Ansgar Klimke

Induction of self awareness in dreams through frontal low current stimulation of gamma activity

Recent findings link fronto-temporal gamma electroencephalographic (EEG) activity to conscious awareness in dreams, but a causal relationship has not yet been established. We found that current stimulation in the lower gamma band during REM sleep influences ongoing brain activity and induces self-reflective awareness in dreams. Other stimulation frequencies were not effective, suggesting that higher order consciousness is indeed related to synchronous oscillations around 25 and 40 Hz.

Dopamine D2 receptor binding before and after treatment of major depression measured by [123I]IBZM SPECT

Fifteen patients fulfilling DSM-IV criteria for major depression were investigated with the specific dopamine D2 receptor antagonist [123I]iodobenzamide (IBZM). Two single photon emission computed tomography (SPECT) examinations were performed before and after 6 weeks of treatment with a selective serotonin re-uptake inhibitor (SSRI). Striatal D2 receptor binding was calculated and normalized to the cerebellum. In a non-psychiatric control group (n = 17), which was investigated once with [123I]IBZM and SPECT, striatal IBZM binding decreased significantly with age (0.092 per decade). The age-dependent correlation was lower in subjects with major depression and did not reach statistical significance. There was no significant difference in mean IBZM binding between depressives and control subjects. Age-corrected baseline IBZM binding in the striatum was significantly lower in treatment responders than in depressed non-responders and control subjects. Furthermore, in the depressive group there was a significant linear correlation between treatment response and change of D2 receptor binding during treatment in the basal ganglia. IBZM binding increased in treatment responders and decreased in non-responders. In accordance with animal studies, the results suggest an association between changes in the dopaminergic system and treatment response in major depression.

In VivoEvidence for the Involvement of Dopamine-D2Receptors in Striatum and Anterior Cingulate Gyrus in Major Depression

The dopaminergic system is a candidate neurotransmitter system thought to be involved in the pathogenesis of depression. This study addresses the issue whether the antidepressant efficacy of serotonin reuptake inhibition is related to changes in the cerebral dopaminergic system. Cerebral dopamine-D2 receptors were characterized in 13 patients with major depression using the dopamine-D2 receptor antagonist iodobenzamide and single photon emission tomography. Dopamine receptor binding was assessed twice, before and during serotonin reuptake inhibition. An increase in dopamine-D2 receptor binding during serotonin reuptake inhibition was found in striatum and anterior cingulate gyrus in treatment responders, but not in nonresponders. The increase in dopamine-D2 receptor binding correlated significantly with clinical recovery from depression as assessed with the Hamilton depression scale (r = 0.59 for right and left striatum respectively, P < 0.05; r = 0.79 for the anterior cingulate gyrus, P < 0.05 after Bonferroni correction). Qualitatively similar correlations were observed in the precentral gyrus, the medial frontal gyrus, the inferior frontal gyrus, and the frontal part of the opercular gyrus, but these correlations failed to reach statistical significance after correction for the effects of multiple testing. No such correlations were found in the superior frontal gyrus, the orbitofrontal gyrus, the gyrus rectus, the superior parietal gyrus, or the superior temporal gyrus. The data strengthen the concept that the striatum and the anterior cingulate gyrus are involved in mood regulation. Dopamine-D2 receptors may constitute a central role in this domain.

Relapse prevention in first-episode schizophrenia--maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia.

