Search

Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) offer a promising alternative to psychotherapeutic and pharmacological treatments for depression. This paper aims to present a practical guide for its clinical implementation based on evidence from the literature as well as on the experience of a group of leading German experts in the field.The current evidence base for the use of rTMS in depression was examined via review of the literature. From the evidence and from clinical experience, recommendations for the use of rTMS in clinical practice were derived. All members of the of the German Society for Brain Stimulation in Psychiatry and all members of the sections Clinical Brain Stimulation and Experimental Brain Stimulation of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Mental Health were invited to participate in a poll on whether they consent with the recommendations.Among rTMS experts, a high consensus rate could be identified for clinical practice concerning the setting and the technical parameters of rTMS treatment in depression, indications and contra-indications, the relation of rTMS to other antidepressive treatment modalities and the frequency and management of side effects.

STUDY OBJECTIVES: Esmirtazapine (1.5–4.5 mg) has demonstrated short-term sleep-promoting effects in nonelderly outpatients with chronic insomnia. This phase 3, randomized, double-blind study (NCT00631657) and its open-label extension (NCT00750919) investigated efficacy and safety of long-term esmirtazapine treatment in adult outpatients with chronic insomnia. METHODS: Participants were randomized to receive esmirtazapine 4.5 mg or placebo for 6 months; those receiving esmirtazapine were then rerandomized to esmirtazapine or placebo for an additional 7 days. Participants could enter the 6-month open-label extension with esmirtazapine 4.5 mg. The primary objective of the double-blind study was to assess long-term efficacy of esmirtazapine vs placebo on self-reported total sleep time. Assessing long-term safety and tolerability were secondary and primary objectives of the double-blind and extension studies, respectively. RESULTS: Overall, 457 participants received treatment in the double-blind study (esmirtazapine, n = 342; placebo, n = 115) and 184 participants (prior esmirtazapine, n = 136; prior placebo, n = 48) received esmirtazapine in the extension. In the double-blind study, a 48.7-minute increase in average nightly total sleep time was observed for esmirtazapine vs placebo (95% confidence interval, 35.0–62.5; P < .0001) at months 4–6. There was no evidence of residual effects on next-day alertness or daytime functioning and no evidence of rebound insomnia or withdrawal symptoms upon treatment discontinuation. Esmirtazapine was generally well tolerated; somnolence and weight gain were the most common adverse events. CONCLUSIONS: Esmirtazapine improved sleep duration vs placebo over at least 6 months. There was no evidence of next-day residual effects or of withdrawal symptoms or rebound insomnia following abrupt treatment discontinuation. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A 6-Month Efficacy and Safety Study of Org 50081 in Adult Patients With Chronic Primary Insomnia (21106/P05701/MK-8265-002); URL: https://clinicaltrials.gov/ct2/show/NCT00631657; Identifier: NCT00631657; and Registry: ClinicalTrials.gov; Name: Twenty-Six Week Extension Trial of Org 50081 (Esmirtazapine) in Outpatients With Chronic Primary Insomnia (176003/P05721/MK-8265-007); URL: https://clinicaltrials.gov/ct2/show/NCT00750919); Identifier: NCT00750919. CITATION: Ivgy-May N, Hajak G, van Osta G, Braat S, Chang Q, Roth T. Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension. J Clin Sleep Med. 2020;16(9):1455–1467.

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

ZusammenfassungAls transkranielle Magnetstimulation (TMS) wird ein Verfahren bezeichnet, bei dem ein Stimulator über eine Spule kurze elektromagnetische Pulse mit einer Flussdichte von bis zu 2 Tesla induziert, welche die Schädelkalotte mit wenig Abschwächung durchdringen und zu einer Depolarisierung neuronaler Zellverbände führen. Die Stromdichte am Stimulationsort wird von einer Vielzahl physikalischer und biologischer Parametern bestimmt: Spulengeometrie sowie -positionierung, der Abstand der Spule zum Kortex, die Pulsform, die Intensität, Frequenz und das Muster der Stimulation sowie die dreidimensionale Orientierung der stimulierten neuronalen Strukturen im Verhältnis zur Geometrie des Magnetfeldes. Bei der repetitiven transkraniellen Magnetstimulation (rTMS) werden mehrere elektromagnetische Einzelstimuli als Reizserien mit konstanter Wiederholungsrate appliziert. Mithilfe dieser repetitiven TMS können Veränderungen der neuronalen Aktivität induziert werden, die über die eigentliche Stimulationsdauer hinweg andauern. Im vorliegenden Themenheft wird die Datenlage zu etablierten und potenziellen therapeutischen Anwendungen der repetitiven transkraniellen Magnetstimulation in psychiatrischen Indikationsgebieten zusammengefasst. Eine Empfehlung mit Evidenzgrad A kann für die hochfrequente rTMS-Behandlung des linken dorsolateralen präfrontalen Kortex (DLPFC) bei depressiven Störungen ausgesprochen werden. Empfehlungen mit dem Evidenzgrad B bestehen für niederfrequente rTMS des rechten DLPFC bei der Behandlung depressiver Störungen und für hochfrequente rTMS des linken DLPFC bei depressiver Symptomatik von Patienten mit Parkinson-Syndrom. Wahrscheinlich besteht ein additiver Effekt von rTMS des DLPFC zu einer antidepressiven Pharmakotherapie. Eine Empfehlung mit dem Evidenzgrad C kann folgenden rTMS-Paradigmen zugesprochen werden: hochfrequente rTMS des linken DLPFC bei Patienten mit schizophrener Negativsymptomatik (trotz einer großen negativen Multicenterstudie), niederfrequente rTMS des linken TPC bei chronischem Tinnitus und akustischen Halluzinationen (trotz vieler Publikationen eher niedriges Evidenzniveau), hochfrequente rTMS des rechten DLPFC bei Patienten mit posttraumatischer Belastungsstörung und hochfrequente rTMS des linken DLPFC bei Nikotinabhängigkeit. Gerade bei der Behandlung von Patienten mit chronischem und therapieresistentem Erkrankungsverlauf ist zu erwarten, dass dem gesamten Bereich neurostimulatorischer Methoden eine steigende Bedeutung zukommen wird. Es bleibt zu hoffen, dass vor dem Hintergrund innovativer technischer Entwicklungen und verbesserter Studienmethodologie die transkranielle Magnetstimulation in der nahen Zukunft ihr volles therapeutisches Potenzial entfalten wird.

