Neural Correlate of Anterograde Amnesia in Wernicke-Korsakoff Syndrome.

The neural correlate of anterograde amnesia in Wernicke-Korsakoff syndrome (WKS) is still debated. While the capacity to learn new information has been associated with integrity of the medial temporal lobe (MTL), previous studies indicated that the WKS is associated with diencephalic lesions, mainly in the mammillary bodies and anterior or dorsomedial thalamic nuclei. The present study tested the hypothesis that amnesia in WKS is associated with a disrupted neural circuit between diencephalic and hippocampal structures. High-density evoked potentials were recorded in four severely amnesic patients with chronic WKS, in five patients with chronic alcoholism without WKS, and in ten age matched controls. Participants performed a continuous recognition task of pictures previously shown to induce a left medial temporal lobe dependent positive potential between 250 and 350 ms. In addition, the integrity of the fornix was assessed using diffusion tensor imaging (DTI). WKS, but not alcoholic patients without WKS, showed absence of the early, left MTL dependent positive potential following immediate picture repetitions. DTI indicated disruption of the fornix, which connects diencephalic and hippocampal structures. The findings support an interpretation of anterograde amnesia in WKS as a consequence of a disconnection between diencephalic and MTL structures with deficient contribution of the MTL to rapid consolidation.

Multicenter study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in depression.

Pharmacogenetic tests and therapeutic drug monitoring may considerably improve the pharmacotherapy of depression. The aim of this study was to evaluate the relationship between the efficacy of mirtazapine (MIR) and the steady-state plasma concentrations of its enantiomers and metabolites in moderately to severely depressed patients, taking their pharmacogenetic status into account. Inpatients and outpatients (n = 45; mean age, 51 years; range, 19-79 years) with major depressive episode received MIR for 8 weeks (30 mg/d on days 1-14 and 30-45 mg/d on days 15-56). Mirtazapine treatment resulted in a significant improvement in mean Hamilton Depression Rating Scale total score at the end of the study (P < 0.0001). There was no evidence for a significant plasma concentration-clinical effectiveness relationship regarding any pharmacokinetic parameter. The enantiomers of MIR and its hydroxylated (OH-MIR) and demethylated (DMIR) metabolites in plasma samples on days 14 and 56 were influenced by sex and age. Nonsmokers (n = 28) had higher mean MIR plasma levels than smokers (n = 17): S(+)-enantiomer of MIR, 9.4 (SD, 3.9) versus 6.2 (SD, 5.5) ng/mL (P = 0.005); R(-)-enantiomer of MIR, 24.4 (SD, 6.5) versus 18.5 (SD, 4.1) ng/mL (P = 0.003). Only in nonsmokers, plasma levels of S(+)-enantiomer of MIR and metabolites depended on the CYP2D6 genotype. Therefore, high CYP1A2 activity seen in smokers seems to mask the influence of the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n = 8), S-OH-MIR concentrations were higher those in the other patients (n = 37). Although it is not known if S-OH-MIR is associated with the therapeutic effect of MIR, the reduction of the Hamilton scores was significantly (P = 0.016) more pronounced in the CYP2B6 *6/*6-genotyped patients at the end of the study. The role of CYP2B6 in the metabolism and effectiveness of MIR should be further investigated.

Attitudes toward psychopharmacology among hospitalized patients from diverse ethno-cultural backgrounds.

BACKGROUND: Biological factors influencing individual response to drugs are being extensively studied in psychiatry. Strikingly, there are few studies addressing social and cultural differences in attitudes toward psychotropic medications. The objective of this study was to investigate ethno-culturally determined beliefs, expectations and attitudes toward medication among a sample of hospitalized psychiatric patients. METHODS: An ad hoc questionnaire was designed to assess patients' expectations, attitudes and prejudice toward medication. The study included 100 adult patients hospitalized in Geneva, Switzerland. RESULTS: Patients were in majority male (63%), originated from Switzerland (54%) and spoke the local language fluently (93%). They took on the average 3 different psychotropic drugs. Sixty-eight percent of patients expected side effects and 60% were ready to stop medication because of them. Thirty percent of patients expected negative personal changes with treatment and 34% thought that their mental disorder could have been treated without drugs. Thirty six percent of the sample used alternative or complementary medicines. 35% of immigrant patients believed that medication had different effects on them than on local patients. When compared with Swiss patients, they more often reported that significant others had an opinion about medication (p = 0.041) and more frequently valued information provided by other patients about treatment (p = 0.010). CONCLUSION: Patients' attitudes toward medication should be investigated in clinical practice, as specific expectations and prejudice exist. Targeted interventions, especially for immigrant patients, might improve adherence.

The "rut metaphor": a conceptualization of attractor-shaping properties of addictive drugs.