OBJECTIVE After acute treatment of the first illness episode in schizophrenia, antipsychotic maintenance treatment is recommended for at least 1 year. Evidence for the optimal subsequent treatment is still scarce. Targeted intermittent treatment was found to be less effective than continuous treatment at preventing relapse in multiple episode patients; however, a post hoc analysis of our own data from a previous study suggested comparable efficacy of the 2 treatment approaches in first-episode patients. The current study was therefore designed to compare prospectively the relapse preventive efficacy of further maintenance treatment and targeted intermittent treatment in patients with ICD-10-diagnosed first-episode schizophrenia. METHOD A randomized controlled trial was conducted within the German Research Network on Schizophrenia. Entry screening took place between November 2000 and May 2004. After 1 year of antipsychotic maintenance treatment, stable first-episode patients were randomly assigned to 12 months of further maintenance treatment or stepwise drug discontinuation and targeted intermittent treatment. In case of prodromal symptoms of an impending relapse, patients in both groups received early drug intervention, guided by a decision algorithm. The primary outcome measure was relapse (increase in the Positive and Negative Syndrome Scale positive score > 10, Clinical Global Impressions-Change score ≥ 6, and decrease in Global Assessment of Functioning score > 20 between 2 visits). RESULTS Of 96 first-episode patients, only 44 were eligible for the assigned treatment (maintenance treatment, n = 23; intermittent treatment, n = 21). The rates of relapse (19% vs 0%; P = .04) and deterioration (up to 57% vs 4%; P < .001) were significantly higher in the intermittent treatment group than in the maintenance treatment group, but quality-of-life scores were comparable. Intermittent treatment patients received a significantly lower amount of antipsychotics (in haloperidol equivalents; P < .001) and tended to show fewer side effects, particularly extrapyramidal side effects. CONCLUSIONS Maintenance treatment is more effective than targeted intermittent treatment in preventing relapse, even in stable first-episode patients after 1 year of maintenance treatment, and should be the preferred treatment option. However, about 50% of patients remain stable at a significantly lower drug dose and show fewer side effects, and a substantial proportion refuse maintenance treatment. Alternative long-term treatment strategies, including targeted intermittent treatment, should therefore be provided in individual cases. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00159120.

Increased serum S100B in elderly, chronic schizophrenic patients: Negative correlation with deficit symptoms

In schizophrenia, elevations of serum and CSF S100B levels have been reported and related to state of the disease and negative symptoms. In elderly chronic schizophrenic inpatients with stable medication, S100B may be increased and correlated to psychopathology and neuropsychological deficits. We have measured serum levels of S100B in 41 elderly, chronic schizophrenic patients and 23 age- and gender-matched controls using an immunoluminometric assay. In patients, we assessed detailed psychopathology and neuropsychological performance and determined serum levels of haloperidol, clozapine and its two main metabolites desmethylclozapine and clozapine metabolite N-oxid by HPLC. S100B levels were increased in elderly chronic schizophrenic patients compared to healthy controls. In patients, levels were negatively correlated with deficit symptoms and positively with age. There were no significant differences of S100B between medication groups and no correlation with serum levels of antipsychotics or neuropsychological scores. Elevations of S100B in elderly chronic schizophrenic patients may be related to an active disease process lasting until old-age. Correlations point to the impact of S100B in neuroplasticity and ageing. Post-mortem studies should clarify the presence of altered S100B function in the brain and its relationship to neuroplastic or neurodegenerative processes.

Clozapine induces oxidative stress and proapoptotic gene expression in neutrophils of schizophrenic patients.

Abstract: The present study examined cellular effects of the atypical antipsychotic drug clozapine on blood cells of treated patients with and without clozapine-induced agranulocytosis (CA). Blood from one patient who commenced clozapine treatment was examined at weekly intervals for 128 days. Olanzapine-treated (n = 5) and polymedicated (n = 14) schizophrenic patients, as well as healthy subjects (n = 19) and septic shock patients (n = 8), were studied for comparison. We observed dramatically increased numbers of native neutrophils stained for superoxide anion production (P ≤ 0.005, n = 10) and significantly elevated expression levels of the proapoptotic genes p53 (P ≤ 0.020), bax α (P ≤ 0.001), and bik (P ≤ 0.002) in all tested non-CA patients (n = 19) and CA patients (n = 4). In non-CA patients, the expression of these genes did not correlate to the percentage of apoptotic neutrophils (2.0% ± 1.3%), but in CA patients about 37% of the neutrophils show morphologic signs of apoptosis (P ≤ 0.001). Under G-CSF therapy of CA, the number of apoptotic neutrophils and the expression of the proapoptotic genes decreased significantly. In conclusion, high production of reactive oxygen species in neutrophils of clozapine-treated patients, together with increased expression of proapoptotic genes, suggests that neutrophils are predisposed to apoptosis in schizophrenic patients under clozapine therapy. The correlation between drug and proapoptotic markers was highest for clozapine and bax α as well as superoxide anion radicals. This indicates oxidative mitochondrial stress in neutrophils of clozapine-treated patients which probably contributes to the induction of apoptosis and sudden loss of neutrophils and their precursors in CA patients.

