High frequency repetitive transcranial magnetic stimulation (rTMS) reduces EEG-hypofrontality in patients with schizophrenia.

The reduced metabolic activity in the prefrontal brain lobes, so-called hypofrontality, is associated with increased electrophysiological delta-band activity. Schizophrenia inpatients (N=35) received sham-controlled 10Hz rTMS over the left dorsolateral prefrontal cortex in a randomised design. After treatment, the resting electroencephalography revealed a significant decrease in the delta-band activity, which originated in the right prefrontal cortex and correlated with improvements in facial affect recognition.

Repetitive transcranial magnetic stimulation (rTMS) improves facial affect recognition in schizophrenia.

OBJECTIVE: Facial affect recognition, a basic building block of social cognition, is often impaired in schizophrenia. Poor facial affect recognition is closely related to poor functional outcome; however, neither social cognitive impairments nor functional outcome are sufficiently improved by antipsychotic drug treatment alone. Adjunctive repetitive transcranial magnetic stimulation (rTMS) has been shown to enhance cognitive functioning in both healthy individuals and in people with neuropsychiatric disorders and to ameliorate clinical symptoms in psychiatric disorders, but its effects on social cognitive impairments in schizophrenia have not yet been studied. Therefore, we evaluated the effects of sham-controlled rTMS on facial affect recognition in patients with chronic schizophrenia. METHOD: Inpatients (N = 36) on stable antipsychotic treatment were randomly assigned to double-blind high-frequency (10 Hz) rTMS or sham stimulation for a total of ten sessions over two weeks. In the verum group, each session consisted of 10 000 stimuli (20 trains of 5 s) applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. Facial affect recognition was assessed before (T0) and after (T1) the ten sessions. RESULTS: Facial affect recognition improved significantly more after rTMS (accuracy change: mean = 8.9%, SD = 6.0%) than after sham stimulation (mean = 1.6%, SD = 3.5; Cohen's d = 1.45). There was no correlation with clinical improvement. CONCLUSION: Our results indicate that prefrontal 10 Hz rTMS stimulation may help to ameliorate impaired facial affect recognition in schizophrenia.

Can an early weight management program (WMP) prevent olanzapine (OLZ)-induced disturbances in body weight, blood glucose and lipid metabolism? Twenty-four- and 48-week results from a 6-month randomized trial.

OBJECTIVES: This study was designed to investigate whether a preventive weight management program (WMP) reduces weight gain during olanzapine (OLZ) treatment. Moreover, we examined the effects of intervention on metabolic parameters. METHODS: Patients (N = 100) with schizophrenia or schizoaffective disorder (DSM-IV) who had commenced treatment with OLZ were recruited. Following a run-in period of 4 weeks, 74 patients who had gained at least 1.5 kg body weight were randomized to receive either 12 bi-weekly WMP sessions (prevention group (PG), n = 36), or usual care (control group (CG), n = 38). Anthropometric and metabolic parameters were assessed after the 24-week intervention phase and a 24-week follow-up. RESULTS: Forty-two percent of 74 participants (PG: 36.1%, CG: 47.4%) finished the 24-week intervention phase while 34% of them (PG: 30.6%, CG: 36.8%) completed the 48-week study. There was no significant difference in weight gain between groups (PG: + 3.4 ± 4.2 kg vs. CG: + 4.5 ± 6.1 kg, P = 0.184) after 24 weeks. Nevertheless, PG showed a significantly smaller increase in waist circumference than CG (PG: + 4.6 ± 8.3 cm, CG: + 10.1 ± 7.3 cm, P = 0.019) after 48 weeks. Furthermore, PG showed a significantly smaller increase in fasting glucose (P = 0.031) and 2-h glucose after oral glucose load (P = 0.018) than CG. CONCLUSIONS: These results suggest that preventive WMP may reduce the risk of abdominal obesity and deterioration of glucose metabolism in OLZ-treated patients.

Clomipramine-induced serum prolactin as a marker for serotonin and dopamine turnover: results of an open label study.

