A case report of cholinergic rebound syndrome following abrupt low-dose clozapine discontinuation in a patient with type I bipolar affective disorder.

BACKGROUND: Rebound cholinergic syndrome is a rare, but well known unwanted phenomenon occurring after abrupt clozapine discontinuation. There have been previous reported cases of cholinergic rebound in the literature; however, these reports described cholinergic rebound following cessation of high doses of clozapine in patients diagnosed with schizophrenia. Here, we report a case of rebound cholinergic syndrome and catatonia in a male patient three days after abrupt discontinuation of 50 mg of clozapine prescribed for type I bipolar affective disorder. CASE PRESENTATION: A 66-year old male of Spanish origin, treated for type I bipolar affective disorder for 15 years and for Crohn disease, was brought to the emergency department because of a sudden onset of mutism, dysphagia and trismus. He was described catatonic and presented hypertension, tachycardia and tachypnea. His body temperature was normal and the laboratory tests were unremarkable at presentation. A head CT and an EEG were in the normal range. While reviewing his history, it appeared the he was on clozapine 50 mg a day, first introduced 2 months ago, during a previous hospitalization for a manic episode resistant to other mood stabilizers. For an unknown reason, the patient's psychiatrist stopped clozapine three days before the admission and replaced it by risperidone 5 mg and quetiapine 200 mg daily. A cholinergic rebound syndrome was then evoked. The patient's ability to speak recovered dramatically and fast after the intravenous administration of 2.5 mg of biperiden supporting the diagnosis. Risperidone and quetiapine were also stopped. The patient fully recovered in 20 days after the reintroduction of 50 mg of clozapine and 2.5 mg of biperiden daily. CONCLUSIONS: This case report underscores that cholinergic rebound syndrome may occur in patients suffering from bipolar affective disorders, being on clozapine as a mood stabilizer. The low dose clozapine does not preclude severe manifestations of the phenomenon. Progressive tapering should therefore be adopted in any case.

[Prescription of antidepressants in the treatment of pain: role of pharmacogenetics]. / Prescription d'antidépresseurs dans le traitement de la douleur: rôle de la pharmacogénétique.

Antidepressants, mainly tricyclic and non-selective reuptake inhibitors of serotonin antidepressants, are part of the treatment of chronic pain. The management is complicated by a large interindividual variability of efficacy and tolerance. Important part of this variability is associated with nucleotide polymorphisms of genes encoding enzymes involved in the pharmacokinetics and pharmacodynamics of these molecules. Identification of these genetic variants could to predict clinical consequences and allowed individualized adjustments in medication or dosage. This article presents the current knowledge on the influence of genetics on the efficacy and adverse effects of antidepressants used in chronic pain treatment.

Markers of Individual Drug Metabolism: Towards the Development of a Personalized Antidepressant Prescription.

The development of a personalized psychopharmacotherapy could potentially reduce treatment failure associated with drug intolerance or resistance, and therefore the burden and costs of affective disorders. An important challenge in realising this potential will be to identify suitable markers of an individual's metabolic response to specific pharmaceuticals. In the absence of suitable markers related directly to drug mechanism, the drug-metabolizing enzymes and transporters have emerged as major determinants of variability in drug metabolism and response. In keeping with this emergent general pharmacological trend, numerous studies concerning the relationship between antidepressants, their metabolism, transport, pharmacokinetic properties, efficacy and tolerability have now been published. These studies are reviewed in this article. The studies considered here frequently support a link between enzyme/transporter activity and/or the pharmacokinetic parameters of antidepressants. However, the majority of studies explored the variability of tricyclic antidepressants, which are less often prescribed today. Furthermore only a few studies have been conducted in naturalistic clinical conditions, seeking to determine whether the systematic assessment of the variability may improve the management of 'real-world' patients. Nonetheless recent studies have yielded promising results regarding the potential benefits of determining drug metabolism variability which might encourage additional large-scale prospective systematic studies be set up to assess the relevance of this approach in everyday practice.

Pharmacogenetics and analgesic effects of antidepressants in chronic pain management.

Antidepressants are widely administered to chronic pain patients, but there is large interindividual variability in their efficacy and adverse effect rates that may be attributed to genetic factors. Studies have attempted to determine the impact of genetic polymorphisms in enzymes and transporters that are involved in antidepressant pharmacokinetics, for example, cytochrome P450 and P-gp. The impacts of genetic polymorphisms in the targets of antidepressants, such as the serotonin receptor or transporter, the noradrenaline transporter and the COMT and monoamine oxydase enzymes, have also been described. This manuscript discusses the current knowledge of the influence of genetic factors on the plasma concentrations, efficacy and adverse effects of the major antidepressants used in pain management.

