S.D. Schindler

Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophrenia.

In the present study, the occurrence of tardive dyskinesia (TD) in chronic schizophrenia patients was investigated in relation to pharmacogenetic polymorphisms. It is known that the metabolism of important neuroleptic drugs is influenced by polymorphisms of the CYP2D6 gene, which encodes the cytochrome P450 enzyme debrisoquine/spartein hydroxylase. Forty-five patients meeting the DSM IV criteria for schizophrenia, chronic course, were recruited. The patients were examined for the mutations CYP2D6*3, CYP2D6*4 and CYP2D6*5. The CYP2D6 genotype distribution in the patient group did not differ from that in healthy Caucasian populations. Tardive dyskinesia was found in 26 patients (57.8%). When comparing patients without CYP2D6 mutations with patients heterozygous for one mutation, we found a higher incidence of TD in the latter (81.3% vs. 46.4%, p = 0.031, multiple regression analysis), which demonstrates a significant influence of the CYP2D6 genotype of the manifestation of TD. As slight differences in the metabolism of drugs in patients heterozygous for CYP2D6 mutations and patients without such mutations are known, we conclude that heterozygous carriers of 2D6 mutated alleles may show an increased susceptibility to developing TD.

The citalopram challenge test in patients with major depression and in healthy controls

Neuroendocrine challenge tests in depressed patients have revealed a blunted hormonal reaction to serotonergic stimuli. In the present study, citalopram was chosen as the serotonergic agent for neuroendocrine stimulation. Compared to earlier challenge agents, citalopram has the advantage of serotonergic selectivity, its application is well tolerated and the possibility of intravenous application reduces pharmacokinetic interference. Sixteen patients suffering from an acute episode of major depression and 16 healthy controls underwent the stimulation procedure with 20 mg of citalopram and placebo. Whereas significant differences in the secretion of prolactin and cortisol between citalopram and placebo challenge were observed in the control group, no differences were found in the group of depressed patients. Comparison of depressed patients and controls showed a significantly blunted prolactin secretion in patients. Differences in cortisol secretion following serotonergic stimulation with citalopram did not become significant. The stimulation procedure was well tolerated in all subjects, although a higher number of side effects was observed in the control group. The amount of side effects did not correlate with the hormone responses. These results are in line with the hypothesis of serotonergic hypofunction in depressed patients. In conclusion, the 20-mg citalopram challenge test is thought to be a promising tool for further investigation of serotonergic function in psychiatric illness.

Effective open-label treatment of tourette's disorder with olanzapine.

&NA; Olanzapine is an atypical antipsychotic drug which shows a high antagonistic affinity to the D1, D2 and D4 and the 5‐HT2A and 5‐HT2C receptors. The goal of our investigation was to assess the efficacy of olanzapine in patients with Tourettes disorder who were either antipsychotic naive or who did not tolerate and/or did not respond to previous antipsychotic treatments in an open‐label pilot study. Fourteen patients with a mean (SD 12.4) age of 32.6 years were treated for a period of 6 weeks. Seven patients did not respond to, or did not tolerate, previous neuroleptic treatments and seven patients were antipsychotic naive. All patients received olanzapine in ascending dosage, following a washout period of 1 week. Initial dosage was 10 mg/day with a maximum dosage of 20 mg/day. The Yale Global Tic Severity Scale (YGTSS), Fischer Symptom Check List‐Neuroleptika and the Clinical Global Impression Severity Scale (CGI) were used. Two of the 14 patients did not complete the investigation. The mean dosage of olanzapine was 15 mg/day (SD 3.3) at day 42 (end of the study). The YGTSS scores and the CGI significantly decreased over the treatment period. The only side‐effect observed was mild sedation which decreased during the course of the investigation and two patients had weight gain of 3‐5 kg with increased appetite. In our study, we found that olanzapine was a safe and effective treatment alternative to other antipsychotics. In order to confirm these preliminary results, double‐blind placebo controlled trials are warranted.

No change in striatal dopamine re-uptake site density in psychotropic drug naive and in currently treated Tourette’s disorder patients: a [123I]-β-CIT SPECT-study

BACKGROUND There is evidence that Tourettes disorder (TD) is associated with abnormalities in the dopaminergic system involving the dopamine transporter (DAT). Data from [(123)I]-beta-CIT single photon emission computed tomography (SPECT) studies and postmortem findings concerning DAT densities in TD patients are not conclusive. The objective of our study was to measure DAT densities with [(123)I]-beta-CIT binding in TD patients who were either psychotropic drug naive or currently treated with antipsychotics (AP) and healthy controls. METHOD Altogether 20 TD patients were investigated. A total of 15 patients were psychotropic drug naive and five were currently treated with AP. Ten psychotropic drug naive patients were compared with ten age and sex matched healthy subjects. Five currently treated patients were compared with five age and sex matched psychotropic drug naive TD patients. The investigation was carried out using [(123)I]-beta-CIT (2-beta-carbomethoxy-3-beta(4-iodophenyl)-tropane and SPECT. Regions of interest (ROI) were drawn over the striatum and the cerebellum. RESULTS The DAT densities measured by the striatal/cerebellar (S/C) binding ratio did not differ between drug naive TD patients and the controls. The difference between currently AP treated and psychotropic drug naive TD patients did not reach the level of significance. There was no correlation between the ratio and severity of tics and illness. CONCLUSION Our study with psychotropic drug naive TD patients contributed to clarify the inconsistent results concerning the DAT.