Summary Objectives Transcranial magnetic stimulation (TMS) studies reported changes in motor evoked potential amplitude after acupuncture needling both at traditional acupoints and non-acupoints. However, the effects of needle penetration per se have not yet been investigated with TMS. The present study aimed at exploring effects of deep manual acupuncture needling compared to a state-of-the-art, non-penetrating control condition on several standard TMS measures of motor system excitability. Methods Twenty healthy volunteers received both verum and sham acupuncture applied at the acupoint GB 34 near the right knee, using a crossover design. A needle with a retractable tip (“Streitberger needle”) was used as sham condition to minimize non-specific effects. TMS parameters (resting motor threshold, active motor threshold, cortical silent period, short intracortical inhibition, and intracortical facilitation) were calculated from the abductor digiti minimi (ADM) of both hands 15 min before and after needling by a researcher blind to the treatment condition. Results Verum compared to sham acupuncture significantly increased resting motor threshold. No significant treatment effect was found for any other measure, though cortical silent period and intracortical facilitation showed trends to increase in the hemisphere contralateral to the needling site after verum acupuncture. Conclusions These results suggest a subtle but specific inhibitory effect of acupuncture needle penetration at acupoint GB 34 on motor system excitability. Further investigations should be performed with a particular emphasis on the measurements of resting motor threshold, cortical silent periods and intracortical facilitation.

Agomelatine, an MT1/MT2 receptor agonist and 5-HT2C receptor antagonist antidepressant, is known to have beneficial effects on subjective sleep in major depressive disorder patients. This international multicenter, randomized, double-blind study compared the effects of agomelatine (25-50 mg/day) and escitalopram (10-20 mg/day) on sleep polysomnographic parameters in major depressive disorder patients treated up to 24 weeks. A total of 138 outpatients were randomly allocated to agomelatine (n=71) or escitalopram (n=67). Treatment with agomelatine was associated with a reduction in sleep latency from week 2 onward. The difference between treatments was significant on all evaluations. Rapid eye movement latency was increased with escitalopram compared with agomelatine, with significant between-group differences at every visit. Agomelatine preserved the number of sleep cycles, whereas it was decreased with escitalopram with significant between-group differences at every visit. Assessments on visual analogue scales indicated that treatment with agomelatine improved morning condition, and reduced daytime sleepiness compared with escitalopram.17-item Hamilton depression rating scale total score was reduced in both groups, agomelatine was statistically noninferior to escitalopram at 6 weeks. Both treatments were well tolerated. This study showed that the clinical effects of agomelatine on sleep and wake parameters are different from that of escitalopram.

Hintergrund Hypothermien unter Antipsychotikabehandlung sind seit Jahrzehnten bekannt, finden jedoch im klinischen Alltag nur geringe Beachtung.

Sleep deprivation has multiple effects on brain function. It increases the risk for epileptic seizures both in healthy individuals and in patients with epilepsy. Furthermore it represents an effective antidepressive intervention with rapid onset. However, the mechanisms underlying these effects are still largely unknown. Transcranial magnetic stimulation (TMS) can be used as a non-invasive method for the measurement of motor cortex excitability. Here we used TMS for assessing sleep deprivation effects on cortical excitability in healthy individuals. Before and after 24 h of sleep deprivation, parameters of cortical excitability (resting motor threshold, short intracortical inhibition, intracortical facilitation, cortical silent period) were measured in a sample of 15 healthy volunteers (11 women, 4 men, aged between 21 and 30 years with a mean of 24.3±2.7 years). We detected a significant (p=0.042) reduction of short intracortical inhibition (SICI) after sleep deprivation. Motor threshold, intracortical facilitation and contralateral silent period remained unchanged. Our results confirm previous studies which have demonstrated changes of SICI after sleep deprivation. Our findings further suggest that the increased risk for epileptic seizures after sleep deprivation is mediated by a reduction of intracortical inhibition. Whether this mechanism is also involved in mediating the antidepressant effect of sleep deprivation has to be addressed by further studies in depressive patients.

Wahrend des Schlafs finden fur die Schlafqualitat wichtige thermoregulatorische Vorgange statt. In der Literatur wurde die endogene Absenkung der Korperkerntemperatur wahrend des Schlafs als eine Voraussetzung fur erholsamen Schlaf beschrieben. Die meisten experimentellen Studien zu thermoregulatorischen Aspekten im Schlaf veranderten bislang Raumtemperatur bzw. Klima der Schlafumgebung. Die vorliegende Pilotstudie uberprufte passive Anderungen des Bettklimas auf die Schlafqualitat gesunder Versuchspersonen. Bei konstanten Ausenbedingungen wurde mit Hilfe zweier verschiedener Oberbetten, die sich bezuglich ihres Warmedurchgangverhaltens und insbesondere ihrer Feuchteableitung unterscheiden, ein unterschiedliches Mikroklima in der Betthohle erzeugt. Die Auswirkung dieser passiven Klimaveranderung auf zentrale Schlafparameter wurde unter standardisierten, randomisierten und doppelblinden Bedingungen bei 12 gesunden Versuchspersonen, die fur jeweils 3 aufeinander folgende Nachte im Schlaflabor schliefen, polysomnographisch uberpruft. Bei 6 Versuchspersonen wurden zudem Temperatur und Luftfeuchtigkeit des Zimmers und der Betthohle kontinuierlich erfasst. Die Ergebnisse zeigen ein trockeneres und kuhleres Klima unter der Studiendecke. Gesamtschlafzeit, Schlafeffizienz und Arousalindex verbesserten sich tendenziell (p

Die Therapie des Schichtarbeitersyndroms beinhaltet Anderungen der Schlafhygiene und der Schichtabfolge sowie die Anwendung hellen Lichts am Arbeitsplatz ebenso wie eine unterstutzende Medikation. Medikamente losen das Problem jedoch nicht, sondern helfen zu funktionieren. Eine Indikation fur eine medikamentose Behandlung besteht v. a. dann, wenn ein Dienstwechsel nicht umsetzbar ist, die Storung voll ausgepragt ist und subjektiv erheblicher Leidensdruck besteht, die Vigilanz gestort und die Leistungsfahigkeit beeintrachtigt ist, der Betroffene einer dadurch verminderten Lebensbewaltigung und erhohten Fehler -und Unfallrate in Beruf und Privatleben ausgesetzt ist oder gesundheitliche Folgen der Storung auftreten, wie gastrointestinale, metabolische oder kardiale Erkrankungen. Pharmaka lassen sich erfolgreich einsetzen, wenn deren individuelles Nutzen-Risiko-Profil beachtet wird. Die evidenzbasierte und zulassige Pharmakotherapie umfasst die Schlafverbesserung durch Hypnotika und die Vigilanz- und Leistungssteigerung durch Stimulanzien. Sie wird bevorzugt mit kurzwirksamen Benzodiazepinrezeptoragonisten wie Zaleplon, Zolpidem oder Zopiclon und mit modernen Stimulanzien wie Modafinil durchgefuhrt. Explorativ konnen chronobiotisch wirksame Substanzen, z. B. mit melatoninrezeptoragonistischer Wirkung, schlaf- oder vigilanzfordernde Antidepressiva sowie zahlreiche, die Folgeerkrankungen kompensierende Pharmaka eingesetzt werden.