Drug-induced long QT in adult psychiatric inpatients: the 5-year cross-sectional ECG Screening Outcome in Psychiatry study.

OBJECTIVE: The authors aimed to determine the prevalence of drug-induced long QT at admission to a public psychiatric hospital and to document the associated factors using a cross-sectional approach. METHOD: All ECG recordings over a 5-year period were reviewed for drug-induced long QT (heart-rate corrected QT ≥500 ms and certain or probable drug imputability) and associated conditions. Patients with drug-induced long QT (N=62) were compared with a sample of patients with normal ECG (N=143). RESULTS: Among 6,790 inpatients, 27.3% had abnormal ECG, 1.6% had long QT, and 0.9% qualified as drug-induced long QT case subjects. Sudden cardiac death was recorded in five patients, and torsade de pointes was recorded in seven other patients. Relative to comparison subjects, patients with drug-induced long QT had significantly higher frequencies of hypokalemia, hepatitis C virus (HCV) infection, HIV infection, and abnormal T wave morphology. Haloperidol, sertindole, clotiapine, phenothiazines, fluoxetine, citalopram (including escitalopram), and methadone were significantly more frequent in patients with drug-induced long QT. After adjustment for hypokalemia, HCV infection, HIV infection, and abnormal T wave morphology, the effects of haloperidol, clotiapine, phenothiazines, and citalopram (including escitalopram) remained statistically significant. Receiver operating characteristic curve analysis based on the number of endorsed factors per patient indicated that 85.5% of drug-induced long QT patients had two or more factors, whereas 81.1% of patients with normal ECG had fewer than two factors. CONCLUSIONS: Drug-induced long QT and arrhythmia propensity substantially increase when specific psychotropic drugs are administered to patients with hypokalemia, abnormal T wave morphology, HCV infection, and HIV infection.

A major change of prescribing pattern in absence of adequate evidence: benzodiazepines versus newer antidepressants in anxiety disorders.

We performed a systematic review of controlled trials on anxiety disorders treatment (generalized anxiety disorder, panic disorder, social phobia and post-traumatic stress disorder) published from 1980 to 2006, and identified trials comparing the efficacy of benzodiazepines (BZD) with that of antidepressants, in particular comparisons between BZD and newer antidepressants. Among 969 publications, 274 double-blind randomized controlled studies remained after using our exclusion criteria. These studies comprised altogether 439 comparisons. There were in total 23 comparisons of antidepressants versus BZD. Among these, 22 compared the efficacy of older antidepressants versus BZD, whereas only 1 concerned the comparison of a newer antidepressant versus BZD. It showed comparable efficacy between venlafaxine and diazepam in the treatment of generalized anxiety disorder. Our study shows that the major change of prescribing pattern from BZD to newer antidepressants in anxiety disorders has occurred in absence of comparative data of high level of proof.

Dose-response relationship of recent antidepressants in the short-term treatment of depression.

Antidepressant drugs are widely recommended for the treatment of depressive disorders, and finding the "right dose for the right patient" is an important issue. Whatever antidepressant is prescribed, a proportion of adult patients with major depression fail to respond satisfactorily to adequate first-line treatment. A frequent strategy for patients with insufficient response to an initial antidepressant dose is to increase the dose. This review is about this strategy, ie, the possible benefits of prescribing higher doses of recent antidepressants. The results show that a flat dose-response curve is a class phenomenon for selective serotonin reuptake inhibitors (SSRIs), according to randomized, controlled, fixed-dose clinical trials. For the serotonin and noradrenaline reuptake inhibitors (SNRIs), the strategy of dose increase may be relevant for venlafaxine, in order to increase the number of responders. Thus, the subgroup of patients for whom high doses of SSRIs could be useful remains to be defined.

Clinicians' predictions of patient response to psychotropic medications.

Clinicians prescribe a medication when they assume that there is a reasonable probability of its success. There are many studies on the predictive value of social or clinical information, but these studies do not include the prognosis made by psychiatrists before treatment. These studies indicate that a small to moderate proportion of the total variance of outcome can be predicted from social or clinical information. It is peculiar that there are very few studies on the accuracy of psychiatrists' "bets" about the effects of psychotropic drugs when they use the clinical characteristics of patients as predictors, considering the practical relevance of predicting the outcome of a psychiatric treatment. The absence of studies on the accuracy of clinicians' bets or predictions in psychiatry is unfortunate.

Moclobemide discontinuation syndrome predominantly presenting with influenza-like symptoms.

A case of moclobemide discontinuation syndrome who predominantly presented with influenza-like symptoms is presented. Sertraline treatment did not modify the symptoms, which may suggest different mechanisms with regard to different antidepressant drug discontinuation syndromes. Implications for clinical care are reviewed.