[In process]. / Insomnie, anxiété: faut-il réguler la prescription des benzodiazépines?

Benzodiazepine hypnotics bear a higher risk of high dose dependence than benzodiazepine anxiolytics, according to a recent study in Luxemburg. This article summarizes the main indications of these molecules and the current treatment recommendations. It provides an overview of public health actions of the past and the future to reduce their excessive consumption.

[Iatrogenic psychiatric-like symptoms recognition]. / Reconnaître les symptômes psychiatriques iatrogènes liés aux antipsychotiques.

INTRODUCTION: This article proposes a review of atypical multicentre studies for drug-induced movement disorders (and related psychiatric symptoms) and supersensitivity psychosis. A well-conducted antipsychotic treatment consists of regular attempts to reduce the dose by finding the minimal therapeutic dose. To achieve optimal antipsychotic treatment, it is important to distinguish psychiatric symptoms associated with drug-induced movement disorder(s) (DIMD) or supersensitivity psychosis from true relapse. LITERATURE FINDINGS: Persistent DIMD have been found to be a predictor of supersensitivity psychosis or tardive dyskinesia (DT). DIMD-associated psychiatric symptoms can be classified into three types: directly induced by DIMD; resulting from confounding DIMD with psychiatric symptoms; and supersensitivity symptoms associated with DIMD. Without this distinction, the beneficial effects of antipsychotics are masked by emergent DIMD psychiatric symptoms (as was confounded in the CATIE study). DISCUSSION: A constant decline in the prevalence of TD (hyperkinetic, involuntary and purposeless movement disorder) has been observed since the introduction of atypical antipsychotics. The neurotoxic effects of classical antipsychotics are well documented and their discontinuation is required. However, the risk of TD still exits with atypical antipsychotics and continued surveillance of emerging cases is very important for clinicians. Moreover, a regular evaluation of DIMD and associated psychiatric symptoms is crucial. It is important to underline the fact that DIMD persists with antipsychotics, with significantly higher total PANSS scores than in patients without DIMD. CONCLUSION: Supersensitivity psychosis is a drug-induced psychotic relapse (6 weeks following the decrease or withdrawal of an antipsychotic). Discontinuation syndromes can produce psychiatric symptoms (and be confounded with true relapse), but can be improved more quickly after reintroduction of treatment. Interestingly, various data suggest that lower doses of antipsychotics could prevent such symptoms. Anticonvulsants can be efficient adjuvants in the treatment of psychosis. In the United States, many patients received valproate or gabapentin treatment. These adjuvants, by antikindling effect, can facilitate minimal maintenance drug treatment and be efficient for anxiety. Resistant schizophrenia can be related to supersensitivity psychosis; gabapentin and lamotrigine are effective in this case.

Phytophagy by the Mullein Bug (Hemiptera: Miridae) on Apples: Feeding Behavior and Fruit Damage.