Opioid Addiction Changes Cerebral Blood Flow Symmetry

Changes in regional cerebral blood flow (rCBF) due to long-term abuse of opioids such as heroin or morphine are not yet fully understood in humans. The goal of the present study was to investigate rCBF alterations in a large sample of long-term opioid addicts in comparison to healthy controls. We investigated 21 opioid-dependent subjects, who were currently abusing heroin or were enrolled in a methadone or morphine maintenance program, and 36 healthy controls with 99mTc-HMPAO single photon emission computed tomography. We found a decrease in rCBF in most regions of interest in patients in comparison to controls. Long-term opioid dependence seems to decrease prefrontal CBF in particular. A right-greater-than-left CBF asymmetry in healthy subjects was reversed in patients. This change in CBF symmetry could reflect the different emotional status of opioid-dependent patients. Our findings are in line with neuropsychological investigations indicating a correlation of mood states with lateralization of hemispheric activation patterns.

Risk of suicide in depression and its implication for psychopharmacological treatment

&NA; Suicide is one of the leading causes of death among adults in the general population. There is a well‐established relationship between suicide and mood disorders and it has been estimated that 50‐80% of completed suicides are associated with mood disorders. About 15% of depressed patients commit suicide, with tablet poisoning (mostly antidepressants) often chosen as the suicide method. Naturally, this presents the doctor with a dilemma since certain antidepressants are suitable both for the treatment of depression and for a suicide attempt. Two questions seem to be of particular practical relevance in this respect, which will be reviewed and discussed in more detail in this paper: (1) can antidepressants induce a suicidal tendency? and (2) can the degree of toxicity of antidepressants be estimated in cases of overdosage? There is no evidence that newer antidepressants, like the selective serotonin reuptake inhibitors (SSRIs), induce a suicidal tendency as has been suggested by a spectacularly written case report. In fact, it seems likely that antidepressants with a predominantly serotonergic mechanism of action may be of particular benefit in patients with suicidal problems, which is in line with neurobiological theories about suicidal behaviour. This and the decreased toxicity of SSRIs makes them an attractive choice for treatment of depressed patients who are at risk for suicide.

Clonazepam in the long-term treatment of patients with unipolar depression, bipolar and schizoaffective disorder

Abstract The value of a long-term treatment with clonazepam in the prophylaxis of affective disorder is discussed controversially in the scientific literature. Altogether there are only a few reports on the use of this compound as a mood stabilizer, most of them describing patients suffering from bipolar affective disorder. The aim of this investigation was to evaluate clonazepam as a phase prophylactic medication in affective disorder. We conducted a retrospective chart review in 34 out-patients of our lithium clinic (15 suffering from unipolar depression, 15 from bipolar disorder, four from schizoaffective disorder), who had been treated with clonazepam as a long-term medication. Clonazepam was either given as monotherapy, or as in the case of lithium non-responders, as adjunctive therapy. Patients with unipolar depression had significantly (P=0.026) less depressive episodes after initiation of treatment with clonazepam. Patients with bipolar disorder did not benefit from this therapy. Neither manic/hypomanic phases nor depressive episodes were reduced in this group of patients. Interestingly, clonazepam also reduced affective phases in our four schizoaffective patients on a trend level. Our results indicate that patients with unipolar depression may benefit from a maintenance treatment with clonazepam. Due to methodological limitations our results need to be replicated in controlled double-blind randomized clinical trials.

Prevalence and Distribution of Hepatitis C Subtypes in Patients with Opioid Dependence

