 and 2 years later. The results are discussed in relation to the background of environmental sensitisation. A comparison is made with the data obtained from other places, particularly the Lebanon, where there is little sensitisation from the environment. Although the high level of Tuberculin conversion achieved after BCG suggested that the vaccine might have an important protective effect, the large size of Tuberculin responses in comparison with those obtained in the UK was worrying. Evidence was obtained suggesting that sensitisation to mycobacteria may occur in very young children which is not detected by the Tuberculin test, but which influences responses to BCG vaccination.