M. Stamenkovic

Double-blind, placebo-controlled, hormonal, syndromal and EEG mapping studies with transdermal oestradiol therapy in menopausal depression

In a double-blind, placebo-controlled study, the antidepressant and vigilance-promoting properties of transdermal oestrogen in post-menopausal depression were investigated utilizing hormonal, syndromal and EEG mapping evaluations. Sixty-nine menopausal women, aged 45–60 years without previous hormonal replacement therapy, diagnosed as major depression without psychotic or suicidal symptoms (DSM-III-R criteria), were randomly assigned to a 3-month treatment with transdermal oestradiol [Estraderm TTS (ETTS) 50 µg, applied twice weekly] or placebo. No other psychoactive medication was allowed. After removal of protocol violators, 32 patients were evaluable in each group, which did not differ in age, height or weight. As five patients discontinued prematurely in both groups and in one placebo patient a post-drug EEG could not be obtained, 27 patients remained in the ETTS and 26 in the placebo group for efficacy analysis. While in the placebo group, oestradiol (E2) and follicle stimulating hormone (FSH) remained unchanged, E2 increased and FSH decreased significantly in the ETTS group. Syndromal evaluation showed a significant improvement in the Kupperman Index (KI) as well as Hamilton Depression Rating Scale (HAMD) in both groups, with no inter-group difference. However, EEG mapping demonstrated significant interdrug differences in brain function, mostly over the left temporal region. While ETTS patients showed an increase of alpha and alpha-adjacent theta activity and a decrease of beta activity, as well as an acceleration of the delta/theta centroid and a slowing of the alpha, beta and total power centroid, no changes occurred in the placebo-treated patients. These neurophysiological findings suggest improvement of vigilance by oestrogen, previously referred to as “mental tonic” effect. There were no changes, however, in the frontal alpha asymmetry index, reflecting left frontal hypo- and right frontal hyperactivation. Thus, this neurophysiological variable represents a state-independent marker for depression. The tolerability of ETTS was very good.

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.

Hormonal, syndromal and EEG mapping studies in menopausal syndrome patients with and without depression as compared with controls.

UNLABELLED The aim of the study was to investigate brain function in menopausal depression by EEG mapping, as compared with menopausal syndrome patients without depression and normal controls, and to correlate neurophysiological with clinical and hormonal findings in order to elucidate the pathogenesis of depression in the menopause. METHODS One hundred and twenty-nine menopausal women, aged 45-60 years, with no previous hormonal replacement therapy were investigated in regard to hormones (estradiol [E2], follicle stimulating hormone [FSH]), clinical symptomatology (Kupperman Index [KI], Hamilton depression score [HAMD]) and brain function (EEG mapping). Based on KI and DSM-III-R research criteria for major depression, 3 groups were available for statistics (after removal of protocol violators): group A had a KI of <15 and no depression (n = 29); group B had a KI of > or = 15 and no depression (n = 29) and group C had a KI of > or = 15 and fulfilled the criteria for major depression (n = 60). RESULTS EEG maps of depressed patients demonstrated less total power and absolute power in the delta, theta and beta band, more relative delta and less alpha power as well as a slower delta/theta and faster alpha and beta centroid than controls, suggesting a vigilance decrement. Group B did not differ from group A. Correlation maps showed significant relationships between estradiol levels and EEG measures (the lower the E2, the worse the vigilance) and between the EEG measures and the Hamilton depression (HAMD) score (the worse the vigilance, the higher the depression score). There were no correlations between the hormones E2 and FSH and the syndromes KI and HAMD. In the target variable, the asymmetry index, depressed patients showed less alpha power over the right than left frontal lobe, whereas normal controls exhibited the opposite. Group B did not differ from group A. The frontal asymmetry index was significantly correlated with the Hamilton depression score and suggests right frontal hyper- and left frontal hypoactivation in depression. CONCLUSIONS Although hormonal findings are not directly linked to psychic changes, low estradiol levels do contribute to a decreased vigilance at the neurophysiological level , which is in turn correlated with higher depressive and menopausal symptomatology at the behavioural level. Depression is further correlated to a right frontal hyper- and left frontal hypoactivation.

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.

Molecular and genomic studies of IMMP2L and mutation screening in autism and Tourette syndrome

We recently reported the disruption of the inner mitochondrial membrane peptidase 2-like (IMMP2L) gene by a chromosomal breakpoint in a patient with Gilles de la Tourette syndrome (GTS). In the present study we sought to identify genetic variation in IMMP2L, which, through alteration of protein function or level of expression might contribute to the manifestation of GTS. We screened 39 GTS patients, and, due to the localization of IMMP2L in the critical region for the autistic disorder (AD) locus on chromosome 7q (AUTS1), 95 multiplex AD families; however, no coding mutations were found in either GTS or AD patients. In addition, no parental-specific expression of IMMP2L was detected in somatic cell hybrids containing human chromosome 7 and human cell lines carrying a maternal uniparental disomy for chromosome 7 (mUPD7). Despite the fact that no deleterious mutations in IMMPL2 (other than the inverted duplication identified previously) were identified in either GTS or AD, this gene cannot be excluded as a possible rare cause of either disorder.

Sequence analysis of the complete SLITRK1 gene in Austrian patients with Tourette's disorder.

Mutations in the gene SLITRK1 (Slit and Trk-like 1) have been reported in patients with Tourettes disorder (TD). We sequenced the entire SLITRK1 gene including the coding region the 5′ and 3′ untranslated region in 92 Austrian patients with TD. No nucleotide changes within the protein-coding region were identified. One patient was found to carry a variant within the 3′ untranslated region (3383g>a), which was absent in 192 control individuals and which segregated in two additional family members with tic symptoms. In conclusion, our results provide no evidence for SLITRK1 playing a major role in TD.

Recurrent Brief Depression

SummaryRecurrent brief depression (RBD) fulfils DSM-IV criteria for major depression, with the exception of the duration of the depressive episodes. Recent epidemiological studies have confirmed the existence of RBD and estimated that it has a high prevalence in the general population and in general practice (approximately 10%). These studies also indicate a high comorbidity of RBD with attempted suicide, other forms of depression, anxiety disorders and substance abuse.At present, data on the treatment of this disorder are sparse. Results from the few preliminary treatment studies that have been performed to date do not indicate that antidepressants are the treatment of choice. However, the mechanism of action and appropriate dosage of antidepressants in this disorder and the influence of comorbid disorders on treatment response have not yet been addressed sufficiently. Studies in carefully selected patient samples with RBD using various pharmacological approaches are required to further clarify which drugs might be specifically effective in this disorder.

Genetic association signal near NTN4 in Tourette syndrome

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10−3) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry‐matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10−4) remained significant after Bonferroni correction. Meta‐analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10−7). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case–control status (p = 0.042), suggesting that many of these variants are true TS risk alleles. Ann Neurol 2014;76:310–315

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.