Central nervous system (CNS) monoamine deficits have been linked to a number of pathological conditions such as major depressive disorder. Individual biological variations in 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) might account for the variation in responses of neurotransmitter systems observed after the administration of clomipramine. The prolactin response to clomipramine has been widely used to assess CNS functioning. This open label study investigates the prolactin response induced by clomipramine in the plasma of healthy volunteers and whether it is related to changes in monoamine metabolites. The effects of clomipramine challenge on prolactin, 5-HIAA, HVA and MHPG were measured in 12 healthy volunteers. Samples were drawn directly before and 50 min after clomipramine infusion. A statistically significant increase in serum prolactin concentrations was measured in women 50 min after CMI infusion, but not in men. We found no significant increases in the serum monoamine metabolite concentrations 50 min after CMI infusion. Changes in HVA and 5-HIAA correlated statistically significantly and positively with the amount of prolactin release in the whole sample. Furthermore, positive correlations were found between ∆(50-0 min) 5-HIAA and ∆(50-0 min) HVA, although we did not find a correlation between ∆(50-0 min) prolactin and ∆(50-0 min) MHPG after clomipramine challenge. The pronounced prolactin release in healthy adult women might indicate a higher physiological sensitivity. Correlations between intra-individual changes in HVA, 5-HIAA and serum prolactin might indicate a central nervous effect of clomipramine on monoamine turnover. We conclude that monoamine changes in relation to prolactin response after clomipramine challenge may be suitable for characterizing the relationship between central serotonergic and dopaminergic function.

Effects of 10 Hz repetitive transcranial magnetic stimulation (rTMS) on clinical global impression in chronic schizophrenia.

UNLABELLED: We conducted a randomized, sham-controlled repetitive transcranial magnetic stimulation (rTMS) study in chronic schizophrenia in-patients (n=35) to evaluate the therapeutic efficacy of 10 Hz stimulation. Patients, who were on stable antipsychotic treatment, were randomly assigned to the active or sham condition. In the active rTMS group, ten sessions with a total of 10,000 stimuli were applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. The sham group received corresponding sham stimulation. Clinical improvement was measured by the Clinical Global Impression scale (primary outcome measure), the Global Assessment of Functioning Scale (GAF) and the Positive and Negative Symptom Scale (PANSS; secondary outcome measures). Between-group comparisons revealed no significant differences in clinical outcome variables. Only a subgroup of patients with pronounced negative symptoms developed some clinical improvement as indicated by significant changes in the GAF-scale. Besides there is some evidence for a more favourable clinical outcome within this subgroup after rTMS in the CGI-S and PANSS negative scale, too. In line with earlier investigations, our results suggest a moderate - potentially clinically relevant - treatment effect of prefrontal 10 Hz rTMS stimulation in chronic patients. However, in our study this beneficial effect was restricted to subjects with pronounced negative symptoms. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrial.gov Identifier: NCT00169689, http://www.clinicaltrials.gov.

Acute effects of sildenafil on flow mediated dilatation and cardiovascular autonomic nerve function in type 2 diabetic patients.

BACKGROUND: Sildenafil, frequently used as on demand medication for the treatment of erectile dysfunction (ED), has been suggested to improve endothelial function but also to alter blood pressure (BP) and induce sympathetic activation. In people with type 2 diabetes mellitus (T2DM), a high-risk population, the safety profile and the effects on endothelial function of a maximal sildenafil dose (100 mg) have not been investigated and therefore constituted the aim of our study. METHODS: A double-blind, placebo-controlled, cross-over trial using a single dose of 100 mg sildenafil or placebo has been conducted in 40 subjects with T2DM without known CVD. Haemodynamic parameters, flow mediated dilatation (FMD) in brachial artery, cardiovascular autonomic function tests and spontaneous baroreflex sensitivity (BRS) were measured. RESULTS: Sixty minutes after administration of sildenafil but not placebo, a fall of supine systolic blood pressure (SBP) (-5.41 +/- 1.87 vs. + 0.54 +/- 1.71 mmHg) and diastolic blood pressure (DBP) (-4.46 +/- 1.13 vs. + 0.89 +/- 0.94 mmHg), as well as orthostatic SBP (-7.41 +/- 2.35 vs. + 0.94 +/- 2.06 mmHg) and DBP (-5.65 +/- 1.45 vs. + 1.76 +/- 1.00 mmHg) during standing occurred, accompanied by an increase in heart rate (+1.98 +/- 0.69 vs. - 2.42 +/- 0.59 beats/min) (all p < 0.01 vs. placebo). Changes in BP to standing up, FMD, time domain and frequency domain indices of heart rate variability (HRV) and BRS were comparable between sildenafil and placebo. CONCLUSIONS: Sildenafil administered at a maximum single dose to T2DM men results in a mild increase in heart rate and decrease in BP, but it induces neither an acute improvement of FMD nor any adverse effects on orthostatic BP regulation, HRV and BRS.