The zoophytophagous mullein bug, Campylomma verbasci (Meyer-Dür) (Hemiptera: Miridae), is a beneficial predator of mites and aphids, but also a pest causing damage when it feeds on apples. The aim of this study was to evaluate three different parameters of phytophagy of the mullein bug both in laboratory (phytophagous behavior) and field (fruit damage) tests: 1) apple cultivar, 2) fruit size, and 3) nymphal instar. In the laboratory, nymphs were observed individually for 15 min in Petri dishes containing agar gel and an apple fruitlet to evaluate feeding punctures of four apple cultivars, four fruit sizes, and five nymphal instars. In the orchard, nymphs were caged at bloom in sleeve cages to evaluate damage on the developing fruit of seven apple cultivars and three nymphal instars on 'Red Delicious'. The feeding punctures in the laboratory were higher on 'Red Delicious' than on 'Honeycrisp'; fruit damage in the orchard did not differ among cultivars at mid-season, but was higher on 'Red Delicious' than on 'Lobo' and 'Marshall McIntosh' at harvest. The number of feeding punctures in the laboratory was higher on 7-9 mm than on 18-20 mm size fruit for 'Red Delicious', but not for 'Honeycrisp'. The number of feeding punctures in the laboratory made by the fifth nymphal instar was higher than those made by younger nymphs, but fruit damage in the orchard did not differ among nymphal instars. Our results will help to elaborate a management chart for this insect by minimizing risks and promoting its use for biocontrol. RÉSUMÉ: .La punaise de la molène, Campylomma verbasci (Meyer-Dür) (Hemiptera: Miridae), est un prédateur bénéfique zoophytophage des acariens et pucerons dans les vergers, mais également un ravageur causant des dommages lorsqu'il se nourrit sur les pommes. Le but de cette étude était d'évaluer trois paramètres différents sur la phytophagie de la punaise de la molène, à la fois en laboratoire (comportement phytophage) et sur le terrain (dommages aux fruits) : 1) les cultivars de pommes, 2) la taille des fruits, et 3) les stades larvaires. En laboratoire, les larves étaient observées individuellement pendant 15 min dans des boites de Petri contenant un gel d'agar et une jeune pomme afin de déterminer les piqûres de nutrition sur quatre cultivars de pommes, quatre tailles de fruit et cinq stades larvaires différents. En verger, des larves ont été encagées à la floraison dans des manchons en mousseline afin d'évaluer les dommages sur les fruits en développement. Les essais ont été effectués sur sept cultivars de pommes ainsi qu'avec trois stades larvaires sur le cultivar "Délicieuse rouge". Les piqûres de nutrition en laboratoire étaient plus nombreuses sur "Délicieuse rouge" que sur "Honeycrisp"; les dommages aux fruits en verger ne différaient pas entre les cultivars à mi-saison, mais étaient plus nombreux sur "Délicieuse rouge" que sur "Lobo" et "Marshall McIntosh" à la récolte. Les piqûres de nutrition en laboratoire étaient plus nombreuses pour la taille de fruit 7-9 mm que 18-20 mm sur "Délicieuse rouge", mais pas sur "Honeycrisp". Le nombre de piqûres de nutrition (en laboratoire) faites par les larves de stade 5 étaient plus nombreuses que celles faites par les larves plus jeunes, mais les dommages aux fruits (en verger) ne différaient pas entre les stades larvaires. Ces résultats vont aider à élaborer une charte de gestion de cet insecte en minimisant les risques et en favorisant son rôle d'agent de lutte biologique.

Phenothiazine-induced ECG abnormalities: effect of a glucose load.

A total of 54 schizophrenic patients, 27 male and 27 female, satisfying study criteria, were randomly assigned to one of three treatments: placebo; perphenazine, 20 mg/day; or the combination of amitriptyline, 125 mg/day, with perphenazine, 20 mg/day. Medication was administered under double-blind conditions for 12 weeks, after which ECGs were taken following an overnight fast and again following a 600-calorie meal. Among patients receiving perphenazine or amitriptyline-perphenazine, there was a statistically significant increase in repolarization abnormally after eating, whereas placebo-treated patients incurred no such increases. This supports the hypothesis that phenothiazine-induced ECG changes may be caused or facilitated by the glucose load. The incidence of increase in repolarization abnormality after the meal was higher among female patients than among male patients. The findings are of practical significance for readings of abnormality in the ECG of phenothiazine-treated patients.

Amitriptyline-perphenazine interaction in ambulatory schizophrenic patients. A controled study of drug interaction.

In a double-blind placebo, controlled clinical study, lasting 12 weeks, 48 male and 48 female ambulatory schizophrenic patients were randomly assigned to one of four treatments: placebo; amitriptyline hydrochloride, 125 mg/day; perphenazine, 20 mg/day; or amitriptyline-perphenazine, 20 mg/day. Treatment groups contained an equal number of male and female patients. Perphenazine alone or in combination was substantially more effective in reducing psychopathological disorder than was the placebo, but there was no evidence to indicate the superiority of the amitriptyline-perphenazine combination over perphenazine alone. Amitriptyline alone was not substantially better than placebo and could not be considered an efficacious medication for the maintenance treatment of these patients. Less response to treatment was made by patients with longer-term records of prior hospitalization.

Double-blind parallel comparison of three dosages of sertraline and placebo in outpatients with obsessive-compulsive disorder.

