Sylvia Quiner

Receptor and Transporter Imaging Studies in Schizophrenia, Depression, Bulimia and Tourette's Disorder—Implications for Psychopharmacology-

Summary: Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourettes disorder. Striatal D2 and 5-HTIA receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naive or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D2 receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D2 receptor occupancy rates and antipsychotic efficacy has been found. The measurement of S-HTIA receptors in drug-naïve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HTIA receptor binding potential in schizophrenia. β-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age-and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [124I]/β-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the β-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourettes disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-naïve TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drugnaive TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments.

Dopamine- and serotonin-receptors in schizophrenia: results of imaging-studies and implications for pharmacotherapy in schizophrenia.

Abstract Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. Since psychopharmacological treatment is thought to act on the underlying biological basis of the disease, brain imaging techniques enable us to understand the mechanism of action of such compounds. Positron emission tomography (PET) as well as single photon emission computerized tomography (SPECT) are important tools used to determine patterns of brain dysfunction and to uncover the mechanism of action for antipsychotic compounds. These techniques allow us to determine striatal D2 receptor as well as cortical 5-HT2A receptor occupancy rates which are linked, at least partly, to clinical efficacy as well as side effect rates. In general it has been shown that atypical antipsychotics have a lower striatal D2 receptor occupancy rate than typical antipsychotics, parallelling the more favorable extrapyramidal side effects of atypical antipsychotics, and as a group effect they have a high 5-HT2A occupancy compared to low rates for typical agents. However, there is no association between striatal D2 receptor occupancy rates and antipsychotic efficacy but 5-HT2A occupancy rates are associated with favorable treatment for depressive symptoms within schizophrenia and improvement of cognitive function. The availability of ligands for measurement of extrastriatal D2 receptors or different 5-HT receptors (e.g. 5-HT1A) will further shed light on the pathophysiology of schizophrenia as well as possible psychopharmacological treatment perspectives.

Efficacy, cardiac safety and tolerability of sertindole: a drug surveillance.

&NA; Sertindole is a novel atypical antipsychotic, which has shown efficacy in the treatment of positive and negative symptoms of schizophrenia in phase II and III studies. Furthermore, these studies have demonstrated tolerability and a favourable side‐effect profile. In contrast to classical antipsychotics, sertindole was not associated with extrapyramidal symptoms (EPS). We report drug surveillance data in 34 comorbid and comedicated sertindole treated patients suffering from different psychotic disorders. The drug surveillance consisted of two distinct phases: inpatient treatment and outpatient follow‐up. Clinical global impression (severity and improvement of illness), psychotic symptoms, side‐effects, and blood parameters have been carefully documented. With special respect to cardiac safety electrocardiograms (ECGs) have been recorded twice (during sertindole treatment and during treatment with an antipsychotic different from sertindole). Recommended ECG‐parameters for assessment of the proarrhythmic risk of a drug have been calculated (QTc‐, QTc2‐interval; QT‐, QTc‐dispersion). The majority of patients (n = 29) have been treated previously with several typical and/or atypical antipsychotics. We observed a clinical response to sertindole treatment in 29 patients (85%). Both positive and negative symptoms improved with sertindole and no severe side‐effects have been documented. EPS occurred at placebo level. A mean QTc‐interval prolongation of 19.7 ms (4.7%) has been detected. None of the patients developed clinical or electrocardiographic evidence of cardiac dysrhythmia during sertindole treatment, or other clinical evidence of cardiac abnormalities. In summary, sertindole did show efficacy for positive and negative symptoms together with a favourable side‐effect profile. No evidence for an increased proarrhythmic risk has been found.

Zotepine in the treatment of acute hospitalized schizophrenic episodes.

The atypical antipsychotic zotepine was studied in an open, multicentre uncontrolled, post-marketing surveillance study in 108 schizophrenic patients hospitalized in 12 trial centres in Austria. Within the dosage range of 50-450 mg (mean at the end of the study, 207 ± 125 mg/day), a significant reduction of positive as well as negative symptoms was noted. There was no increase in extrapyramidal side-effects during the study and a significant decrease in akathisia scores. The medication was well tolerated during the 42-day observation period. Zotepine improved both positive and negative symptoms and was not accompanied by extrapyramidal side-effects, justifying its classification as an atypical antipsychotic.

A Comparison of Patterns of Tranquiliser Intake, Anxiety and Health Locus ofControl between Short- and Long-TermBenzodiazepine Users

This study investigates the impact of physical illness, health locus of control and anxiety level on long- and short-term benzodiazepine (BZD) use in patients of an internal medicine department. There was no significant difference observed between the continuing and discontinuing group after hospital admission in terms of average daily dose of BZD. However, the continuing patients rated the condition of their somatic illness significantly higher than the discontinuing group, although this difference was not confirmed by the objective assessment of the treating physician. The non-continuing group displayed significantly higher control over health- and sickness-related events. The somatic and physical anxiety factor was significantly higher in the continuing group at initial investigation as well as at follow-up. On the basis of these results, we conclude that an increased focus on the psychosomatic element might reduce the risk of long-term tranquiliser use in patients with physical illness.