Chronic tinnitus is a highly prevalent and often incapacitating condition frequently associated with sensorineural hearing loss. While its etiology remains incompletely understood there is a growing awareness of genetic factors that predispose to, or aggravate chronic tinnitus. Candidate genes for the disorder include KCNE1, a potassium channel subunit gene that has been implicated in maturation defects of central vestibular neurons, in Meniere's disease, and in noise-induced hearing loss. 201 Caucasian outpatients with a diagnosis of chronic tinnitus were systematically screened for mutations in the KCNE1 open reading frame and in the adjacent sequence by direct sequencing. Allele frequencies were determined for 46 known variants, plus two novel KCNE1 mutations. These comprised one missense substitution (V47I) in the highly conserved region encoding the KCNE1 transmembrane domain, and one rare variant in the gene's 3'UTR. When genotypes were grouped assuming dominance of the minor alleles, no significant genotype or compound genotype effects were observed on tinnitus severity. The newly identified V47I substitution argues in favor of an enlarged spectrum of mutations in hearing disorders. However, with regard to allele frequencies in healthy control populations from earlier studies, more common KCNE1 variants are unlikely to play a major role in chronic tinnitus. Further investigations are invited to address variation in additional channel subunits as possible risk factors in tinnitus.

Tinnitus affects 10% of the population, its pathophysiology remains incompletely understood, and treatment is elusive. Both animal models and functional imaging data in tinnitus patients suggest that tinnitus is associated with increased neuronal activity, increased synchronicity and functional reorganisation in the auditory cortex. Therefore, targeted modulation of auditory cortex has been proposed as a new therapeutic approach for chronic tinnitus. Repetitive transcranial magnetic stimulation (rTMS), a non invasive method for modulation of cortical activity, has been applied in different ways in patients with chronic tinnitus. Single sessions of high-frequency rTMS over the temporal cortex have been used to transiently interfere with the intensity of tinnitus. Repeated sessions of low-frequency rTMS have been investigated as a treatment for tinnitus. Here, we review data from clinical trials and discuss potential neurobiological mechanisms with special focus on the relevance of the stimulation target and the method of TMS coil positioning. Different functional neuroimaging techniques are used for detecting tinnitus-related changes in brain activity. They converge in the finding of increased neuronal activity in the central auditory system, but they differ in the exact localisation of these changes, which in turn results in uncertainty about the optimal target for rTMS treatment. In this context, it is not surprising that the currently available studies do not demonstrate clear evidence for superiority of neuronavigational coil positioning. Further development of rTMS as a treatment for tinnitus will depend on a more detailed understanding of both the neuronal correlates of the different forms of tinnitus and of the neurobiological effects mediating the benefit of TMS on tinnitus perception. (C) 2009 Elsevier Masson SAS. All rights reserved.

Background: There is increasing evidence that repetitive transcranial magnetic stimulation (rTMS) can reduce chronic tinnitus. However, treatment results are characterized by high interindividual variability. Therefore, the identification of predictors for treatment response is of high clinical relevance. Methods: Clinical data of 194 patients with tinnitus were evaluated. All patients were treated with a standardized rTMS procedure (1 Hz, 10 days, 2000 stimuli/day, over the left temporal cortex). A potential influence on the outcome was analysed for the following parameters: age, gender, depression scores in Beck Depression Inventory (BDI) and tinnitus severity (TQ) before rTMS, lateralization, frequency and duration of tinnitus and extent of hearing loss. Results: An effect of tinnitus laterality was observed. In patients with left-sided or bilateral tinnitus, rTMS resulted in a statistically significant reduction of TQ scores, whereas patients with right-sided tinnitus did not show a significant improvement after rTMS treatment. However, in correlation analyses, we found a trend which did not reach statistical significance that in the subgroup of treatment responders tinnitus duration influenced rTMS outcome. In addition, a multiple regression analysis identified the TQ score at baseline as a significant predictor for treatment outcome. For all other investigated parameters, no statistically significant effects were found. Conclusions: This study suggests that left temporal low-frequency rTMS has beneficial effects in left-sided and bilateral tinnitus, but not in right-sided tinnitus. In line with the results from earlier studies involving smaller samples, tinnitus duration was found to influence rTMS outcome.

A growing body of evidence suggests that anthocyanins and anthocyanidins may possess analgesic properties in addition to neuroprotective and anti-inflammatory activities. These functionalities suggest a role for the cannabinoid receptor (CB) in mediating biological effects. Competitive radioligand binding assays identified cyanidin (K(i) = 16.2 microM) and delphinidin (K(i) = 21.3 microM) as ligands with moderate affinity to human CB1. For CB2, similar affinities were achieved by cyanidin (K(i) = 33.5 microM), delphinidin (K(i) = 34.3 microM), and peonidin (K(i) = 46.4 microM). Inhibition constants50 microM were obtained for pelargonidin, malvidin, cyanidin-3,5-di-O-glucoside, cyanidin-3-O-glucoside, cyanidin-3-O-galactoside, and cyanidin-3-O-rutinoside for both CB subtypes.

Background and purpose: Dietary anthocyanins hold great promise in the prevention of chronic disease but factors affecting their bioavailability remain poorly defined. Specifically, the role played by transport mechanisms at the intestinal and blood–brain barriers (BBB) is currently unknown. Experimental approach: In the present study, 16 anthocyanins and anthocyanidins were exposed to the human efflux transporters multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), using dye efflux, ATPase and, for BCRP, vesicular transport assays. Key results: All test compounds interacted with the BCRP transporter in vitro. Of these, seven emerged as potential BCRP substrates (malvidin, petunidin, malvidin-3-galactoside, malvidin-3,5-diglucoside, cyanidin-3-galactoside, peonidin-3-glucoside, cyanidin-3-glucoside) and 12 as potential inhibitors of BCRP (cyanidin, peonidin, cyanidin-3,5-diglucoside, malvidin, pelargonidin, delphinidin, petunidin, delphinidin-3-glucoside, cyanidin-3-rutinoside, malvidin-3-glucoside, pelargonidin-3,5-diglucoside, malvidin-3-galactoside). Malvidin, malvidin-3-galactoside and petunidin exhibited bimodal activities serving as BCRP substrates at low concentrations and, at higher concentrations, as BCRP inhibitors. Effects on MDR1, in contrast, were weak. Only aglycones exerted mild inhibitory activity. Conclusions and implications: Although the anthocyanidins under study may alter pharmacokinetics of drugs that are BCRP substrates, they are less likely to interfere with activities of MDR1 substrates. The present data suggest that several anthocyanins and anthocyanidins may be actively transported out of intestinal tissues and endothelia, limiting their bioavailability in plasma and brain.

