100,000 lumens to treat seasonal affective disorder: A proof of concept RCT of Bright, whole-ROom, All-Day (BROAD) light therapy.

BACKGROUND: Seasonal affective disorder (SAD) is common and debilitating. The standard of care includes light therapy provided by a light box; however, this treatment is restrictive and only moderately effective. Advances in LED technology enable lighting solutions that emit vastly more light than traditional light boxes. Here, we assess the feasibility of BROAD (Bright, whole-ROom, All-Day) light therapy and get a first estimate for its potential effectiveness. METHODS: Patients were randomly assigned to a treatment for 4 weeks; either a very brightly illuminated room in their home for at least 6 h per day (BROAD light therapy) or 30 min in front of a standard 10,000 lux SAD light box. Feasibility was assessed by monitoring recruitment, adherence, and side effects. SAD symptoms were measured at baseline and after 2 and 4 weeks, with the Hamilton Depression Rating Scale-Seasonal Affective Disorders 29-items, self-report version. RESULTS: All 62 patients who started treatment were available at 4-week follow-up and no significant adverse effects were reported. SAD symptoms of both groups improved similarly and considerably, in line with previous results. Exploratory analyses indicate that a higher illuminance (lux) is associated with a larger symptom improvement in the BROAD light therapy group. CONCLUSIONS: BROAD light therapy is feasible and seems similarly effective as the standard of care while not confining the participants to 30 min in front of a light box. In follow-up trials, BROAD light therapy could be modified for increased illuminance, which would likely improve its effectiveness.

Presynaptic vesicular accumulation is required for antipsychotic efficacy in psychotic-like rats.

BACKGROUND: The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their postsynaptic inhibitory functions on the dopamine D2 receptor, which, however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released like neurotransmitters in an activity-dependent manner triggering an auto-inhibitory feedback mechanism. Although closely mirroring therapeutic action onset, the functional consequence of the APD accumulation process remained unclear. AIMS: Here we tested whether the accumulation of the APD haloperidol (HAL) is required for full therapeutic action in psychotic-like rats. METHODS: We designed a HAL analog compound (HAL-F), which lacks the accumulation property of HAL, but retains its postsynaptic inhibitory action on dopamine D2 receptors. RESULTS/OUTCOMES: By perfusing LysoTracker fluorophore-stained cultured hippocampal neurons, we confirmed the accumulation of HAL and the non-accumulation of HAL-F. In an amphetamine hypersensitization psychosis-like model in rats, we found that subchronic intracerebroventricularly delivered HAL (0.1 mg/kg/day), but not HAL-F (0.3-1.5 mg/kg/day), attenuates psychotic-like behavior in rats. CONCLUSIONS/INTERPRETATION: These findings suggest the presynaptic accumulation of HAL may serve as an essential prerequisite for its full antipsychotic action and may explain the time course of APD action. Targeting accumulation properties of APDs may, thus, become a new strategy to improve APD action.

Update on structured pain assessment for the documentation of diagnosis-independent symptoms and signs associated with pain.

Concerning the diagnosis and therapy of pain syndromes, standardized descriptions similar to those used in the examination of psychopathological findings via the system produced by the AMDP ("Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie", i. e., the working group establishing standardized methodology and documentation within psychiatry) are still lacking. Therefore, the authors of this article have founded a working group to establish standardized methodology and documentation for symptoms and signs associated with pain, although not at a diagnosis-specific level, in order to promote standardization in the documentation of pain and rating of the symptoms associated with a given set of medical results. This article presents a system for documenting the symptoms and signs associated with pain globally and independently of the diagnosis (Structured Pain Assessment System) with nomenclature that is inspired by the AMDP system. The objective of this working group is to develop documentation for a uniform multidimensional pain assessment (with defined terminology) that serves as a comparable and unified standard in the field.

A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter.

Antipsychotic drugs are effective interventions in schizophrenia. However, the efficacy of these agents often decreases over time, which leads to treatment failure and symptom recurrence. We report that antipsychotic efficacy in rat models declines in concert with extracellular striatal dopamine levels rather than insufficient dopamine D2 receptor occupancy. Antipsychotic efficacy was associated with a suppression of dopamine transporter activity, which was reversed during failure. Antipsychotic failure coincided with reduced dopamine neuron firing, which was not observed during antipsychotic efficacy. Synaptic field responses in dopamine target areas declined during antipsychotic efficacy and showed potentiation during failure. Antipsychotics blocked synaptic vesicle release during efficacy but enhanced this release during failure. We found that the pharmacological inhibition of the dopamine transporter rescued antipsychotic drug treatment outcomes, supporting the hypothesis that the dopamine transporter is a main target of antipsychotic drugs and predicting that dopamine transporter blockers may be an adjunct treatment to reverse antipsychotic treatment failure.