Aim and Setting: The drug addiction out-patient clinic at the University Hospital for Psychiatry in Vienna performed a study to identify the prevalence of hepatitis C virus (HCV) infections in a group of opiate-dependent patients, to detect the distribution of HCV subtypes and to calculate the comorbidity of human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Design and Participants: We consecutively investigated unselected patients (n = 173) during an observation period of 2 months with the diagnosis of opioid dependence (DSM-IV: 304.0) and polysubstance dependence (DSM-IV: 304.9). Measurements: Blood was investigated focusing on liver enzymes and on viral status including HIV, hepatitis B and hepatitis C, followed by subtyping of the virus. Findings: In 80.3% hepatitis C antibodies were found, 66.5% were HCV RNA (PCR) positive. 3a was the most frequent subtype (35.6%), followed by 1a (28.8%) and 1b (22.0%). Four patients had both subtypes 1a and 1b (6.8%), 3 were 2b positive (5.1%) and 1 patient had subtypes 2a/2c (1.7%). No significant difference in aspartate (AST) and alanine aminotransferases (ALT) concerning the different subtypes (AST: p = 0.290; ALT: p = 0.260) could be calculated; 11.6% showed co-infection with HIV, 2 patients had a chronic infection with hepatitis B. Conclusions: The rate of HCV infection in substance-dependent patients at our drug addiction out-patient clinic is extremely high. The distribution of subtypes showed a relatively homogeneous distribution of the types 1a, 1b and 3a. The recommended therapy with α-interferon should be initiated in drug-dependent patients under considerations of an enrollment in oral maintenance with synthetic opioids.

Buprenorphine maintenance: office-based treatment with addiction clinic support.

Introduction: Buprenorphine has already been registered in 27 European countries for maintenance therapy in opioid-dependent patients. In our office-based prescription study we applied sublingual buprenorphine, initiating the treatment at the addiction clinic with subsequent treatment at the offices of general practitioners (GPs) to evaluate its efficacy and feasibility in two different treatment settings. Methods: Sixty opioid-dependent patients were studied for a period of 15 weeks. The first 3 weeks of treatment initiation took place at the addiction clinic, followed by 12 weeks of treatment by GPs. Mean outcome measures were retention rate and additional consumption of illicit substances in addition to the evaluation of whether buprenorphine can be prescribed successfully by GPs. Results: The retention rate was 57% (n = 34). No significant differences occurred between the treatment phases at the specialized addiction unit and the GPs’ offices. During the 15-week period a significant improvement in well-being and a significant reduction in craving for heroin (p < 0.001) and cocaine (p < 0.001) could be calculated for patients stabilized on a mean dose of 16 mg buprenorphine. Furthermore a significant reduction in additional consumption of opioids (p < 0.001) was found. Discussion: Our results show the involvement of office-based prescription, which should further encourage colleagues to treat opioid-dependent subjects with buprenorphine to make more treatment options for this target group available.

Das Tourette-SyndromEine Übersicht

ZusammenfassungDas Tourette-Syndrom (TS) ist eine sich meist im Kindesalter erstmals manifestierende neuropsychiatrische Erkrankung, die durch das chronische Auftreten von motorischen und vokalen Tics gekennzeichnet ist. Die Prävalenz dieser Erkrankung wird auf 4–5/10.000 Personen geschätzt. TS-Patienten weisen häufig Komorbidität mit anderen psychiatrischen Störungen, wie Zwangsstörungen, der hyperkinetischen Störung (ADHD), Angststörungen und affektiven Störungen auf. Manche Formen der Zwangsstörungen scheinen mit dem TS eine gemeinsame genetische Ätiologie aufzuweisen und somit fakultativer Teil des phänotypischen Spektrums des TS zu sein. Basierend auf Befunden von MRI-, Positronenemissionstomographie (PET)-, und Single-Photonen-Emissions-Computertomographie (SPECT)-Untersuchungen werden Veränderungen in den kortiko-striato-pallido-thalamo-kortikalen Regulationssystemen diskutiert, wobei dem dopaminergen System eine wichtige Rolle zugeschrieben wird. Bei manchen Formen des TS und der Zwangsstörungen, die durch hämolysierende Streptokokken der Gruppe A ausgelöst oder aggraviert werden, scheinen autoimmunologische Mechanismen von Bedeutung zu sein. Dieser Subtyp des TS bzw. der Zwangsstörungen spricht auf immunmodulatorische Behandlungsstrategien an. Es gibt bis dato keine etablierte Pharmakotherapie beim TS, wobei Neuroleptika am häufigsten zur Anwendung kommen.SummaryTourettes syndrome (TS) is a neuropsychiatric disorder characterised by the occurrence of chronic motor and vocal tics that usually begin in childhood. A prevalence of 4–5/10.000 individuals is estimated. Tourettes syndrome patients frequently show comorbidity with other psychiatric disorders such as obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), anxiety, and affective disorders. Some forms of OCD seem to share a common genetic etiology with TS and to be a facultative part of the TS phenotypic spectrum. Based on MRI, positron emission tomography (PET), and single photon emission computed tomography (SPECT), data alterations in the cortico-striato-pallido-thalamo-cortical functional systems have been discussed. Within these systems, dopaminergic neurotransmission is thought to play an important role in the pathophysiology of TS. Autoimmunological mechanisms seem to be important in some subtypes of TS and OCD that are triggered or exacerbated by infections with hemolytic streptococci. In these cases, immune modulatory therapy proved to be efficient. To date, there is no established treatment regimen for TS. The medications used most frequently are antipsychotics.