BACKGROUND: Anecdotal evidence suggests patients with obsessive-compulsive disorder (OCD) are treated with selective serotonin uptake inhibitors at dosages significantly higher than those used with depressed patients. The current study examined the efficacy, safety, and optimal dosing strategy of sertraline in patients with OCD. METHODS: Three hundred twenty-four nondepressed outpatients with OCD from 11 sites followed identical protocols using a double-blind parallel design. Following 1 week of single-blind placebo, patients were randomly assigned to 12 weeks of treatment with one of three fixed dosages of sertraline (50, 100, or 200 mg/d) or placebo. RESULTS: Sertraline patients exhibited significantly greater improvement (P < .05) at end point than placebo patients on all three main efficacy measures in the 50-mg/d and 200-mg/d groups and on one measure in the 100-mg/d group. The placebo response was larger in this population of subjects with OCD than in those previously studied. Adverse experiences were common in the sertraline and placebo groups and appeared to be dose-related in the sertraline-treated patients. CONCLUSIONS: Results support the safety and efficacy of daily dosages of 50, 100, and 200 mg of sertraline in the short-term treatment of patients with OCD.

Loss of striatal cholinergic neurons as a basis for tardive and L-dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia.

In the first section of this paper several aspects of tardive dyskinesia (TD) (clinical, epidemiological, pharmacological) are reviewed. We propose that this syndrome is not the consequence of dopamine receptor proliferation, but results from damage or degeneration of striatal cholinergic interneurons. We suggest that this cellular damage is caused by prolonged overactivation of these neurons, which occurs when they are released from dopaminergic inhibition following neuroleptic administration. Overactivity of central cholinergic systems during akinetic and motor retarded depression could be a contributory cause. The predisposition to L-DOPA-induced peak-dose dyskinesia in Parkinson's disease may depend on the same type of striatal neuronal loss. In the second part of the paper, the subject of supersensitivity psychosis and drug-resistant schizophrenia is reviewed. These two syndromes, are commonly associated with TD, have similar predisposing factors and pharmacology to TD, and are potentially persistent. We suggest that these conditions also result from degeneration of cholinergic striatal interneurons following chronic neuroleptic administration. The efficacy of clozapine for such treatment-refractory psychoses is explained in terms of its blockade of D-1 dopamine receptors. Other drugs effective against refractory psychoses (e.g. risperidone) are predicted to reduce activation at D-1 receptors.

A controlled clinical trial of L-tryptophan in acute mania.

In a 2-week study, 24 newly admitted manic patients were treated for 1 week with L-tryptophan (12 g/day); during the second week, half the patients, chosen at random, continued to receive tryptophan, while placebo was substituted in the other half under double-blind conditions. In the open phase of the study, there was a clinically and statistically (p less than 0.001) significant reduction in manic symptom scores, with little need for haloperidol prn. Patients who continued to be treated with tryptophan showed no significant change in mean scores during the second week, but those who were switched to placebo tended (p less than 0.10) to show an increase in the mean scores for manic symptoms. There was a significant (p less than 0.05) increase in the geometric mean of morning fasting total and free plasma tryptophan concentrations in men, but not in women. These results suggest that increasing the synthesis of 5-hydroxytryptamine has some therapeutic effect in mania.

Antimanic effect of clonazepam.

Twelve acutely manic patients, newly admitted from the emergency room, were treated wih clonazepam or lithium carbonate in a double-blind cross-over design: half the patients chosen randomly received 10 days of treatment with clonazepam followed immediately by 10 days of treatment with lithium, while the others received the same treatments in reverse order. Clonazepam was found to be significantly more efficacious than lithium in reducing manic symptoms despite the fact that during clonazepam treatment less patients required PRNs of haloperidol. Furthermore, both the total dose of PRN haloperidol and the number of days it was needed were significantly lower during clonazepam treatment than during lithium treatment. Clonazepam had a rapid onset of action, was highly sedative, and was well tolerated at high doses. By reducing the need for neuroleptics in the treatment of acute mania, clonazepam may decrease the risk of tardive dyskinesia in manic patients.