Vagus Nerve Stimulation As an Adjunctive Neurostimulation Tool in Treatment-resistant Depression.

Vagus nerve stimulation (VNS) is an approved neurostimulation therapy. The purpose of the method is to treat patients with therapy-resistant depression (TRD). VNS exhibits antidepressive and stabilizing effects. This method is particularly useful as a long-term treatment, in which up to two-thirds of patients respond. The vagus nerve stimulator is positioned on the left vagus nerve during a surgical procedure and is activated telemetrically by a wand connected to a handheld computerized device. The treating physician can perform various adjustments of the vagus nerve stimulator during in-office visits (e.g., by modifying stimulation intensity or stimulation frequency) to achieve maximum therapeutic effects with low side effects. Set-up of the device usually takes several months. Typical side effects include wound infection, temporary salivation, coughing, paralysis of the vocal cords, bradycardia, or even asystole. The patient can stop the VNS by placing a magnet over the generator. The current protocol describes delivery of the specific stimulation tool and methods for adjusting the tuning parameters to achieve the best remission rates in patients with TRD.

Schizophrenia dimension-specific antipsychotic drug action and failure in amphetamine-sensitized psychotic-like rats.

Schizophrenic patients suffer from various disruptions in their psyche, mood and cognition, most of which cannot be effectively treated with the available antipsychotic drugs. Some dimensions of the schizophrenia syndrome in man can be mimicked in animals by the amphetamine (AMPH)-sensitization-induced psychosis model. Using such a sensitization procedure, we induced a psychosis-like syndrome in rats, measured as a deficit in sensory information processing and memory deficits. We then investigated the possible restorative effects of continuous treatment with haloperidol (HAL), a typical antipsychotic drug, on distinct dimensions of the syndrome. We found that, continuous infusion of a clinically relevant dose of HAL (0.5 mg/kg/day) effectively ameliorated AMPH-sensitization-induced sensorimotor gating disruptions after seven days of treatment. However, the sensory information processing deficit reappeared after prolonged HAL treatment, suggesting a treatment failure in this dimension of the syndrome. HAL had at this dose little beneficial effects on the cognitive deficits. In contrast, a continuously administered low dose of HAL (0.05 mg/kg/day) successfully attenuated cognitive deficits, but aggravated the sensorimotor gating deficit under both short- or long-term treatment conditions. Post mortem neurochemical analysis revealed that the psychotic-like behavior induced by our manipulations might be explained by altered monoamine levels in distinct brain regions. These findings provide evidence for dissociating and dose-dependent HAL treatment action and failure at different dimensions of schizophrenia.

Association of Depression and Anxiety Disorders With Autoimmune Thyroiditis: A Systematic Review and Meta-analysis.

Importance: With a prevalence of 4% to 13% in the United States, autoimmune thyroiditis (AIT) is a major health problem. Besides somatic complications, patients with AIT can also experience psychiatric disorders. The extent of these organic psychiatric diseases in patients with AIT, however, is so far not commonly known. Objective: To provide meta-analytic data on the association of depression and anxiety with AIT. Data Sources: Google Scholar, the EBSCO Host databases, the Web of Knowledge, and PubMed were searched from inception through December 5, 2017. Articles identified were reviewed and reference lists were searched manually. Study Selection: Case-control studies that reported the association between AIT and either depression or anxiety disorders or both were included. Data Extraction and Synthesis: Data extraction was performed by multiple observers following the PRISMA guidelines. Two univariate random-effects meta-analyses were performed, and moderators were tested with Bonferroni-corrected meta-regression analysis. Heterogeneity was assessed with the I2 statistic. Sensitivity analyses tested the robustness of the results. Small study effects were assessed with funnel plots and the Egger test. Main Outcomes and Measures: The odds ratio of patients with AIT and depression compared with a healthy control group, as well as the odds ratio of patients with AIT and anxiety disorders compared with a healthy control group. Results: Nineteen studies comprising 21 independent samples were included, with a total of 36 174 participants (35 168 for depression and 34 094 for anxiety). Patients with AIT, Hashimoto thyroiditis, or subclinical or overt hypothyroidism had significantly higher scores on standardized depression instruments, with an odds ratio of 3.56 (95% CI, 2.14-5.94; I2 = 92.1%). For anxiety disorders, patients with AIT, Hashimoto thyroiditis, or subclinical or overt hypothyroidism had an odds ratio of 2.32 (95% CI, 1.40-3.85; I2 = 89.8%). Funnel plot asymmetry was detected for studies of depression. Study quality assessed with the Newcastle-Ottawa Scale for case-control studies (mean [SD] score: anxiety, 5.77 [1.17]; depression, 5.65 [1.14]; of a possible maximum score of 9) and proportion of females did not modulate the meta-analytic estimate, whereas mean age did. Conclusions and Relevance: This meta-analysis establishes the association between AIT and depression and anxiety disorders. Patients with AIT exhibit an increased chance of developing symptoms of depression and anxiety or of receiving a diagnosis of depression and anxiety disorders. This finding has important implications for patients and could lead to the choice of early treatment-and not only psychotherapeutic treatment-of the organic disorder.