Illumination science has long established effects of coloured light on emotional state, cognitive performance, plus tactile, gustatory and olfactory perception. To explore the neurobiological mechanisms underlying these crossmodal phenomena, cortical excitability was addressed by single and paired-pulse transcranial magnetic stimulation (TMS) in 23 men with normal colour vision, and in 10 subjects with red-green blindness. Using a sequential challenge, excitability measures were recorded at baseline and during exposure to either red or green light. Dichromacy did not predict any of the electrophysiological parameters under study regardless of the spectral paradigm. In both dichromats and trichromats, red and green illumination did not induce any significant effects on resting motor threshold, short intracortical inhibition, intracortical facilitation and cortical silent periods. Our results suggest that motor cortex excitability as assessed by TMS is not sensitive to the modulatory effects of context-independent red and green light.

The cytochrome P450 enzyme CYP2C19 is involved in the metabolism of many commonly prescribed drugs, including proton pump inhibitors, antiepileptics and antidepressants. CYP2C19 inhibitors from food and food supplements may augment the toxicity of these agents and lead to noncompliance with treatment. The present investigation addresses CYP2C19 inhibition by 18 berry constituents using a chemiluminescent assay. Test compounds displayed inhibitory properties in a concentration-dependent fashion, with IC(50) values ranging from 20.2 microM up to >316 microM. In the order of decreasing effect size, anthocyanidins were followed by anthocyanidin-monoglycosides and procyanidins. Anthocyanidin-diglucosides exhibited weak and biphasic effects. When compared with the CYP2C19 inhibitor fluvoxamine, the flavonoids under study were 50- to 750-fold less potent. It is concluded that the above natural substances are moderate to poor inhibitors of CYP2C19 in vitro.

Objective Low-frequency repetitive transcranial magnetic stimulation (rTMS) has shown promise for the treatment of tinnitus. Experimental data from motor cortex stimulation in healthy subjects indicate that the suppressing effect of low-frequency rTMS can be enhanced by dopaminergic receptor activation. Here we investigated whether administration of the dopamine precursor levodopa before low-frequency rTMS enhances its efficacy in tinnitus treatment. Study Design Sixteen patients with chronic tinnitus received 100 mg of levodopa before each session of low-frequency rTMS. Results were compared with a matched control group of 16 patients who received the same treatment, but without levodopa. Treatment outcome was assessed with a standardized tinnitus questionnaire. Results Both stimulation protocols resulted in a significant reduction of tinnitus scores after 10 days of stimulation; however, there was no significant difference between the two groups. Conclusion Our data suggest that 100 mg of levodopa does not enhance the effect of rTMS in the treatment of tinnitus.

Summary Objectives Increasing evidence suggests that dysfunctions of the cortico-cerebello-thalamocortical circuit are involved in the pathophysiology of neuropsychiatric disorders. This study explores the effects of cerebellar repetitive transcranial magnetic stimulation (rTMS) on cerebello-thalamocortical pathways. Methods Ten healthy volunteers received MRI-guided rTMS in four separate sessions (120% motor threshold, 1000 stimuli) over either the medial or the right lateral cerebellum using frequencies of 1 and 10 Hz. Motor cortex excitability was assessed before and after the intervention by paired-pulse transcranial magnetic stimulation. Results Depending on stimulation frequency, cerebellar rTMS differentially modified intracortical inhibition. Low frequency rTMS increased short intracortical inhibition (SICI), whereas high frequency rTMS had no significant effect on SICI. Conclusions These results suggest that rTMS over the cerebellum can modulate cerebello-thalamocortical pathways in a frequency-specific manner.

Tinnitus is a frequent disorder that is very difficult to treat. Both functional imaging studies in patients and electrophysiological studies in animals suggest that hyperactivity in the central auditory system due to increased synchronicity may cause tinnitus. Targeted modulation of tinnitus-related cortical activity has been proposed as a promising new treatment. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method that can focally modulate cortical activity. This technique has been used to diagnose and treat tinnitus. Single sessions of high-frequency rTMS over the temporal cortex have been used to suppress tinnitus transiently and could become a useful predictor for treatment outcome of epidural stimulation. Another approach uses rTMS as a treatment for tinnitus by applying repeated sessions of low-frequency rTMS to induce a lasting reduction of excitability in the auditory cortex. Beneficial effects of treatment have been consistently demonstrated in several controlled studies. However results are characterized by high interindividual variability and only moderate effect sizes. Convincing evidence indicates that rTMS represents a promising tool for diagnosis and treatment of tinnitus. Further development of this technique will depend on a more detailed understanding of the neurobiological effects that mediate the clinical effects of TMS.

Recent reports have demonstrated multiple benefits associated with the consumption of berry fruits, including a decreased vulnerability to oxidative stress, reduced ischemic brain damage, protection of neurons from stroke-induced damage and the reversal of age-related changes in brain and behaviour. Berry fruits contain high amounts of anthocyanins, which play a major role as free radical scavengers. The present study addresses proteasome inhibition as a further mechanism by which anthocyanins and their aglycons, the anthocyanidins, may exert health-promoting effects. HL-60 cells were incubated with 19 test substances and inhibition of the chymotrypsin-like enzyme activity was determined in a chemiluminescent assay. Anthocyanins and their aglycons achieved IC(50) values ranging from 7.8 microM for kaempferidinidin and pelargonidin, to 32.4 microM for delphinidin. Thus proteasome inhibitory properties of anthocyanins may contribute to their known anticarcinogenic, antioxidative, anti-inflammatory and neuroprotective activities, rationalizing dietary supplementations with anthocyanins in the prevention and treatment of chronic diseases, including neurodegenerative disorders.