The development of nonlinear models might yield better insight into the dynamics of substance use-related disorders than linear models. Nonlinear modelizations are, however, not always easily intelligible. A metaphor is presented illustrating a nonlinear conceptualization of the development of drug addiction based on recent findings on neural plasticity. Ruts are described as correlates of especially strong mnesic traces, which function as attractors, and hegemonize cognitions and behavior toward drug use. Dopaminergic activity of addictive drugs is proposed to represent the weight of vehicles tracing ruts.

Over- and underreporting of recent drug use in subjects entering an inpatient detoxification unit.

UNLABELLED: Underreporting of drug use is commonly found more often than overreporting. Overreporting may, however, occur in particular settings, e.g. in subjects entering a detoxification program. METHODS: Self-reports (standardized semi structured interview) of recent drug use of 554 patients consecutively admitted to a drug detoxification inpatient unit were compared to urine screening results at admission. Overreporters were defined as indicating a consumption of a specific drug during the preceding 7 days (3 days for cocaine) which was not confirmed by the urine screening. Underreproters denied consumption but presented positive urine. RESULTS: Overreporting was especially prevalent for opiates, and relatively more frequent (59.9% heroin, 40% methadone) than underreporting (6.8% heroin, 20.4% methadone). Signs of intoxication at admission, current methadone substitution, and previous institutional detoxification experiences influenced opiate overreporting. CONCLUSIONS: Some of the retained parameters predicting overreporting of recent opiate consumption corroborated the hypothesis of patients trying to receive more consideration from the therapeutic team and to get more intensive pharmacological care.

Efficacy and tolerability of quetiapine in cluster B personality disorder: an open-label study.

Objective. The aim of this open-label 8-week study was to assess the effectiveness of quetiapine on aggressive behaviour and social dysfunctions in patients suffering from a cluster B personality disorder (DSM-IV). Methods. The visits were performed at baseline and at days 14, 28 and 56. After a standard titration schedule, the patients received a dose augmented or reduced dose, within a range from 50 to 400 mg/day during the visits, depending on efficacy and tolerance. Assessment of efficacy was based on the French version of the Social Disability and Aggression Scale SDAS (SDAS-21). Response was defined as a decrease of ≥50% reduction of the total scores compared to baseline. Tolerability was assessed with the CGI, UKU, EPS-scales. Results and conclusion. Eight of the 12 patients included received 200 mg/day quetiapine after titration (all patients: 50-400 mg/day). At week 8, five out of 12 patients were responders based on the SDAS-21 scores for the average expression of the symptoms, and six out of 12 on the basis of SDAS-21 scores for the peak expression. There was a significant correlation between weight change and total SDAS variation (Kendall's τb= -0.644; p=0.02). These findings should be reexamined in further studies.

Treatment of suicide attempters prior to hospital admission.

OBJECTIVE: Numerous authors have reported serious shortcomings in the treatment of suicidal patients. This study examined the treatment suicide attempters admitted to a psychiatric hospital in Switzerland had received prior to the suicide attempt. METHOD: Thirty-one patients were admitted to this hospital within a year, representing 36 suicide attempts, which corresponds to 6.5% of the annual admission number. Three of these patients were admitted twice, and one patient was admitted three times. Information on previous treatment was collected in personal interviews and included medication, and its dosage, at 1 month and 2 weeks prior to the suicide attempt, and whether the patient had received psychotherapy. In addition, details of the psychosocial event and the means of the suicide attempt were recorded. RESULTS: Twenty-one patients had been prescribed psychotropic drugs in 24 events, but only in 17 events concerning 15 patients, antidepressants were prescribed prior to hospitalisation. Antipsychotics and benzodiazepines were prescribed in 6 and 21 events, respectively (including 8 events with hypnotics). None of the patients was treated with lithium. In 19 events, 16 patients had received psychotherapy prior to admission. In 32 events, psychotropic drugs were used for the suicide attempt. CONCLUSION: The findings confirm the undertreatment of patients attempting suicide reported by other authors. In spite of the majority of patients being under psychiatric care, no adequate pharmacotherapy had been prescribed particularly for depressed patients.

Local back massage with an automated massage chair: general muscle and psychophysiologic relaxing properties.