Off-label prescription of psychiatric drugs by non-psychiatrist physicians in three general hospitals in Germany.

BACKGROUND: Off-label prescribing of psychoactive drugs is a common practice in psychiatry. Here, we sought to investigate the frequency of off-label prescribing in a population of hospitalized patients with a somatic illness who were also suffering from a psychiatric pathology. METHODS: Using a prospective, observational design, we collected data from 982 hospitalized patients with a somatic illness for whom a psychiatric consultation was requested because of the presence of additional psychiatric symptoms. Data were collected at three hospitals in Germany. Demographic and clinical data, including the previous psychoactive medications and an assessment of the suitability of the previous medications, were recorded and analyzed. RESULTS: Data on the previous psychiatric medications were available for 972 patients. In 16.6% of patients, at least one psychoactive drug had been prescribed off-label, 20.2% had received on-label medication, and 63.2% had not received any psychiatric medication. Among all patients receiving psychiatric medication, 45.1% had received off-label medication. The logistic regression analysis showed a significant influence of age on the likelihood of receiving off-label medication (p = 0.018). Benzodiazepines were the most frequent off-label prescription (25.8% of off-label prescriptions), followed by atypical antipsychotics (18.2%) and low-potency antipsychotics (17.2%). Notably, 57.1% of off-label prescriptions were judged to be 'not indicated' by experienced psychiatrists. CONCLUSIONS: Our data show a high frequency of the off-label prescription of psychoactive drugs by physicians treating patients with somatic illnesses in general hospitals. Because more than half of these cases were judged to be "not indicated", these prescriptions indicate a potential risk to patients. Furthermore, the classes of drugs that were most frequently prescribed off-label, benzodiazepines and antipsychotics, both show a substantial risk profile, particularly for elderly patients.

[The AMDS system for the documentation of symptoms and signs associated with pain]. / Das AMDS-System zur Dokumentation von Schmerzbefunden.

The authors present a system for nomenclature and documentation of symptoms and signs associated with pain. The system was compiled in a staged process by the study group for methods and documentation of pain-associated symptoms and signs (Arbeitsgemeinschaft für Methodik und Dokumentation von Schmerzbefunden [AMDS]). The suggested items were elaborated from terms used in current national and international guidelines and classifications and in part integrated into superordinate terms. The items that were built up by this approach aim to reflect the broad spectrum of pain diseases. The items for the description of pain-associated symptoms and signs are divided into the areas of algesiomotor, psychoalgesiological and somatoalgesiological findings. The aim is the documentation of a multidimensional algesiological description of findings with defined terminology, which can serve as a comparable and unified standard, particularly in the field of pain assessment. The AMDS system should enable a systematic description of pain, which is a reliable foundation for diagnostics, therapy planning and expert case evaluation.

Electroconvulsive Therapy Hasn't Negative Effects on Short-Term Memory Function, as Assessed Using a Bedside Hand-Held Device.

Electroconvulsive therapy (ECT) is effective in the treatment of treatment-resistant major depression. The fear of cognitive impairment after ECT often deters patients from choosing this treatment option. There is little reliable information regarding the effects of ECT on overall cognitive performance, while short-term memory deficits are well known but not easy to measure within clinical routines. In this pilot study, we examined ECT recipients' pre- and post-treatment performances on a digital ascending number tapping test. We found that cognitive performance measures exhibited good reproducibility in individual patients and that ECT did not significantly alter cognitive performance up to 2 hours after this therapy was applied. Our results can help patients and physicians make decisions regarding the administration of ECT. Digital measurements are recommended, especially when screening for the most common side effects on cognitive performance and short-term memory.

Visualization and ligand-induced modulation of dopamine receptor dimerization at the single molecule level.

G protein-coupled receptors (GPCRs), including dopamine receptors, represent a group of important pharmacological targets. An increased formation of dopamine receptor D2 homodimers has been suggested to be associated with the pathophysiology of schizophrenia. Selective labeling and ligand-induced modulation of dimerization may therefore allow the investigation of the pathophysiological role of these dimers. Using TIRF microscopy at the single molecule level, transient formation of homodimers of dopamine receptors in the membrane of stably transfected CHO cells has been observed. The equilibrium between dimers and monomers was modulated by the binding of ligands; whereas antagonists showed a ratio that was identical to that of unliganded receptors, agonist-bound D2 receptor-ligand complexes resulted in an increase in dimerization. Addition of bivalent D2 receptor ligands also resulted in a large increase in D2 receptor dimers. A physical interaction between the protomers was confirmed using high resolution cryogenic localization microscopy, with ca. 9 nm between the centers of mass.

