Morbus Darier und Depression - besteht eine genetische Verbindung?: Übersicht und klinischer Fall

Zusammenfassung: Der Morbus Darier ist eine seltene Hauterkrankung, die autosomal-dominant vererbt wird und durch eine Mutation im SERCA (sarco/endoplasmatic reticulum calcium transporter)-2-Gen verursacht wird. In einigen Stammbäumen ist das Auftreten des Morbus Darier eng mit dem Vorkommen affektiver Erkrankungen verknüpft. Die wahrscheinlichste Ursache ist ein Suszeptibilitätsgen für affektive Erkrankungen in der Nähe des SERCA-2-Gens. Als Suszeptibilitätslokus konnte eine 6,5-Mb-Region identifiziert werden. Auch Studien mit affektiv erkrankten Stichproben, die nicht an Morbus Darier leiden, weisen ein Signal in der gleichen Region auf. Das zugrunde liegende Gen ist jedoch noch nicht identifizier

The Use of the Health of the Nation Outcome Scales for Assessing Functional Change in Treatment Outcome Monitoring of Patients with Chronic Schizophrenia.

Schizophrenia is a severe mental disorder that is characterized not only by symptomatic severity but also by high levels of functional impairment. An evaluation of clinical outcome in treatment of schizophrenia should therefore target not only assessing symptom change but also alterations in functioning. This study aimed to investigate whether there is an agreement between functional- and symptom-based outcomes in a clinical sample of admissions with chronic forms of schizophrenia. A full 3-year cohort of consecutive inpatient admissions for schizophrenia (N = 205) was clinically rated with the Positive and Negative Symptom Scale (PANSS) and the Health of the Nation Outcome Scales (HoNOS) as measures of functioning at the time of admission and discharge. The sample was stratified twofold: first, according to the degree of PANSS symptom improvement during treatment with the sample being divided into three treatment response groups: non-response, low response, and high response. Second, achievement of remission was defined using the Remission in Schizophrenia Working Group criteria based on selected PANSS symptoms. Repeated measures analyses were used to compare the change of HoNOS scores over time across groups. More than a half of all admissions achieved a symptom reduction of at least 20% during treatment and around one quarter achieved remission at discharge. Similarly, HoNOS scores improved significantly between admission and discharge. Interaction analyses indicated higher functional improvements to be associated with increasing levels of treatment response. Functional improvement in individuals treated for schizophrenia was linked to a better clinical outcome, which implies a functional association. Thus, improvement of functioning represents an important therapeutic target in the treatment of schizophrenia

Psychopathologie des Ganser-Syndroms: Literaturübersicht und Falldiskussion

Zusammenfassung: Das Kernsymptom des Ganser-Syndroms besteht im "Vorbeiantworten" auf einfache Fragen. Die Ursache dieses seltenen Syndroms ist unklar. Aktuelle Klassifikationssysteme zählen es zu den dissoziativen Störungen, wobei eine psychogene Ursache der Symptome angenommen wird. Anhand einer Literaturrecherche (n=151) wird jedoch gezeigt, dass das Ganser-Syndrom sehr häufig mit Hirnverletzungen assoziiert ist, wobei detaillierte bildgebende, neuropsychologische und neurologische Untersuchungen weitgehend fehlen. Wir stellen eine rechtshändige Patientin mit einem Ganser-Syndrom nach einem großen linkshemisphärischen Mediainfarkt vor. Die detaillierte neuropsychologische Untersuchung zeigte eine untypische Lateralisierung kognitiver Funktionen mit einer sog. gekreuzten Nichtaphasie und ausgeprägten frontal-exekutiven Funktionsstörungen. Unter Berücksichtigung sowohl der psychiatrischen als auch der neuropsychologischen Aspekte wird diskutiert, in welchem Zusammenhang das psychopathologische Symptom des "Vorbeiantwortens" mit spezifischen frontal-exekutiven Hirnfunktionsstörungen stehen könnt

Detailing the effects of polypharmacy in psychiatry: longitudinal study of 320 patients hospitalized for depression or schizophrenia