[Psychosocial problems and mental disorders among immigrants of German origin]. / Psychosoziale Belastungsfaktoren und psychische Erkrankungen bei Spätaussiedlern.

OBJECTIVE: The number of ethnic German immigrants from former East bloc countries (Aussiedler) has considerably increased during the past 20 years. However, studies on the frequency of psychiatric disorders or on psychosocial risk factors for psychiatric morbidity in this partially inhomogenous population group are remarkably rare. METHOD: We undertook a comprehensive research of the current literature to gain the first systematic review on this issue. RESULTS: The most frequent mental disorders among these special group of migrants were depressive disorders, adjustment disorders with brief depressive reactions as well as somatoform disorders, alcoholism and drug dependency. CONCLUSIONS: Ethnic German immigrants are a risk group for mental disorders.

The effects of sildenafil on heart rate variability in healthy subjects.

The effects of sildenafil on heart rate variability were investigated in 20 healthy male subjects aged 24 (21 to 32) years (median; range). Subjects orally received single 100-mg doses of sildenafil and placebo under randomized double-blind crossover conditions on 2 separate study days. Time domain measures of heart rate variability were assessed under conditions of relaxed rest, metronomic breathing (6 cycles per minute), and bicycle ergometry before administration of sildenafil and placebo as well as 60 minutes afterwards. Sildenafil did not alter heart rate nor heart rate variability to a significant extent (P > 0.05).

Volume deficits of subcortical nuclei in mood disorders A postmortem study.

Structural changes in subcortical nuclei may underlie clinical symptoms of mood disorders. The goal was to determine whether macrostructural changes exist in brain areas assumed to be involved in regulation of mood and whether such changes differ between major depressive disorder and bipolar disorder. A case-control design was used to compare volumes of all major subcortical nuclei. Brains of patients with major depressive disorder (n = 9) or bipolar disorder (n = 11) or of individuals without a neuropsychiatric disorder (n = 22) were included. Exclusion criteria were a history of substance abuse or histological signs of neurodegenerative disorders. Volumes of the striato-pallidal nuclei, of the hypothalamus, thalamus, amygdala, hippocampus and basal limbic forebrain were determined in the right and left hemisphere by planimetry of 20 mum whole brain serial paraffin sections. Comparisons between patients with bipolar disorder, major depressive disorder and controls showed a significant (Lambda = 0.35, F(20,56) = 1.93, P = 0.028) overall difference in volumes of all investigated regions with strong effect sizes ( f > 0.40) contributed by the hypothalamus, external pallidum, putamen and thalamus. As compared to controls, a strong effect size (f > 0.40) was found in the bipolar group for smaller volumes of the hypothalamus, external pallidum, putamen and thalamus,whereas in patients with major depressive disorder a strong effect size was only found for a smaller volume of the external pallidum. In conclusion our data suggest that pathways presumably involved in mood regulation have structural pathology in affective disorders with more pronounced abnormalities in bipolar disorder.

Differences in activation of the dorsal raphe nucleus depending on performance of suicide.