Objective: Neurocognitive deficits that persist despite antidepressive treatment and affect social and vocational functioning are well documented in major depressive disorder. Cognitive training approaches have proven successful in ameliorating these deficits in other psychiatric groups, but very few studies have been conducted in unipolar depressive patients by now. In contrast to previous studies solely including outpatients, effects of a cognitive remediation intervention on neurocognitive functioning of depressed inpatients were assessed by the present study. Method: A randomized controlled trial was carried out with 46 depressed inpatients of a psychiatric hospital. Patients were randomly assigned to either a control group that received standard drug and non-drug (cognitive behavioural, occupational, sports, relaxation and music therapy) antidepressive treatment or a remediation group that additionally received 12 sessions of cognitive training for a total of 4 weeks (three sessions per week). An intent to treat analysis and a last observation carried forward method was used for data analyses. Results: Patients of the remediation group demonstrated greater improvements in neurocognitive measures of verbal and nonverbal memory, working memory and executive function (Cohen’s d effect sizes between .52 and .98). Conclusions: These results provide preliminary evidence that cognitive remediation interventions can be successfully applied also in psychiatric inpatients experiencing an acute depressive episode.

We prospectively evaluated the diagnostic accuracy of cerebrospinal fluid (CSF)-beta-amyloid1-42 (Abeta42), -total-tau (tau) and -phosphorylated-tau181 (p-tau181) as measured by sandwich ELISAs in the clinical routine of a community state hospital to discriminate between patients with Alzheimer's disease (AD), healthy controls (HC), non-AD-dementias, a group composed of various psychiatric disorders (non-AD-dementias, mental diseases) and an age-matched random sample (RS) (total N=219). By comparing patients with AD to HC as reference, tau revealed sensitivity (sens)/specificity (spec) of 88%/80%, p-tau(181) 88%/80%, tau/Abeta42-ratio 81%/85% and phospho-tau(181)/Abeta42-ratio 81%/78%. Discriminative power between HC and all dementias under investigation was estimated lower for tau (78%/77%) and p-tau(181) (73%/79%). Relative to patients with AD, ROC analysis for the RS revealed highest sens/spec for p-tau181 (79%/77%) and p-tau181/Abeta42 ratio (78%/75%). Differentiation between AD versus a group made of patients with various psychiatric disorders was optimised by using CSF-p-tau181 (80%/77%). Under clinical routine conditions current CSF-biomarkers show a substantial capacity to discriminate between AD and HC as reference and to mark off AD patients from RS and heterogeneous diagnostic groups composed of non-AD dementias and other psychiatric conditions. Despite a residual substantial overlap between the groups, we conclude that current CSF markers are well suited to support AD-related diagnostic procedures in every-day clinics.

Funktionell bildgebende Untersuchungen bei Tinnituspatienten zeigten gesteigerte neuronale Aktivitat im auditorischen Kortex. Mit der neuartigen niedrigfrequenten repetitiven transkraniellen Magnetstimulation (rTMS) ist die nichtinvasive Verminderung kortikaler Hyperexzitabilitat moglich. 12 Patienten mit chronischem Tinnitus wurden mit Positronenemissionstomographie (PET) und Magnetresonanztomographie (MRT) untersucht. Mit der Fusionierung des PET- und MRT-Datensatzes ist die gesteigerte metabolische Aktivitat im auditorischen Kortex genau lokalisierbar. Mit einem speziellen Neuronavigationssystem wurde die rTMS-Schmetterlingsspule genau uber diesem Zielareal positioniert. Die rTMS-Behandlung (Intensitat: 110% der Motorschwelle; Frequenz: 1 Hz, 2000 Stimuli/Tag uber 5 Tage) wurde im Rahmen eines plazebokontrollierten Cross-over-Designs durchgefuhrt, wobei die Patienten bezuglich der Stimulationsbedingung verblindet waren. Die Plazebostimulation erfolgte mit einer speziellen Sham-Spule. Behandlungseffekte wurden mit dem Tinnitusfragebogen nach Goebel und Hiller erfasst. Bei allen 12 Patienten zeigte sich eine einseitig gesteigerte metabolische Aktivierung im Bereich der Heschl-Querwindung. Verum-rTMS fuhrte zu einer signifikanten Verminderung der Tinnitusbelastung im Vergleich zu Plazebo-rTMS. Die Ergebnisse dieser Pilotstudie zeigen, dass neuronavigierte rTMS ein vielversprechendes Instrument zur Behandlung des chronischen Tinnitus darstellt.

In Germany, the economic situation of psychiatric hospitals has markedly changed during the last years. Whilst the number of patients has steadily increased, many clinics considerably reduced the number of therapeutic staff due to an increasing lack of financial support. The German psychiatry personnel regulations act defines the number of therapeutic staff required for an adequate psychiatric treatment, but the requirements of this regulations act nowadays are widely missed in most of the German psychiatric hospitals. This severely affects the therapeutic work on psychiatric wards. This study analyses tasks and activities of medical doctors on psychiatric wards and compares the hours spent with various types of activities with the amount of time that should be spent according to the personnel regulations act. Results show that doctors spend much more time with documentation and administrative work than originally intended by the personnel regulations act. They compensate this mainly by a reduction of time spent in direct contact with the patients. In this context, the number of psychotherapy sessions as well as sessions with the patients' relatives has been considerably reduced, whereas the time spent for emergency intervention and basic treatment still corresponds to the calculations according to the personnel regulations act. All in all, the results show that a reduction of therapeutic staff in psychiatric hospitals directly leads to a change in treatment settings with a focus on less individual treatment options.

Activation-dependent brain plasticity in humans on a structural level has been demonstrated in adults after 3 months of training a visio-motor skill. The exact timescale of usage-dependent structural changes, whether days, months, or years, is, however, still debated. A better understanding of the temporal parameters may help elucidate to what extent this type of cortical plasticity contributes to fast adapting cortical processes that may be relevant to learning and effects of treatments. Using voxel-based morphometry, we are able to show that repetitive transcranial magnetic stimulation delivered to the superior temporal cortex causes macroscopic cortical changes in gray matter (GM) in the auditory cortex as early as within 5 days of continuous intervention. These structural alterations are mirrored by changes in cortical evoked potentials attributed to the GM changes and demonstrate the rapid dynamics of these processes, which occur within a time range characteristic for the onset of behavioral effects induced by a variety of treatment methods for neuropsychiatric diseases. Our finding suggests that cortical plasticity on a structural level in adult humans is already detectable after 1 week, which provides support for fast adjusting neuronal systems, such as spine and synapse turnover, and contradicts slow evolving mechanisms, such as neuronal or glial cell genesis.