Amyloidogenic amyloid-ß-peptide variants induce microbial agglutination and exert antimicrobial activity.

Amyloid-ß (Aß) peptides are the main components of the plaques found in the brains of patients with Alzheimer's disease. However, Aß peptides are also detectable in secretory compartments and peripheral blood contains a complex mixture of more than 40 different modified and/or N- and C-terminally truncated Aß peptides. Recently, anti-infective properties of Aß peptides have been reported. Here, we investigated the interaction of Aß peptides of different lengths with various bacterial strains and the yeast Candida albicans. The amyloidogenic peptides Aß1-42, Aß2-42, and Aß3p-42 but not the non-amyloidogenic peptides Aß1-40 and Aß2-40 bound to microbial surfaces. As observed by immunocytochemistry, scanning electron microscopy and Gram staining, treatment of several bacterial strains and Candida albicans with Aß peptide variants ending at position 42 (Aßx-42) caused the formation of large agglutinates. These aggregates were not detected after incubation with Aßx-40. Furthermore, Aßx-42 exerted an antimicrobial activity on all tested pathogens, killing up to 80% of microorganisms within 6 h. Aß1-40 only had a moderate antimicrobial activity against C. albicans. Agglutination of Aß1-42 was accelerated in the presence of microorganisms. These data demonstrate that the amyloidogenic Aßx-42 variants have antimicrobial activity and may therefore act as antimicrobial peptides in the immune system.

Pharmacist-Led Medication Reviews to Identify and Collaboratively Resolve Drug-Related Problems in Psychiatry - A Controlled, Clinical Trial.

AIM OF THE STUDY: This prospective, controlled trial aimed to assess the effect of pharmacist-led medication reviews on the medication safety of psychiatric inpatients by the resolution of Drug-Related Problems (DRP). Both the therapy appropriateness measured with the Medication Appropriateness Index (MAI) and the number of unsolved DRP per patient were chosen as primary outcome measures. METHODS: Depending on their time of admission, 269 psychiatric patients that were admitted to a psychiatric university hospital were allocated in control (09/2012-03/2013) or intervention group (05/2013-12/2013). In both groups, DRP were identified by comprehensive medication reviews by clinical pharmacists at admission, during the hospital stay, and at discharge. In the intervention group, recommendations for identified DRP were compiled by the pharmacists and discussed with the therapeutic team. In the control group, recommendations were not provided except for serious or life threatening DRP. As a primary outcome measure, the changes in therapy appropriateness from admission to discharge as well as from admission to three months after discharge (follow-up) assessed with the MAI were compared between both groups. The second primary outcome was the number of unsolved DRP per patient after completing the study protocol. The DRP type, the relevance and the potential of drugs to cause DRP were also evaluated. RESULTS: The intervention led to a reduced MAI score by 1.4 points per patient (95% confidence interval [CI]: 0.8-2.0) at discharge and 1.3 points (95% CI: 0.7-1.9) at follow-up compared with controls. The number of unsolved DRP in the intervention group was 1.8 (95% CI: 1.5-2.1) less than in control. CONCLUSION: The pharmaceutical medication reviews with interdisciplinary discussion of identified DRP appears to be a worthy strategy to improve medication safety in psychiatry as reflected by less unsolved DRP per patient and an enhanced appropriateness of therapy. The promising results of this trial likely warrant further research that evaluates direct clinical outcomes and health-related costs. TRIAL REGISTRATION: Deutsches Register Klinischer Studien (DRKS), DRKS00006358.

The Ca2+ sensor protein swiprosin-1/EFhd2 is present in neurites and involved in kinesin-mediated transport in neurons.

Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca2+ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2-/-/lacZ reporter mice and showed that lacZ was strongly expressed in the cortex, the dentate gyrus, the CA1 and CA2 regions of the hippocampus, the thalamus, and the olfactory bulb. Immunohistochemistry and western blotting confirmed this pattern and revealed expression of EFhd2 during neuronal maturation. In cortical neurons, EFhd2 was detected in neurites marked by MAP2 and co-localized with pre- and post-synaptic markers. Approximately one third of EFhd2 associated with a biochemically isolated synaptosome preparation. There, EFhd2 was mostly confined to the cytosolic and plasma membrane fractions. Both synaptic endocytosis and exocytosis in primary hippocampal EFhd2-/- neurons were unaltered but transport of synaptophysin-GFP containing vesicles was enhanced in EFhd2-/- primary hippocampal neurons, and notably, EFhd2 inhibited kinesin mediated microtubule gliding. Therefore, we found that EFhd2 is a neuronal protein that interferes with kinesin-mediated transport.