The serotonergic system has been implicated in the pathogenesis of mood disorders as well as in suicidal behavior. It is unknown, however, whether raphe neurons, which are mostly serotonergic, show altered activity in patients with mood disorders who complete suicide as compared to those without suicidal behavior. In order to measure cellular markers of serotonergic activity in the dorsal raphe nucleus in brains of 12 people with mood disorders and of 12 controls (C), stereological measurements were carried out of nucleolar organizer regions (AgNORs) and of serotonergic neuron numbers. Six patients died from suicide (S) and the other six patients died from natural causes (NS). Results were assessed using ANOVA and post hoc Tukey-HSD tests looking for effects of diagnostic group (S, NS, C). Results show that in the rostral subnuclei of the dorsal raphe there was a significant effect of diagnostic group on the ratios of the nucleolar organizer regions to nuclear area (NOR ratio) and a nearly significant effect on numbers of serotonergic neurons. Post hoc tests revealed larger values for those dependent variables in S compared to NS. Dose equivalents of antidepressants correlated positively with NOR ratios and numbers of serotonergic neurons in the rostral part of the dorsal raphe. In conclusion, the present data suggest that there are functional differences in the dorsal raphe of patients with mood disorders depending on suicidal behavior. Antidepressants appear to contribute to cellular activation in the rostral part of the dorsal raphe.

A functional-structural model to understand cardiac autonomic nervous system (ANS) dysregulation in affective illness and to elucidate the ANS effects of antidepressive treatment.

Numerous studies provide evidence that major depression (MD) is associated with certain disorders of cardiac autonomic nervous system (ANS) function, in particular, with an autonomic neurocardiac imbalance characterized by a low cardiovagal modulation, a raised sympathetic nerve activity and a high resting heart rate. We assume that such MD-associated cardiac ANS disorders are mainly caused by functional-structural abnormalities within the central autonomic network (CAN), in particular, by well-defined abnormalities of hypothalamic structures in MD. In view of the well-known association between an autonomic neurocardiac imbalance and the risk for cardiac arrhythmias, we assume that MD-associated cardiac ANS disorders are at least partly responsible for the high cardiovascular mortality risk in MD. It is, however, still unclear whether antidepressive treatment will lower the risk for cardiovascular complications in MD. There is convincing evidence that a successful antidepressive treatment with electroconvulsive therapy, cognitive behavioral therapy, or pharmacotherapy with primarily non-antimuscarinergic antidepressants can improve an initially disturbed cardiac ANS function in MD. These studies correspond well to our findings that treatment with both, nefazodone or reboxetine, can induce a reduction of central sympathetic nerve activity and an increase of the initially lowered cardiovagal modulation depending on the improvement of depressive symptoms after treatment. Since both effects occured obviously independent from the primarily serotonergic or noradrenergic action of the antidepressants, our findings suggest the existence of a generally supraordinate and uniform mechanism underlying the ANS effects of antidepressive treatment with drugs inhibiting serotonin- or noradrenaline reuptake.

Relationship between major depression and heart rate variability. Clinical consequences and implications for antidepressive treatment.

A high sympathetic and/or a low cardiovagal activity in patients with major depression (MD) may contribute to the higher cardiac morbidity and mortality of MD patients. Standardized tests of heart rate variability (HRV) allow a quantitative estimation of autonomic nervous system function. However, previous studies on the relationship between HRV and MD have revealed conflicting results. Our study compared time and frequency domain HRV indices (5-min resting study, deep breathing test, Valsalva test) between 32 patients with MD (DSM-III-R) and 64 non-depressed controls. The severity of depressive symptoms was assessed by the Hamilton Depression Scale (HAM-D); patients were divided into subgroups with moderate (M-HAM-D<25) or severe depressive symptoms (S-HAM-D>or=25). After controlling for age, gender and smoking, S-HAM-D patients showed a higher heart rate and a significantly lower modulation of cardiovagal activity compared to controls. Although some of the HRV indices of the M-HAM-D group did not differ significantly from controls, they were in the expected direction. There was a significantly negative correlation between the HAM-D scores and the vagal HRV indices, suggesting a direct association between the severity of depressive symptoms and the modulation of cardiovagal activity. Clinical consequences arising from these findings and possible implications for treatment are discussed.

Superior safety of reboxetine over amitryptiline in the elderly.

Under antidepressive treatment with amitryptiline (100 mg/d) a 71-year old woman developed delirious symptoms, hyponatremia and a grand mal seizure followed by cardiovascular arrest. A few month later she ingested 48 mg reboxetine with suicidal intent. Overdosing of reboxetine, a selective noradrenaline re-uptake inhibitor, proceeded without complications.