ZusammenfassungDer chronische Tinnitus ist eine häufige Erkrankung, deren Pathophysiologie nicht im Detail geklärt ist. Funktionell bildgebende Untersuchungen verweisen auf neuroplastische Veränderungen mit gesteigerter neuronaler Aktivität im Bereich des auditorischen Kortex. Pilotstudien haben gezeigt, dass neuronavigierte PET und NMR-gestützte niedrigfrequente repetitive transkranielle Magnetstimulation (rTMS) zu einer signifikanten Tinnitusreduktion führt. Im Rahmen der vorliegenden Studie soll untersucht werden, ob rTMS auch unter Verwendung einer einfacher durchführbaren Spulenlokalisationsmethode in der Lage ist, Tinnitus zu reduzieren. Elf Patienten fmit chronischem Tinnitus wurden mit rTMS behandelt (110% Motorschwelle, 1Hz, 2 000 Stimuli/Tag, 10 Tage). Die Positionierung der Spule zur Stimulation des linken auditorischen Kortex erfolgte mithilfe anatomischer Landmarken. Therapieeffekte wurden mit dem Tinnitusfragebogen nach Goebel und Hiller erfasst. Nach rTMS Behandlung kam es zu einer signifikanten Verminderung des Tinnitusschweregrades. Niedrigfrequente rTMS über dem linken auditorischen Kortex stellt ein vielversprechendes innovatives Instrument zur Behandlung des chronischen Tinnitus dar.

Introduction: Subjective well-being of schizophrenic patients can be impaired by symptoms of the disease and by adverse effects of antipsychotic medication. We assessed the correlations of subjective well-being with objectively measured gait parameters, expert-rated motor disturbances, and psychopathological status in 25 conventionally treated, 25 atypically treated, and 16 drug-naive patients. Methods: Main variables were the SWN scores (Subjective Well-being under NeurolepticTreatment Scale), the ESRS scores (Extrapyramidal Symptoms Rating Scale), and the PANSS scores (Positive and Negative Syndrome Scale). Gait parameters were determined by using an ultrasonic system for gait analysis. Results: In conventionally treated patients, the SWN total score significantly correlated with stride length (R 2 = 0.39; P < 0.01), whereas in atypically treated and drug-naive patients, it significantly correlated with the PANSS score (atypically treated: R 2 = 0.25, P < 0.05; drug-naive: R 2 = 0.64, P < 0.01), mainly due to the correlations with the "negative symptoms" and the "general psychopathology" sub-scores. Correlations with stride length were significant not only in the "physical functioning" sub-score of the SWN but also in all other sub-scores. Correlations of the SWN scores with ESRS scores were weak. Conclusion: Under conventional antipsychotic treatment, subjective well-being particularly depends on major side effects, whereas in atypically treated and drug-naive schizophrenic patients, it is mainly influenced by psychopathological status. Motor adverse effects of conventional antipsychotic treatment cannot be considered as isolated physical side effects but have severe implications for other aspects of the patients' well-being.

Objectives The pathophysiologic mechanisms of idiopathic tinnitus remain unclear. Recent studies demonstrated focal brain activation in the auditory cortex of patients with chronic tinnitus. Low-frequency repetitive transcranial magnetic stimulation (rTMS) is able to reduce cortical hyperexcitability. Study design Fusing of the individual PET-scan with the structural MRI-scan (T1, MPRAGE) allowed us to identify exactly the area of increased metabolic activity in the auditory cortex of patients with chronic tinnitus. With the use of a neuronavigational system, this target area was exactly stimulated by the figure 8-shaped magnetic coil. In a prospective study, rTMS (110% motor threshold; 1 Hz; 2000 stimuli/day over 5 days) was performed using a placebo controlled cross-over design. Patients were blinded regarding the stimulus condition. For the sham stimulation a specific sham-coil system was used. Fourteen patients were followed for 6 months. Treatment outcome was assessed with a specific tinnitus questionnaire (Goebel and Hiller). Setting Tertiary referral medical center. Results Increased metabolic activation in the auditory cortex was verified in all patients. After 5 days of verum rTMS, a highly significant improvement of the tinnitus score was found whereas the sham treatment did not show any significant changes. The treatment outcome after 6 months still demonstrated significant reduction of tinnitus score. Conclusion These preliminary results demonstrate that neuronavigated rTMS offers new possibilities in the understanding and treatment of chronic tinnitus.

ZusammenfassungDie repetitive Transkranielle Magnetstimulation (rTMS) ist eine innovative Technologie, mit der nicht-invasiv neurobiologische, physiologische und psychologische Funktionen des Gehirns moduliert werden können. In Konferenzen deutscher TMS-Experten wurde, einem formalen Konsensusprozess folgend, das Nutzen/Risiko-Verhältnis der rTMS als therapeutische Technik für die Psychiatrie beurteilt. Die rTMS wurde als viel versprechendes und innovatives Verfahren beurteilt, dessen weitere Erforschung wünschenswert ist. Zurzeit erscheinen depressive Störungen unter der Vielzahl untersuchter Diagnosen als mögliche Hauptindikation einer rTMS-Behandlung. Die überwiegend medikamentös vorbehandelten und zum Teil therapieresistenten depressiven Patienten zeigten in den existierenden Studien ein positives Nutzen/Risiko-Profil im Sinne einer moderaten klinischen Verbesserung bei zugleich niedriger Nebenwirkungsrate. Die rTMS sollte grundsätzlich von in der Methode erfahrenen oder speziell ausgebildeten Ärzten durchgeführt werden. Die aktuellen Sicherheitsempfehlungen sind dabei zu berücksichtigen und ein engmaschiges Therapiemonitoring sollte erfolgen. Obwohl der wissenschaftliche Datenbestand zur rTMS stetig wächst, ist die Methode gegenwärtig noch als experimentelles Therapieverfahren einzuschätzen, das bislang noch weniger gut untersucht ist als vor einer Zulassung stehende Psychopharmaka.

Zusammenfassung„Psychopathy” stellt ein Konzept zur Beschreibung einer schweren Form der dissozialen Persönlichkeitsstörung dar. Die Fähigkeit für emotionales Erleben, Empathie, Kontrolle von aggressiven Impulsen und Lernen aus negativen Erfahrungen ist bei dieser forensisch auffallenden Gruppe von Straftätern stark beeinträchtigt. In Abgrenzung von dieser primären Persönlichkeitsstörung kann eine entsprechende dissoziale Störung auch sekundär posttraumatisch, „Pseudopsychopathy”, auftreten. Mit modernen bildgebenden Verfahren können strukturelle und funktionelle Veränderungen nachgewiesen werden, die auf ein neurobiologisches Korrelat der gestörten Emotionsregulation bei „Psychopathy” hinweisen. Neben der historischen Entwicklung des „Psychopathy”-Konzeptes werden die klinischen Persönlichkeitseigenschaften, neurophysiologische und Bildgebungsbefunde unter Berücksichtigung der aktuellen Literatur dargestellt. Die Befunde legen ein neurobiologisches Modell zu Aggression und Emotion bei einer schweren dissozialen Persönlichkeitsstörung nahe; mögliche juristische Implikationen hinsichtlich der Schuldfähigkeitsbeurteilung von Straftätern mit dieser Störung werden diskutiert.