Genomewide scan and fine-mapping linkage studies in four European samples with bipolar affective disorder suggest a new susceptibility locus on chromosome 1p35-p36 and provides further evidence of loci on chromosome 4q31 and 6q24

We present the findings of a large linkage study of bipolar affective disorder (BPAD) that involved genomewide analysis of 52 families (448 genotyped individuals) of Spanish, Romany, and Bulgarian descent and further fine mapping of the 1p34-p36, 4q28-q31, and 6q15-q24 regions. An additional sample of 56 German families (280 individuals) was included for this fine-mapping step. The highest nonparametric linkage scores obtained in the fine mapping were 5.49 for 4q31 and 4.87 for 6q24 in the Romany families and 3.97 for 1p35-p36 in the Spanish sample. MOD-score (LOD scores maximized over genetic model parameters) analysis provided significant evidence of linkage to 4q31 and at least borderline significance for the 1p and 6q regions. On the basis of these results and previous positive research findings, 4q31 and 6q24 should now be considered confirmed BPAD susceptibility loci, and 1p35-p36 is proposed as a new putative locus that requires confirmation in replication studies.

Influence of atypical neuroleptics on executive functioning in patients with schizophrenia: a randomized, double-blind comparison of olanzapine vs. clozapine

Accepted clinical evidence suggests superior efficacy of novel antipsychotics in the treatment of cognitive symptoms in schizophrenia. Whether this constitutes a primary drug effect or a secondary effect due to easing extrapyramidal side-effects or improving positive symptoms when converting from a first- to a second-generation neuroleptic is still open to debate. Long-term efficacy as well as differential drug effects on cognitive performance are also poorly documented. We therefore compared cognitive performance of olanzapine vs. clozapine treatment in a controlled, randomized, double-blind trial. Fifty-four patients were assessed following a 2- to 9-day washout and again after 4 and 26 wk of neuroleptic treatment. Patients were rated on the PANSS for psychopathological changes, extrapyramidal side-effects were assessed on the Simpson-Angus Scale, and cognitive performance was assessed with the Stroop, Wisconsin Card Sorting and the Tower of London tests. Schizophrenia symptoms, extrapyramidal side-effects and cognitive performance improved significantly in the course of either drug treatment. Stroop test performance and Tower of London planning time improved significantly over 26 wk compared to baseline and 4-wk follow-up assessment while Wisconsin Card Sorting and Tower of London execution time improved significantly after 4 wk with no further improvement after 26 wk. Improved executive function was not related to improving positive symptoms and easing extrapyramidal side-effects, thus indicative of a primary treatment effect of either antipsychotic. However, Stroop reaction time improved with olanzapine while clozapine had a stronger effect on improving negative symptoms, thus suggestive of a differential drug effect.

Die Elektrokrampftherapie in psychiatrischen Kliniken der Bundesrepublik Deutschland 1995