The psychotropic effects of inhibitors of steroid biosynthesis in depressed patients refractory to treatment.

Twenty patients, diagnosed as suffering from treatment-resistant major depression, were treated with one or more drugs that decrease corticosteroid biosynthesis. Nine were psychotic, 11 nonpsychotic. Seventeen completed the treatment (8 psychotic, 9 nonpsychotic); 13 responded (5 psychotic, 8 nonpsychotic; 11 responded completely (i.e., a drop in the Hamilton Depression Scale of at least 50%, to < or = 15), and 2 responded partially. The mean age of the responders (45.2 +/- 12.6 years) did not differ significantly from that of the nonresponders (48.7 +/- 12/3). Data were analyzed in the following categories; (1) the presence or absence of psychosis, (2) response or nonresponse to treatment, and (3) the drug(s) used (aminoglutethimide, ketoconazole, or a combination of either of these with metyrapone). The patients improved over time on the Hamilton Depression Scale independent of the medication used. Responders demonstrated improvement in mood, insomnia, anxiety, diurnal variation, paranoia and obsessive compulsiveness. Nonpsychotics responded better than psychotics.

Penfluridol in the treatment of newly admitted schizophrenic patients in a brief therapy unit.

The authors compared penfluridol, a long-acting neuroleptic that can be administered orally once a week, with chlorpromazine in the treatment of 33 newly admitted schizophrenic patients in a brief therapy unit. Patients receiving either drug improved enough to be discharged in 3 weeks. Penfluridol-treated patients experienced less drowsiness than those treated with chlorpromazine, but the severity of extrapyramidal symptoms appeared to be greater with penfluridol.

Clonazepam in the treatment of recurrent symptoms of depression and anxiety in a patient with systemic lupus erythematosus.

A patient undergoing steroid therapy for systemic lupus erythematosus developed symptoms of depression and anxiety that did not respond to conventional drug therapy. A regimen of clonazepam, an anticonvulsant drug, did relieve the symptoms.

Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment.

In this double-blind, placebo-controlled study of 4 weeks of benzodiazepine treatment followed by 3 weeks of abrupt or gradual drug withdrawal, 16 patients whose benzodiazepine was withdrawn abruptly were worse (p less than .05) than 13 who had received placebo in terms of change in mean anxiety scores from the pretreatment level. The scores of seven patients (44%) whose benzodiazepine was withdrawn abruptly increased 10% or more on both the Hamilton Rating Scale for Anxiety and the Self Rating Symptom Scale. There were no cases of rebound anxiety in 14 patients whose benzodiazepine was withdrawn gradually; fewer cases of rebound anxiety were seen with a benzodiazepine that had a long half-life.

Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics.

Tardive dyskinesia is thought to result from neostriatal dopaminergic receptor supersensitivity induced by chronic treatment with neuroleptics. The authors suggest that dopaminergic supersensitivity also occurs in the mesolimbic region after chronic neuroleptic exposure, resulting in the development of a supersensitivity psychosis. Neuroleptic-induced supersensitivity psychosis is illustrated by data from 10 patients that demonstrate the syndrome's clinical and pharmacologic characteristics. An implication of neuroleptic-induced mesolimbic supersensitivity is that the tenaency toward psychotic relapse in such patients is determined by more than just the normal course of the illness.

Fast-cycling bipolar disorder induced by withdrawal from long-term treatment with a tricyclic antidepressant.

A unipolar depressed patient developed a fast-cycling bipolar disorder on abrupt discontinuation of long-term treatment with a tricyclic antidepressant. The case illustrates the potential for drug withdrawal to induce mood disturbance that is more severe than the original illness.

Factors related to tardive dyskinesia.

The authors found a 31% incidence of tardive dyskinesia among 261 schizophrenic outpatients treated with neuroleptics. Multiple linear logistic regression analysis revealed a higher incidence of tardive dyskinesia among elderly patients, those with longer records of hospitalization, those for whom neuroleptic medication had little therapeutic effect, and those treated with fluphenazine. Patients manifesting tardive dyskinesia tended to have fewer parkinsonian symptoms than those without the disorder, especially when tremors and akathisia were excluded from consideration. Multiple linear regression analysis indicated that brain-damaged patients and male patients were more susceptible to severe forms of the disorder, even though these factors were not implicated in its initial appearance.