Current treatment standards in psychiatry are oriented towards polypharmacy, that is, patients receive combinations of several antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics, antihistamines, and anticholinergics, along with other somatic treatments. In tandem with the beneficial effects of psychopharmacological drug treatment, patients experience significant adverse reactions which appear to have become more frequent and more severe with the rise of ubiquitous polypharmacy. In this study, we aimed to assess today's acute inpatient treatment of depressive and schizophrenic disorders with focus on therapeutic strategies, medications, adverse side effects, time course of recovery, and efficacy of treatments. Of particular interest was the weighing of the benefits and drawbacks of polypharmacy regimens. We recruited a total of 320 patients hospitalized at three residential mental health treatment centers with a diagnosis of either schizophrenic (ICD-10: "F2x.x"; n = 94; "F2 patients") or depressive disorders (ICD-10: "F3x.x"; n = 226; "F3 patients"). The study protocol included (1) assessment of previous history by means of the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medications and adverse side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. Polypharmacy was by far the most common treatment regimen (85%) in this study. On average, patients received 4.50 ± 2.68 medications, consisting of 3.30 ± 1.84 psychotropic drugs, plus 0.79 ± 1.13 medications that alleviate adverse side effects, plus 0.41 ± 0.89 other somatic medications. The treating psychiatrists appeared to be the main determining factor in this context, while «previous history» and «severity at baseline» played a minor role, if at all. Adverse drug reactions were found to be an inherent component of polypharmacy and tended to have a 2-3 times higher incidence compared to monotherapy. Severe adverse reactions could not be attributed to a particular drug or drug combination. Rather, the empirical data suggested that severe side effects can be triggered by virtually all combinations of drugs, provided patients have a respective vulnerability. In terms of efficacy, there were no advantages of polypharmacy over monotherapy. The results of this study underlined the fact that polypharmacy regimens are not equally suited for every patient. Specifically, such regimens appeared to have a negative impact on treatment outcome and to obfuscate the "natural" time course of recovery through a multitude of interfering factors. Evidence clearly speaks against starting just every therapeutic intervention in psychiatry with a combination of psychopharmaceuticals. We think that it is time for psychiatry to reconsider its treatment strategies, which are far too one-sidedly fixated on psychopharmacology and pay far too little attention to alternative approaches, especially in mild cases where psychotherapy without concurrent medication should still be an option. Also, regular exercises and sports can definitely be an effective therapeutic means in a considerable number of cases. General practitioners (GPs) are particularly in demand here

The Role of the Subgenual Anterior Cingulate Cortex and Amygdala in Environmental Sensitivity to Infant Crying

This work was supported by the Swiss National Science Foundation (SNF): Grant 51A240-104890 to FHW and ES, and the Swiss National Science Foundation (SNF): Grant PA00P1_145418 to IM and the Freiwillige Akademische Gesellschaft to IM

Ketamine decreases resting state functional connectivity between networks via the dorsal nexus: implications for major depression

