Relative toxicity of mood stabilisers and antipsychotics: case fatality and fatal toxicity associated with self-poisoning.

BACKGROUND: Bipolar and other psychiatric disorders are associated with considerably increased risk of suicidal behaviour, which may include self-poisoning with medication used to treat the disorder. Therefore, choice of medication for treatment should include consideration of toxicity, especially for patients at risk. The aim of this study was to estimate the relative toxicity of specific drugs within two drug categories, antipsychotics and mood stabilizers, using large-scale databases to provide evidence that could assist clinicians in making decisions about prescribing, especially for patients at risk of suicidal behaviour. METHOD: Two indices were used to assess relative toxicity of mood stabilisers and antipsychotics: case fatality (the ratio between rates of fatal and non-fatal self-poisoning) and fatal toxicity (the ratio between rates of fatal self-poisoning and prescription). Mood stabilisers assessed included lithium [reference], sodium valproate, carbamazepine, and lamotrigine, while antipsychotics included chlorpromazine [reference], clozapine, olanzapine, quetiapine and risperidone. Fatal self-poisoning (suicide) data were provided by the Office for National Statistics (ONS), non-fatal self-poisoning data by the Multicentre Study of Self-harm in England, and information on prescriptions by the Clinical Practice Research Datalink. The primary analysis focussed on deaths due to a single drug. Cases where the drug of interest was listed as the likely primary toxic agent in multiple drug overdoses were also analysed. The study period was 2005-2012. RESULTS: There appeared to be little difference in toxicity between the mood stabilisers, except that based on case fatality where multiple drug poisonings were considered, carbamazepine was over twice as likely to result in death relative to lithium (OR 2.37 95% CI 1.16-4.85). Of the antipsychotics, clozapine was approximately18 times more likely to result in death when taken in overdose than chlorpromazine (single drug case fatality: OR 18.53 95% CI 8.69-39.52). Otherwise, only risperidone differed from chlorpromazine, being less toxic (OR 0.06 95% CI 0.01-0.47). CONCLUSIONS: There was little difference in toxicity of the individual mood stabilisers. Clozapine was far more toxic than the other antipsychotics. The findings are relevant to prescribing policy, especially for patients at particular risk of suicidal behaviour.

A comparison of pharmacoepidemiological study designs in medication use and traffic safety research.

In order to explore how the choice of different study designs could influence the risk estimates, a case-crossover and case-time-control study were carried out and their outcomes were compared with those of a traditional case-control study design that evaluated the association between the exposure to psychotropic medications and the risk of having a motor vehicle accident (MVA). A record-linkage database availing data for 3,786 cases and 18,089 controls during the period 2000-2007 was used. The study designs (i.e., case-crossover and case-time-control) were derived from published literature, and the following psychotropic medicines were examined: antipsychotics, anxiolytics, hypnotics and sedatives, and antidepressants, stratified in the two groups selective serotonin reuptake inhibitors (SSRIs) and other antidepressants. Moreover, in order to further investigate the effects of frequency of psychoactive medication exposure on the outcomes of the case-crossover analysis, the data were also stratified by the number of defined daily doses (DDDs) and days of medication use in the 12 months before the motor vehicle accident. Three-thousand seven-hundred fifty-two cases were included in this second part of the case-crossover analysis. The case-crossover design did not show any statistically significant association between psychotropic medication exposure and MVA risk [e.g., SSRIs-Adj. OR = 1.00 (95 % CI: 0.69-1.46); Anxiolytics-Adj. OR = 0.95 (95 % CI: 0.68-1.31)]. The case-time-control design only showed a borderline statistically significant increased traffic accident risk in SSRI users [Adj. OR = 1.16 (95 % CI: 1.01-1.34)]. With respect to the stratifications by the number of DDDs and days of medication use, the analyses showed no increased traffic accident risk associated with the exposure to the selected medication groups [e.g., SSRIs, <20 DDDs-Adj. OR = 0.65 (95 % CI: 0.11-3.87); SSRIs, 16-150 days-Adj. OR = 0.55 (95 % CI: 0.24-1.24)]. In contrast to the above-mentioned results, our recent case-control study found a statistically significant association between traffic accident risk and exposure to anxiolytics [Adj. OR = 1.54 (95 % CI: 1.11-2.15)], and SSRIs [Adj. OR = 2.03 (95 % CI: 1.31-3.14)]. Case-crossover and case-time-control analyses produced different results than those of our recent case-control study (i.e., case-crossover and case-time-control analyses did not show any statistically significant association whereas the case-control analysis showed an increased traffic accident risk in anxiolytic and SSRI users). These divergent results can probably be explained by the differences in the study designs. Given that the case-crossover design is only appropriate for short-term exposures and the case-time-control design is an elaboration of this latter, it can be concluded that, probably, these two approaches are not the most suitable ones to investigate the relation between MVA risk and psychotropic medications, which, on the contrary, are often use chronically.

Rapid tranquilization: new approaches in the emergency treatment of behavioral disturbances.