ZusammenfassungZwei Aspekte der transkraniellen Magnetstimulation (TMS) finden zunehmend Einzug in die Psychiatrie. Zum einen die repetitive transkranielle Magnetstimulation (rTMS) zur Behandlung psychischer Erkrankungen, zum anderen die diagnostische Variante des Verfahrens. Methodische Erweiterungen dieser diagnostisch ausgerichteten TMS eröffnen die Möglichkeit, schmerzfrei und nichtinvasiv die kortikale Exzitabilität des motorischen Systems zu messen. Damit lassen sich neue Erkenntnisse zur Wirkungsweise von Psychopharmaka gewinnen. Besonders interessant erscheint zudem die Möglichkeit der biologischen Phänotypisierung mittels dieses Verfahrens. Hierbei lassen sich so genannte neurophysiologische Endophänotypen definieren, die zum Teil genetisch determiniert sind.

ZusammenfassungWährend zur antidepressiven Wirkung der repetitiven transkraniellen Magnetstimulation (rTMS) eine große Zahl an Studien vorliegt, ist der Einsatz dieser Methode in der Behandlung der Schizophrenie bisher wenig untersucht. Es finden sich jedoch zunehmend Hinweise für die Wirksamkeit der rTMS bei Schizophrenie. Besonders beeindruckend ist dabei, dass die Negativsymptomatik durch rTMS beeinflussbar scheint. In diesem Zusammenhang ist zum Verständnis der rTMS-Wirkung bei Schizophrenie die Differenzierung zwischen Negativsymptomatik und depressiver Symptomatik von besonderer Bedeutung.Unter Verwendung eines plazebokontrollierten Paralleldesigns wurden 10 Patienten mit Schizophrenie in die Studie eingeschlossen. Die Stimulation erfolgte hochfrequent (10 Hz) über dem linken dorsolateralen praefrontalen Kortex (DLPFC) an 10 Tagen. Bei der Evaluation der rTMS-Wirkung wurde durch Auswahl geeigneter Ratingskalen auf die Diskriminierung von Negativ- und depressiver Symptomatik Wert gelegt.Es zeigte sich, dass die aktive hochfrequente rTMS verglichen mit Plazebostimulation zu einer grenzwertig signifikanten Verminderung der Negativsymptomatik führt. Weiter fand sich ein Trend bezüglich der Verminderung depressiver Symptomatik.Die selektive Modulation mesolimbischer und mesostriataler dopaminerger Systeme, die in mehreren Untersuchungen im Zusammenhang mit hochfrequenter rTMS demonstriert wurde, könnte die therapeutischen Effekte auf Negativsymptomatik und depressive Symptomatik erklären.

Partial sleep deprivation (PSD) has a profound and rapid effect on depressed mood. However, the transient antidepressant effect of PSD - most patients relapse after one night of recovery sleep—is limiting the clinical use of this method. Using a controlled, balanced parallel design we studied, whether repetitive transcranial magnetic stimulation (rTMS) applied in the morning after PSD is able to prevent this relapse. 20 PSD responders were randomly assigned to receive either active or sham stimulation during the following 4 days after PSD. Active stimulation prolonged significantly (p

Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral-prefrontal cortex (DLPFC) exerts antidepressant effects. In this randomised controlled clinical trial we aimed to test the safety and therapeutic efficacy of bilateral theta-burst stimulation (TBS) as an add-on therapy to standard treatment of major depression.Fifty-six patients diagnosed with a moderate to severe depressive episode received 15 daily treatments of either rTMS (110% motor-threshold; rightDLPFC, 1000 stimuli at 1 Hz + leftDLPFC, 1000 stimuli at 10 Hz), theta-burst stimulation (80% motor-threshold; rightDLPFC, continuous TBS, 1200 stimuli + leftDLPFC, intermittent TBS, 1200 stimuli), or sham TMS (N = 17, sham coil with the TBS protocol).There was no significant effect in the primary outcome measures (change of the 21-item Hamilton Rating Scale for Depression). However, there was a tendency towards an increased responder rate at the end of the follow-up period for both active treatments as compared to sham, and this tendency was most pronounced for the TBS group.This pilot study did not reveal significant advantages of bilateral TBS or rTMS over sham treatment as an add-on treatment for major depression. A tendency towards a superior effect of bilateral TBS at the end of the follow-up period may warrant further studies.

Objective Chronic tinnitus is a highly prevalent condition and has been hypothesized to result from an innate disturbance in central nervous serotonergic transmission. Given the frequent comorbidity with major depression and anxiety, we argue that candidate genes for these disorders are likely to overlap. The present study addresses the gene encoding for the 5-HT1A receptor as a putative risk factor for tinnitus. Methods In 88 subjects with a diagnosis of chronic subjective tinnitus who underwent a detailed neurootological examination, the entire 5-HT1A gene was amplified using overlapping PCR products. Amplicons were custom sequenced bidirectionally and were screened for variants in multiple alignments against the human genome reference. Results We identified a synonymous C>T exchange at residue 184 (Pro) in 7/88 subjects, but detected no missense variants in the population under study. Specifically, the following residues were fully conserved: 16 (Pro), 22(Gly), 28(Ile), 98 (Val), 220(Arg), 267 (Val), 273 (Gly), and 418 (Asn). Discussion The present data count against the causation of chronic tinnitus by a change in the 5-HT1A receptor’s amino acid sequence. However, the allele frequency for the 184Pro minor allele (0.04) reached twice the frequency reported in control cohorts from the same ethnicity. Additional investigations are invited to clarify the role of the 5-HT1A polymorphism in larger samples, and to control for comorbid affective disorders.