Dopamine D4 receptor variant, D4GLYCINE194, in Africans, but not in Caucasians: no association with schizophrenia.

Because antipsychotic drugs selectively block dopamine receptors and since dopamine D4 receptors are elevated sixfold in postmortem schizophrenia brain, we searched for possible abnormalities in the coding region of the genomic DNA sequence for the dopamine D4 receptor in control and schizophrenia tissues. The DNA sequence for the first 250 bases of exon 3 of this receptor was examined in the genomic DNA from 296 control individuals and 58 schizophrenics. Twenty-three out of 183 control blacks (12.6%) and 3 out of 24 (12.5%) schizophrenic blacks revealed a replacement of T by G, predicting a substitution of valine by glycine at amino acid position 194. The identical prevalence of 12.5% indicates that the variant is not associated with schizophrenia. The amino acid replacement occurs one amino acid away from a serine amino acid which is critical for the attachment of dopamine. None of the 147 Caucasians (113 controls; 34 schizophrenics) revealed this variant, termed D4GLYCINE194.

Bupropion and amitriptyline in the treatment of depressed patients.

Bupropion, a specific dopamine reuptake inhibitor, was compared to amitriptyline in two multicenter studies involving 183 depressed outpatients and inpatients. Initial results from these ongoing studies provide additional evidence of the antidepressant activity of bupropion. At the end of the treatment periods (6 weeks for inpatients and 13 weeks for outpatients), bupropion appeared to be at least as effective as amitriptyline. However, bupropion exerted a slightly but nonsignificantly smaller overall therapeutic effect than amitriptyline during the first 4 weeks of drug treatment. Slight weight loss and dopaminergic side effects, such as insomnia, nausea/vomiting, and anorexia, were somewhat more common among bupropion-treated patients. Compared to bupropion, amitriptyline induced more weight gain and had more anticholinergic, antihistaminic, and antiadrenergic side effects. In view of its numerous sites of action, amitriptyline does not appear to be the ideal antidepressant. It remains to be demonstrated whether bupropion has any advantage over secondary amine tricyclic antidepressants, such as nortriptyline and desipramine.

A double-blind controlled clinical trial of fluoxetine and amitriptyline in the treatment of outpatients with major depressive disorder.

Fluoxetine, a specific serotonin reuptake inhibitor, was compared to amitriptyline in the treatment of 51 outpatients with primary major depressive disorder. After a 1-week placebo washout, patients were randomly assigned to 5 weeks of treatment with fluoxetine or amitriptyline. Fluoxetine was found to have a therapeutic effect comparable to that of amitriptyline; however, the fluoxetine treatment group had a better Efficacy Index-Side Effects rating and a lower incidence of anticholinergic autonomic side effects. Four amitriptyline-treated patients had to discontinue the study because of serious side effects, while in the fluoxetine treatment group there were no terminations due to side effects. The amitriptyline-treated patients gained significantly more weight than the fluoxetine-treated patients.

The use of benzodiazepines in the treatment of manic-depressive illness.

The benzodiazepine clonazepam was approved for the treatment of epilepsy in 1976. To study its use in acute mania, the author compared clonazepam with lithium in a crossover trial. Clonazepam proved more effective than lithium in controlling the symptoms of mania and caused fewer manifestations of parkinsonism. Associated side effects included ataxia, drowsiness, and behavioral changes. No treatment-emergent depression was observed. Neither clonazepam nor any other benzodiazepine is recommended in schizoaffective or schizophrenic disorders because of the high risk of dependence in those patients, in contrast to manic-depressives. For the maintenance treatment of bipolar disorder, lithium is recommended as the initial agent, with L-tryptophan added if concomitant medication is needed. Clonazepam can then be added as the anticonvulsant, if necessary. In the treatment of acute mania, clonazepam is recommended for the first week of treatment, and lithium is added in the beginning of the second week, thus avoiding the use of neuroleptics.