Question: Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate modulating NMDA receptor antagonist ketamine [1, 2]. Targeting the glutamatergic system might thus provide a novel therapeutic strategy for antidepressant drug treatment [3]. Since glutamate is the most abundand and major excitatory neurotransmitter in the human brain, pathophysiological changes in glutamatergic signalling are likely to affect neurobehavioural plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder (MDD) [4]. Using resting state functional MRI (rsfMRI), the „dorsal nexus“ (DN) was recently identified as a bilateral dorsal medial prefrontal cortex (DMPFC) region showing dramatically increased depression-associated fMRI connectivity with large portions of the cognitive control network (CCN), the default mode network (DMN), and the affective network (AN) [5]. Hence, Sheline and colleagues [5] proposed that reducing increased connectivity of the DN might play a critical role in reducing depressive symptomatology and thus represent a potential therapeutic target for affective disorders. Since little is known about how ketamine affects large-scale neural network dynamics in the human brain, we aimed to test the hypothesis that ketamine as an antidepressant glutamatergic agent decreases resting state connectivties via the DN. Methods: Study design: 17 healthy subjects (mean age, 40.5 +/- 7.5 [SD]; 9 males) completed four resting state fMRI sessions in a double-blind, randomized, crossover study design (s. Fig 1). The baseline scan was followed by an intravenous infusion (45 mins) of either S-ketamine (0.25 mg/kg) or placebo (saline) outside the scanner. Since the antidepressant effect of ketamine is most prominent after one day [1], the followup scans were scheduled 24 hours after the ketamine or placebo infusion in order to assess the mid-term effects on neuronal network dynamics that might contribute to its antidepressant efficacy. To avoid a possible carry-over effect, the time lag between the two baseline measurements was set to at least 10 days. rsfMRI data acquisition and analysis: Measurements were performed on a Philips Achieva TX 3-T whole-body MR unit equipped with an 8-channel SENSE head coil. During each session a total of 200 functional images were collected in 10 minute runs (eyes closed) using the following acquisition parameters: TE = 35 ms, TR = 3000 ms (θ = 82°), FOV = 22 cm, acquisition matrix = 80 x 80 interpolated to 128 x 128, voxel size = 2.75 x 2.75 x 4 mm, 32 contiguous axial slices (placed along the anterior-posterior commissure plane), and sensitivity-encoded acceleration factor R = 2.0. A 3-dimensional T1-weighted anatomical scan was obtained for structural reference. Data were analyzed using the SPM8 (Wellcome Trust Center for Neuroimaging, London, England) based data processing assistant for resting state fMRI (DPARSF, by Yan Chao-Gan et al.) which includes a resting state fMRI data analysis toolkit (REST, by Song Xiao-Wei et al.). The postprocessing steps followed the standard protocol described by Yan and Zang (2010) [6]. Results: To test our hypothesis, we created a seed region of interest in the left and right DMPFC (10 mm sphere at ± 6 51 24) representing the DN. 24 h following ketamine administration, functional connectivity was exclusively reduced to the posterior cingulate cortex (PCC), to the subgenual anterior cingulate cortex (sgACC), and to anterior and mediodorsal parts of the thalamus (compared to placebo). The backprojection from a seed in the PCC confirmed these results and revealed an additional significant reduction of functional connectivity to the pregenual ACC (PACC) and medioprefrontal cortex (MPFC). For details, see Fig. 2 A, B and bar diagrams (functional connectivity change, paired t tests). Conclusion: While pharmacological effects of ketamine on task induced fMRI BOLD signals have been studied extensively, this is the first randomized, placebo-controlled, double-blind, crossover study demonstrating changes in resting state functional connectivity in response to ketamine administration in healthy subjects. Here, we report a significant decrease in functional connectivity of the sgACC (AN) and the PCC (DMN) via the DN 24 hours following ketamine administration, thus reflecting a neuronal pattern of normalization with regard to MDD where increased connectivities of the AN and DMN via the DN have been observed [5]. As critical hub of the AN, the sgACC plays an important role in mood regulation. Subgenual cortical activity was shown to be elevated in MDD and effective antidepressant treatment was associated with a reduction in sgACC activity [for review see ref. 7]. In addition, the observed reduction in functional connectivity between anterior (PACC/MPFC) and posterior parts of the DMN (PCC) may partially reverse the disrupted neurobehavioral homeostasis in MDD where a failure to normally down-regulate activity within the DMN during emotional stimulation was found [8], with increasing levels of DMN dominance being associated with higher levels of maladaptive, depressive rumination and lower levels of adaptive, reflective rumination [9]. Finally, reductions in cortico-thalamic connectivity may reflect functional alterations in thalamocortical loops via the prefrontal cortex. Based on the fact that the antidepressant effect of ketamine peaks one day after a single intravenous administration [1], we conclude that pharmacologically reducing the hyperconnectivity via the DN may play a critical role in reducing depressive symptomatology and in representing a systems level mechanism of treatment response for major depression

No Abuse Potential of Silexan in Healthy Recreational Drug Users: A Randomized Controlled Trial