Psychiatric emergencies are often accompanied by behavioral disturbances that interfere with normal assessment and call for immediate intervention. Different pharmacological treatment regimens have been used for this purpose. Most of these regimens are based upon common clinical practice and have limited evidence base. Recently, a major publication by experts in the field of emergency psychiatry has covered this topic and the therapeutic armamentarium has been extended with the atypical antipsychotics. However, research is still hampered by different methodological limitations: unclear definition of the agitated state and therapeutic goal, idiosyncratic measurement, small sample sizes. The perspective of the patient and the interaction between the emergency care setting and treatment regimen also need further attention. All these important, but often neglected issues are covered in a selective review of the literature.

Impact of neuroleptic chemotherapies on schizophrenic psychoses.

The author reviews the impact of neuroleptic chemotherapy on various forms of schizophrenia in the 25 years since the introduction of chlorpromazine in psychiatry. The activities of the different types of compounds are related to the symptomatic and progressive forms of the psychosis, with an emphasis on the "dual structure" of the illness. Problems of drug efficacy, the need for new drug treatments, and methodological issues in research in these areas are discussed.

Classification and discrimination for data analysis in pharmacology.

Classification and discrimination are described as methods of inference and decision-making in pharmacological data analysis. Principal components and multiple discriminant analysis are applied to animal and human spectra of the neuroleptics. A preliminary step is required to separate differences in potency from the spectral information.

Clinical and pharmacological spectral maps of the neuroleptics.

The clinical and pharmacological activity spectra of the neuroleptics can be projected into a map where compounds with similar spectra, but with possibly different potencies, are grouped together. The spectral maps were devised for classification and for the prediction of therapeutic effects from pharmacological observations. Significant correlations are observed within and between pharmacological and clinical classifications (Spearman test, p less than 0.01). Pharmacological maps appear to be one-dimensional and resemble the Lambert incisive/sedative bipolar scale. The Liége clinical physiognomy of neuroleptics shows an additional component which may be related to antimanic/antiaustistic effects.

Spectral mapping, a technique for classifying biological activity profiles of chemical compounds.

A mathematical technique is described that separates potency from spectral information in biological activity spectra. The technique is a preliminary step in the classification of chemical compounds and in the structuring of pharmacological assays. The method is illustrated using previously reported results on 40 neuroleptics in 12 assays on rats. Principal component analysis and cluster analysis are shown to provide complementing information.

Classification of psychoactive drugs by visually evoked potentials in rabbits by means of multiple discriminant analysis. A possible way of predicting the clinical efficacy of new psychoactive drugs.

The influence of representatives of various groups of antipsychotic drugs on the visually evoked potential (EP) was investigated with the aid of a modified recording and evaluation technique for the rabbit EEG from cortical and subcortical structures. The starting point was the hypothesis that changes in the EP in animal experiments caused by representative members of these "substance groups" (neuroleptics with predominantly antipsychotic or predominantly sedative effect, and antidepressants with predominantly mood-brightening or predominantly sedative main components) make predictions of the clinical efficacy of "unknown" substances possible on the basis of clinical therapeutic principles of classification. Experiments were carried out with haloperidol and fluphenazine, chlorpromazine, amitriptyline and doxepin, and with imipramine and clomipramine, as representatives of these classes of substances. The hypothesis was checked by attempts to assign amitriptyline and chlorprothixene in varying dosage, haloperidol, benzperidol and mianserine to appropriate classes. As classification and assignment procedure we used stepwise multiple discriminant analysis (SWDA) according to our modification of the BMD 0 7 M Program. The purpose of the latter program, and its applicability to our studies, are described and discussed. It was found 1. that with EP data from animal experiments it is possible to classify various groups of psychoactive drugs on the basis of clinical therapeutic findings, using SWDA; 2. that assignment of "unknown" compounds can be based on this classification; 3. that hence with some caution predictions of the clinical effect of newly developed substances may be made on the basis of findings in animal experiments. The EP variables which contain most information for making up the separation formula and hence are of special importance, are investigated with respect to their possible neurophysiological evidential value, and their significance is discussed. It was found that the EP from the visual cortex are of particular significance for the separation of groups in the form presented here.

Spectral maps of the Liege-physiognomies of the neuroleptics.

Spectral mapping is a classification technique that has been applied to the Liege physiognomies of the neuroleptics. The method makes use of a special projection that separate potency from spectral information. Principal component analysis revealed a dominant component resembling a bipolar incisive/sedative scale. A second antimanic/antiautistic scale is apparent in the revised. Liege physiognomie. Spectral mapping allows to compare observations on neuroleptics in different frames of reference and from different methodologies (e.g. clinical and pharmacological).

[Attempt at classification and orientation of prescriptions using an index of psychotropic drugs in computers]. / Essais de classification et d'orientation de la prescription au moyen d'un fichier des médicaments psychotropes en ordinateur

We designed a method of rational classification of psychotropic drugs belonging to neuroleptic class. Standard profiles were determined along BELSON'S Method (partially modified). Neuroleptic population is analysed according to two leading variables : desinhibiting action and powerful sedative action. The remaining variables are graded depending upon their binding with leading variable, we called them explanatory variables. Profile of drug is found along these explanatory variables. Results are set out with : list of decomposition with clauses, list of variables selected by method, dichotomic graphic, identification of drugs. Our purpose is to find objective tests, for classification of these therapeutic drugs. It must enable a best evaluation of indications and contra-indications, practice in every day.