Effects of reboxetine, a selective norepinephrine reuptake inhibitor, on sympathetic and parasympathetic outflow to the heart: preliminary data.

RATIONALE: Antidepressants exert distinct effects on cardiac autonomic nervous system (ANS) function, depending on their receptor profile. Reboxetine is a selective norepinephrine (NE) reuptake inhibitor and shows only low affinity for adrenergic and muscarinic receptors. Data on reboxetine's effects on ANS function in patients with major depression (MD) are sparse. OBJECTIVE: This study evaluates the effects of reboxetine on cardiac ANS function assessed by standardized measurements of heart rate variability (HRV). METHODS: Twenty-five MD patients (DSM-III-R) underwent serial ANS function tests ( n = 94) including conventional electrocardiograms and standardized measurements of HRV and blood pressure prior to reboxetine treatment as well as on days 2, 10 and 21 during reboxetine therapy. The starting dose was 4 mg; on day 10, reboxetine was increased to 8 mg/day. The effects of reboxetine on ANS function were evaluated using the paired Wilcoxon test. RESULTS: Reboxetine treatment was associated with 1) a significant decrease in absolute and relative low-frequency power as well as in mean arterial pressure on day 2, and 2) a significant decrease in the average low- to high-frequency ratio on days 2 and 10. No significant changes in any of the vagally mediated HRV indices occurred. CONCLUSION: These preliminary findings are compatible with the hypothesis that inhibition of brain NE reuptake by reboxetine resulted in an inhibition of central noradrenergic activity via a local increase of NE concentration at inhibitory alpha(2)-autoreceptors. Long-term treatment (21 days) may cause desensitization and down-regulation of alpha(2)-autoreceptors, so that attenuation of the inhibitory restraint on sympathetic outflow results.

Short-term effects of intravenous benzodiazepines on autonomic neurocardiac regulation in humans: a comparison between midazolam, diazepam, and lorazepam.

OBJECTIVES: To evaluate the effects of intravenously applied diazepam, lorazepam, and midazolam on autonomic neurocardiac regulation assessed by standardized measurements of heart rate variability. DESIGN: Prospective, randomized clinical study. SETTING: University teaching hospital. PATIENTS: Forty-five patients, who underwent a gastroscopy, were randomly assigned to intravenous premedication with midazolam (5 mg), diazepam (10 mg), or lorazepam (4 mg). Six subjects refused an injection and served as nonpremedicated controls. INTERVENTIONS: Serial recordings of the 5-min resting heart rate variability were obtained before and 15 and 30 mins after premedication. Seven benzodiazepine-treated patients received intravenous flumazenil (0.5 mg). MEASUREMENTS AND MAIN RESULTS: The average doses applied were 0.07 mg/kg for midazolam, 0.13 mg/kg for diazepam, and 0.06 mg/kg for lorazepam. Fifteen minutes after intravenous benzodiazepines were administered, we found an increase in resting heart rate and a reduction of vagal tone compared with baseline in all three benzodiazepine-treated subgroups. Multivariate analysis (covariate age) of the changes in heart rate variability indices over the experimental course revealed a significant reduction in absolute high-frequency power with midazolam or diazepam compared with nonpremedicated subjects. Moreover, midazolam-treated subjects showed a significantly larger reduction in relative high-frequency power not only compared with nontreated subjects, but also compared with lorazepam- or diazepam-treated subjects. Vagal tone remained reduced compared with baseline even 30 mins after benzodiazepine application, however, the resting heart rate decreased toward baseline levels. After flumazenil administration, there was a linear correlation between an increase in high-frequency power and a corresponding decrease in resting heart rate. CONCLUSIONS: Benzodiazepines can influence autonomic neurocardiac regulation in man, probably through their interaction with the gamma-aminobutyric acidA-receptor chloride ion channel complex. The pattern of findings suggests that intravenous midazolam, diazepam, and lorazepam influence human autonomic neurocardiac regulation in a biphasic way. First, they cause a reduction of central vagal tone, and second, they may decrease the cardiac pacemaker directly. Flumazenil completely abolished the autonomic neurocardiac regulation effects of benzodiazepines.