BACKGROUND Silexan is a lavender essential oil with established anxiolytic and calming efficacy. Here we asked whether there is a potential for abuse in human patients. METHODS We carried out a phase I abuse liability single-center, double-blind, 5-way crossover study in healthy users of recreational central nervous system depressants. They received single oral doses of 80 mg (therapeutic dose) and 640 mg Silexan, 2 mg and 4 mg lorazepam (active control) and placebo in randomized order, with 4- to 14-day washout periods between treatments. Pharmacodynamic measures included validated visual analogue scales assessing positive, negative, and sedative drug effects and balance of effects; a short form of the Addiction Research Center Inventory; and a drug similarity assessment. The primary outcome measure was the individual maximum value on the drug liking visual analogue scale during 24 hours post-dose. RESULTS Forty participants were randomized and 34 were evaluable for pharmacodynamic outcomes. In intraindividual head-to-head comparisons of the drug liking visual analogue scale maximum value, both doses of Silexan were rated similar to placebo whereas differences were observed between Silexan and lorazepam and between placebo and lorazepam (P < .001). These data were supported by all secondary measures of positive drug effects and of balance of effects. Differences between placebo and both doses of Silexan were always negligible in magnitude. Moreover, Silexan showed no sedative effects and was not perceived to be similar to commonly used drugs that participants had used in the past. CONCLUSIONS Silexan did not exhibit any abuse potential in a standard abuse potential detection screen study and is unlikely to be recreationally abused

Normalizing effect of heroin maintenance treatment on stress-induced brain connectivity

A single dose of heroin can reduce stress responses in heroin-dependent patients. Schmidt et al. report that increased amygdala-related functional connectivity during fearful face processing in heroin-dependent patients transiently normalises after a single dose of heroin. This measure may help to assess the efficacy of maintenance treatments in drug addictio

Sex differences in neurodevelopmental and common mental disorders examined from three epidemiological perspectives.

Sex differences in neurodevelopmental and common mental disorders are a ubiquitous, well-known, though poorly understood phenomenon. This study examined the issue from three epidemiological perspectives: congruence in age of onset, distribution of sex-ratios with respect to age of onset and similarity of comorbidity and risk factor patterns. The analysis was based on data from the population-based PsyCoLaus study (N = 4874, age 35-82 y). Congruence in age of onset and distribution of sex-ratios were examined with the Mann-Whitney test and cluster analysis. The similarity of comorbidity and risk factor patterns, which were represented by 35 variables, was assessed with the Jaccard coefficient and, after factor analysis, with Tucker's congruence coefficient. While age of onset parameters differed little by sex, the sex ratio varied markedly both in early and in late onset disorders. Moreover, the Jaccard coefficients for most disorders indicated that the similarity of comorbidity and further association patterns was low. Similarly, Tucker's congruence coefficient remained below the range of fair similarity in all factor combinations. In sum, sex differences in common mental disorders were impressively reflected by diverging sex ratios and comorbidity / risk factor patterns. This outcome supports the notion that most mental disorders need a sex-specific etiopathogenetic understanding

The relationship between resting-state functional connectivity, antidepressant discontinuation and depression relapse

The risk of relapsing into depression after stopping antidepressants is high, but no established predictors exist. Resting-state functional magnetic resonance imaging (rsfMRI) measures may help predict relapse and identify the mechanisms by which relapses occur. rsfMRI data were acquired from healthy controls and from patients with remitted major depressive disorder on antidepressants. Patients were assessed a second time either before or after discontinuation of the antidepressant, and followed up for six months to assess relapse. A seed-based functional connectivity analysis was conducted focusing on the left subgenual anterior cingulate cortex and left posterior cingulate cortex. Seeds in the amygdala and dorsolateral prefrontal cortex were explored. 44 healthy controls (age: 33.8 (10.5), 73% female) and 84 patients (age: 34.23 (10.8), 80% female) were included in the analysis. 29 patients went on to relapse and 38 remained well. The seed-based analysis showed that discontinuation resulted in an increased functional connectivity between the right dorsolateral prefrontal cortex and the parietal cortex in non-relapsers. In an exploratory analysis, this functional connectivity predicted relapse risk with a balanced accuracy of 0.86. Further seed-based analyses, however, failed to reveal diferences in functional connectivity between patients and controls, between relapsers and non-relapsers before discontinuation and changes due to discontinuation independent of relapse. In conclusion, changes in the connectivity between the dorsolateral prefrontal cortex and the posterior default mode network were associated with and predictive of relapse after open-label antidepressant discontinuation. This fnding requires replication in a larger dataset