ZusammenfassungEs wurde eine Umfrage unter 451 bundesdeutschen Kliniken im Jahr 1995 zur Anwendung der Elektrokrampftherapie (EKT) durchgeführt, die Vergleichsdaten zu 2 Umfragen aus den Jahren 1977 und 1985 und Informationen aus den neuen Bundesländern erbringen sollte. Die EKT steht als therapeutisches Verfahren grundsätzlich nicht mehr zur Diskussion. Die Anwendungshäufigkeit hat sich in den knapp 20 Jahren zwischen der ersten und dieser Studie insgesamt deutlich erhöht. Die Verteilung der Standorte der Kliniken, die häufig die EKT anwenden, ist ungleich über das Gebiet der BRD verteilt. Hauptindikationen für die EKT sind febrile Katatonie/febriler Stupor und depressiver Stupor. Depressionen werden als Indikation angeführt bei Psychopharmaka-Resistenz/-Unverträglichkeit. Die Modi der Vorbereitung und Durchführung entsprechen den Standards. Die Einstellungen der leitenden Ärzte zur EKT wurden eruiert und mit Daten einer Umfrage aus dem Jahre 1985 verglichen. Die positiven Stellungnahmen zur EKT sind richtungsgleich sind, fallen 1995 aber pointierter aus. Insgesamt zeigt sich, daß die EKT als Therapieverfahren innerhalb der leitenden Ärzteschaft sehr positiv gesehen wird; die Koppelung an eine enge Indikation gilt allgemein als Voraussetzung. Von dieser grundsätzlichen Einstellung ist die tatsächliche Anwendung der EKT nur bedingt abhängig, soziale Faktoren wie z.B. Haltung der Mitarbeiterschaft, politische Einstellung und Stereotypien der Bevölkerung beeinflussen die Anwendung in Richtung Zurückhaltung bzw. Nichtanwendung oftmals mehr.SummaryA total of 451 German psychiatric hospitals were asked in 1995 about their use of electroconvulsive therapy (ECT). As ECT nowadays is well accepted as a therapeutic tool, we wanted to compare our data with data collected in former inquiries in 1977 and 1985 and to acquire information from the new German States. Since 1977, the use of ECT has evidently increased. The psychiatric hospitals that often use ECT are for scattered throughout the whole country. ECT is mainly indicated for febrile catatonia/febrile stupor and depressive stupor, not for schizophrenia. ECT is applied especially when depressive patients are resistant or intolerant of psychopharmacotherapy. The preparation and application correspond to the standards. One focus in the present study was the attitudes of the managing directors towards ECT. Data were collected by open questionnaires. When these data were compared with data from a standardized inquiry of 1985, a similar trend was found regarding positive statements about ECT. Statements are emphasized even more when using open questionnaires. If there is a strong indication for ECT, the basic attitudes of the managing directors toward ECT are very positive. However, its application is in fact much more influenced by social factors than by indication because of negative attitudes by colleagues and nursing staff and political and stereotypic thinking of the general population.

Withdrawal Symptoms and Rebound Syndromes Associated with Switching and Discontinuing Atypical Antipsychotics: Theoretical Background and Practical Recommendations

With the widespread use of atypical or second-generation antipsychotics, switching treatment has become current practice and more complicated, as the pharmacological profiles of these agents differ substantially despite their similarity in being ‘atypical’. All share the ability to block dopamine D2 receptors, and most of them also block serotonin 5-HT2A receptors. Apart from these common features, some atypical antipsychotics are also able to block or stimulate other dopamine or serotonin receptors, as well as histaminergic, muscarinergic or adrenergic receptors. As a result of the varying receptor affinities, in switching or discontinuing compounds several possible pitfalls have to be considered, including the occurrence of withdrawal and rebound syndromes. This article reviews the pharmacological background of functional blockade or stimulation of receptors of interest in regard to atypical antipsychotics and the implicated potential withdrawal and rebound phenomena. A MEDLINE search was carried out to identify information on withdrawal or rebound syndromes occurring after discontinuation of atypical antipsychotics. Using the resulting literature, we first discuss the theoretical background to the functional consequences of atypical antipsychotic-induced blockade or stimulation of neurotransmitter receptors and, secondly, we highlight the clinical consequences of this. We then review the available clinical literature on switching between atypical antipsychotics, with respect to the occurrence of withdrawal or rebound symptoms. Finally, we offer practical recommendations based on the reviewed findings. The systematic evaluation of withdrawal or rebound phenomena using randomized controlled trials is still understudied. Knowledge of pharmacological receptor-binding profiles may help clinicians in choosing adequate switching or discontinuation strategies for each agent. Results from large switching trials indicate that switching atypical antipsychotics can be performed in a safe manner. Treatment-emergent adverse events during or after switching are not always considered to be, at least in part, associated with the pre-switch antipsychotic. Further studies are needed to substantiate the evidence gained so far on different switching strategies. The use of concomitant medication, e.g., benzodiazepines or anticholinergic drugs, may help to minimize symptoms arising from the discontinuation or switching of antipsychotic treatment.