OBJECTIVES: The objective of the present study was to test massage applied with an automated massage chair on the back muscles with regard to the effects on the tension of other muscles or on the neurovegetative tone, and to compare three different automated massage techniques. METHODS: Ten healthy volunteers participated in the study. The experiment consisted of an initial 5-minute period of relaxation without massage, and 5-minute periods of three different massage programs (roll-stretch massage, shiatsu massage, and beat massage). Subjects were randomized as to the presentation order. The following physiologic data were collected: frontalis and gastrocnemius electromyogram (EMG) activity, skin conductance, and peripheral skin temperature. Judgments of valence and arousal were registered using the pencil and- paper version of the five-point Self-Assessment Manikin. RESULTS: Roll-stretch and shiatsu massage were rated by participants as more pleasant than the relaxation period without massage or the beat massage. Whereas the four conditions were similar with regard to the mean frontal EMG values (reflecting primarily affective states), they differed regarding the gastrocnemius EMG (relating more to a general level of tension), roll-stretch massage, and shiatsu massage, resulting in less muscle tension than the control condition. Shiatsu massage was associated with significantly lower skin conductance than the control condition, whereas beat massage increased it significantly. A significant increase of skin temperature was found during the roll-stretch massage compared to the no-massage condition. CONCLUSIONS: Automated roll-stretch massage and shiatsu massage applied on the back can rapidly induce measurable relaxation in distant muscles not directly massaged, and is accompanied by signs of neurovegetative calming. Back massage applied by an automated massage chair may be an efficient and inexpensive general relaxation approach, and is especially interesting for patients who dislike to be touched.

Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine: pharmacokinetic and clinical aspects.

The chiral antidepressant venlafaxine (VEN) is both a serotonin and a norepinephrine uptake inhibitor. CYP2D6 and CYP3A4 contribute to its metabolism, which has been shown to be stereoselective. Ten CYP2D6 genotyped and depressive (F32x and F33x, ICD-10) patients participated in an open study on the pharmacokinetic and pharmacodynamic consequences of a carbamazepine augmentation in VEN non-responders. After an initial 4-week treatment with VEN (195 +/- 52 mg/day), the only poor metabolizer out of 10 depressive patients had the highest plasma concentrations of S-VEN and R-VEN, respectively, whereas those of R-O-demethyl-VEN were lowest. Five non-responders completed the second 4-week study period, during which they were submitted to a combined VEN-carbamazepine treatment. In the only non-responder to this combined treatment, there was a dramatic decrease of both enantiomers of VEN, O-demethylvenlafaxine, N-desmethylvenlafaxine and N, O-didesmethylvenlafaxine in plasma, which suggests non-compliance, although metabolic induction by carbamazepine cannot entirely be excluded. The administration of carbamazepine [mean +/- SD, range: 360 +/- 89 (200-400) mg/day] over 4 weeks did not result in a significant modification of the plasma concentrations of the enantiomers of VEN and its O- and N-demethylated metabolites in the other patients. In conclusion, these preliminary observations suggest that the combination of VEN and carbamazepine represents an interesting augmentation strategy by its efficacy, tolerance and absence of pharmacokinetic modifications. However, these findings should be verified in a more comprehensive study.

Prevalence of social phobia in a clinical sample of drug dependent patients.

INTRODUCTION: Social phobia is among the most frequent psychiatric disorders and can be classified into two subtypes, nongeneralized and generalized. Whereas it significantly worsens the morbidity of comorbid substance abuse disorders, and it often is associated with reduced treatment responses, there is still lacking data on its prevalence in clinical populations of drug abusing patients. METHODS: The study sample consisted of 75 inpatients and 75 outpatients meeting DSM-IV criteria for drug dependence. Symptoms of social phobia were assessed with the French-language version of the Liebowitz Social Anxiety Scale (LSAS). RESULTS: Prevalence rate were 20% for the generalized subtype and 42.6% for the nongeneralized subtype. Gender difference emerged in the severity of fear, women reporting significantly greater fear relating to performance situations than men. CONCLUSIONS: An important proportion of patients with substance dependence present a comorbid generalized or nongeneralized social phobia. Early recognition of social phobia and adequate interventions is warranted for these patients in order to improve their treatment response with regard to quality of life and relapse prevention.

The efficiency of a carbamazepine-mianserin combination scheme in opiate detoxification.

A recent comparative randomized double-blind study has suggested the utility of a carbamazepine/mianserin combination as a treatment for opiate withdrawal. The aim of the present study was to explore the feasibility and efficiency of this combination under naturalistic conditions. Five hundred and fifty mostly polysubstance abusing patients treated with a standardized scheme combining carbamazepine and mianserin were assessed with regard to deviations to the protocol, used co-medications and retention in treatment. Three hundred and sixty three patients (66.0%) received the carbamazepine/mianserin combination as specified by the standardized protocol. In 350 patients (63.7%) the whole 10 days was completed. The most frequently used p.r.n. medications were for anxiety (47.5%) and insomnia (54.5%). The treatment of opiate withdrawal with a carbamazepine/mianserin combination scheme in an inpatient setting seems to be feasible and applicable with few adaptations to most patients, and may represent an interesting treatment option for multidrug users.

Topiramate in benzodiazepine withdrawal.

There is an increasing interest in anticonvulsants for the treatment of benzodiazepine withdrawal symptoms. The new anticonvulsant compound topiramate seems to be an especially promising drug for this indication. It acts, among others, as an AMPA antagonist, which may be responsible in part for its anticonvulsant efficacy, but may also modulate the withdrawal-induced activation of noradrenergic neurons in the locus coeruleus, which are related to some behavioural effects of benzodiazepine withdrawal. A case is presented of a rapid benzodiazepine-withdrawal treated successfully with topiramate.