Schizophrenia is a severe, debilitating, chronic disease that is accompanied by morphologic changes within the brain. However, it is unclear to what extent alterations of grey and white matter in schizophrenia are linked to the disease itself, or whether they are a consequence of neuroleptic treatment. Typical and atypical antipsychotics exert differential effects on brain structure. Moreover, atypical antipsychotics may have distinct profiles with respect to grey matter in schizophrenic patients. Findings on drug-induced grey matter changes are heterogeneous due to variation in stage of illness, duration of treatment and use of multiple antipsychotics. Using voxel-based morphometry applied to high-resolution magnetic resonance images, we show that monotherapy with the atypical agent quetiapine (mean daily dose = 445 mg ± 200 s.d.) may induce structural brain changes in first-episode schizophrenia patients (N = 20) within 21 d of treatment. Specifically, we demonstrate longitudinal macroscopic changes (i.e. grey matter increases) in the left amygdalohippocampal region that were predicted by drug plasma levels but not daily doses. These structural alterations were accompanied by a clinical improvement of schizophrenic symptoms. Comparison with healthy controls (n = 30) showed that grey matter amount in the respective amygdalar region was significantly reduced in unmedicated first-episode schizophrenia patients. These findings suggest that drug-induced neuroplastic changes in schizophrenia can occur quickly and are dependent on pharmacokinetics.

Tinnitus is related to alterations in neuronal activity of auditory and nonauditory brain areas. Targeted modulation of these areas by repetitive transcranial magnetic stimulation (rTMS) has been proposed as a new therapeutic approach for chronic tinnitus.Two randomized, double-blind, parallel-group, controlled clinical trials were performed subsequently and pooled for analysis. A total of 192 tinnitus patients were randomly allocated to receive 10 stimulation sessions of either sham rTMS, PET-based neuronavigated 1 Hz rTMS, 1Hz r TMS over the left auditory cortex, or combined 20 Hz rTMS over the left frontal cortex, followed by 1 Hz rTMS over the left auditory cortex.rTMS treatment was well tolerated and no severe side effects were observed. All active rTMS treatments resulted in significant reduction of the TQ as compared to baseline. The comparison between treatment groups failed to reach significant differences. The number of treatment responders was higher for temporal rTMS(38%) and combined frontal and temporal rTMS (43%), as compared to sham (6%).This large study demonstrates the safety and tolerability of rTMS treatment in patients with chronic tinnitus. While the overall effect did not prove superior to placebo, secondary outcome parameters argue in favour of the active stimulation groups, and specifically the combined frontal and temporal rTMS protocol.

In the treatment of depressive disorders the onset of action can be accelerated if the antidepressant drug is initially administered by intravenous infusion. It is not clear whether this effect is due to pharmacological or to psychological effects of the infusion setting. The necessary switch to oral administration may be problematic. Uncontrolled observations indicate that it could be associated with a remarkable deterioration in the course of the disease. This randomized double-blind placebo-controlled study on doxepin is the first investigation of the effect of the switch from parenteral to oral administration on symptoms of endogenous depression. The hypothesis to be tested, that there is a significant worsening of treatment response during the switch, must be rejected on the basis of objective and subjective psychometric tests. There was in fact a continuous improvement. Precondition was a selection of patients with typical "endogenous" depressions and maintenance of at least constant plasma levels of the active antidepressants. In patients under the age of 65 years this can generally be achieved by switching in a ratio of 125 mg i.v. to 250 per os in the case of doxepin. Individual case studies indicated that a worsening in the patient's progress after switching was correlated with a decreasing plasma level of the active drug. Low plasma level already during the infusion period, insufficient response, and questionable compliance on oral medication were associated. Due to large interindividual differences of plasma levels by a factor of 10, measurements before and after switching are required.

We investigated the therapeutic effect of marked body weight reduction on the predominantly obstructive sleep apnea syndrome by the application of an out-patient, behaviour therapy based body weight reduction program (Optifast-program) in five of our obese apnea patients (mean overweight by Broca 53.6 +/- 24.8 kg). Mean body weight reduction was 32.7 +/- 15.8 kg after six months. The mean apnea-index of 34.5 +/- 23.1/h prior to the weight reduction dropped to 7.8 +/- 6.1/h after therapy. The mean apnea-hypopnea-index (so called "respiratory disturbance index", RDI) could be reduced from 45,7 +/- 26.0/h to 14.0 +/- 11.4/h. The best therapeutic effect on the sleep related respiratory parameters was seen in patients who reached their normal weight whereas the absolute weight reduction itself seems to be less important. Our results should encourage this causal therapy in appropriate patients.

Background Cognitive deficits are stable features of schizophrenia that are linked to functional outcome. Cognitive remediation approaches have been proven successful in ameliorating these deficits, although effect sizes vary considerably. Whether cognitive deficits are serious predictors of clinical outcome is less clear. Methods Sixty patients suffering from schizophrenia were included in our sample, thirty of them received computer-assisted cognitive training, and thirty received occupational therapy. For a subsample of 55 patients, who could be traced over a period of five years after the end of the cognitive remediation intervention, time until first relapse and time in psychosis were determined retrospectively from their medical records. Results Cognitive remediation significantly improved problem solving, memory and attention with high effect sizes. Employment status, a post test verbal memory performance measure and a measure of executive functioning outperformed all other measures in the prediction of time to relapse, while allocation to treatment group outperformed all other variables in the prediction of both cognitive measures. Conclusions Cognitive remediation of neurocognitive deficits thus makes sense in a twofold fashion: It enhances cognition directly and positively acts on clinical course indirectly via improved neurocognition. Trial registration German Clinical Trials Register: DRKS00004880

To estimate the prevalence and associations of broadly defined (i.e., meeting full ICD-10, DSM-IV, or RDC/ICSD-2 inclusion criteria) insomnia with work performance net of comorbid conditions in the America Insomnia Survey (AIS).Cross-sectional telephone survey.National sample of 7,428 employed health plan subscribers (ages 18+).None.Broadly defined insomnia was assessed with the Brief Insomnia Questionnaire (BIQ). Work absenteeism and presenteeism (low on-the-job work performance defined in the metric of lost workday equivalents) were assessed with the WHO Health and Work Performance Questionnaire (HPQ). Regression analysis examined associations between insomnia and HPQ scores controlling 26 comorbid conditions based on self-report and medical/pharmacy claims records. The estimated prevalence of insomnia was 23.2%. Insomnia was significantly associated with lost work performance due to presenteeism (χ² (1) = 39.5, P0.001) but not absenteeism (χ² (1) = 3.2, P = 0.07), with an annualized individual-level association of insomnia with presenteeism equivalent to 11.3 days of lost work performance. This estimate decreased to 7.8 days when controls were introduced for comorbid conditions. The individual-level human capital value of this net estimate was $2,280. If we provisionally assume these estimates generalize to the total US workforce, they are equivalent to annualized population-level estimates of 252.7 days and $63.2 billion.Insomnia is associated with substantial workplace costs. Although experimental studies suggest some of these costs could be recovered with insomnia disease management programs, effectiveness trials are needed to obtain precise estimates of return-on-investment of such interventions from the employer perspective.