Topiramate in opiate withdrawal.

The alpha2-adrenergic agonist clonidine is the mainly used drug for the opiate withdrawal. Its efficacy and tolerance in treating withdrawal symptoms is, however, suboptimal. The pharmacological profile of topiramate suggests it could be rather valuable for opiate withdrawal, as there is some evidence that topiramate acts, among others, through inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, which play an important role in the withdrawal-induced activation of the locus coeruleus (LC) by glutamate. Three patients undergoing an inpatient opiate detoxification program were treated with topiramate, which achieved a nearly complete control of withdrawal symptoms.

Olanzapine improves social dysfunction in cluster B personality disorder.

Treatment with antipsychotics is a common approach for personality disorder. Conventional antipsychotics may be efficacious particularly against psychoticism, but less against other symptoms in these patients. They are, furthermore, associated with adverse drug reactions poorly tolerated by patients with personality disorder. Atypical antipsychotics have a more convenient pharmacological profile with a lower risk for extrapyramidal symptoms and a broader therapeutic profile, showing some efficacy against impulsivity, aggressivity and affective symptoms. The medical records of ten patients with a DSM-IV diagnosis of a cluster B personality disorder who had received olanzapine treatment were reviewed. A mirror-image design anchored to the start date of olanzapine treatment and extending 8 weeks in either direction was used. The assessment consisted of a qualitative chart review and a retrospective completion of the GCI-C and an adapted French version of the SDAS, using the observer-rated items. The olanzapine dose range was 2.5-20 mg during the 8 weeks of observation. The mean SDAS score (items 1-15) was 28.8+/-8.4 for the 8 weeks preceding olanzapine prescription and was improved to 13.6+/-5.8 after 8 weeks of treatment.

Enantiomers' potential in psychopharmacology--a critical analysis with special emphasis on the antidepressant escitalopram.

Stereochemistry is now influencing most areas of pharmacotherapy, with a growing awareness in the field of psychiatry and, more specifically, depression. This is due to the fact that the enantiomers of many chiral drugs may have distinct pharmacological, pharmacokinetic and/or pharmacogenetic profiles. Consequently, in some instances there may be an advantage in using a single enantiomer over the racemic form-thus providing a basis for the development of new therapeutic agents, as well as the potential to improve current treatments. This review highlights some of the potential advantages and disadvantages that using single enantiomers might offer. The principles are exemplified through reference to the stereoselective properties of several established chiral psychotropic drugs, including thioridazine, methadone, trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. Emphasis is given to the treatment of depression and how the potential of one pure enantiomer-escitalopram, the S-enantiomer of the selective serotonin reuptake inhibitor citalopram-appears to be fulfilling its preclinical promise in the clinic.

Carbamazepine augmentation in depressive patients non-responding to citalopram: a pharmacokinetic and clinical pilot study.

Citalopram is a chiral antidepressant drug. Its eutomer, S-citalopram (escitalopram), has recently been introduced as an antidepressant. In an open pilot study, four outpatients and two inpatients with a major depressive episode (ICD-10), and who were nonresponders to a 4-week pretreatment with 40-60 mg/day citalopram, were comedicated for another 4-week period with carbamazepine (200-400 mg/day). Some of the patients suffered also from comorbidities: Phobic anxiety disorder with panic attacks (n=2), generalised anxiety disorder, alcohol abuse, dependent personality disorder, hypertension (n=1). After a 4-week augmentation therapy with carbamazepine, a significant (P<0.03) decrease of the plasma concentrations of S-citalopram and R-citalopram, by 27 and 31%, respectively, was observed. Apparently, the probable induction of CYP3A4 by carbamazepine results in a nonstereoselective increase in N-demethylation of citalopram. Moreover, there was a significant (P<0.03) decrease of the ratio S/R-citalopram propionic acid derivative, the formation of it being partly regulated by MAO-A and MAO-B. Already, within 1 week after addition of carbamazepine, there was a slight but significant (P<0.03) decrease of the MADRS depression scores, from 27.0+/-7.7 (mean+/-S.D.) to 23.3+/-6.6, and the final score on day 56 was 18.8+/-10.9. The treatment was generally well tolerated. There was no evidence of occurrence of a serotonin syndrome. After augmentation with carbamazepine, treatment related adverse events were: Nausea in one case, diarrhea in one case, and rash in two cases. In conclusion, the results of this pilot study suggest that carbamazepine augmentation of a citalopram treatment in previous nonresponders to citalopram may be clinically useful, but that in addition carbamazepine can lead to a decrease of the plasma concentrations of the active enantiomer escitalopram.