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

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 posttreatment 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

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

Abstract 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

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

Co-localization of EFhd2 with neurites marked by tau and MAP2 in murine cortical neurons.

<p>(<i>A</i>) Murine cortical neurons (DIV7) were stained with the primary antibodies anti EFhd2 or an isotype matched control antibody (IgG1k) and analyzed by confocal microcsopy. (<i>B</i>) Murine cortical neurons were stained with the primary antibodies anti EFhd2, tau and MAP2. Single images were taken by confocal microscopy and merged (right panel). (<i>C</i>) Murine cortical neurons were double-transfected with constructs encoding dTomato (red) and Myc-tagged EFhd2 (EFhd2Myc; green) and images were taken with an Apoptome. (<i>D</i>) Quantification of the sub-neuronal distribution of EFhd2; data are represented as mean ± SEM (*** <i>P</i><0.001; two-tailed student's t-test).</p

Co-localization of EFhd2 with Synapsin and PSD95 revealed deconvolution microscopy.

<p>(<i>A</i> and <i>B</i>) DIV11 and DIV13 cortical neurons were fixed and stained with anti EFhd2 mAb (green), anti-synapsin 1a/b (red) (<i>A</i>) and rabbit anti-PSD95 (red) (<i>B</i>) antibodies. Mounted cells were analyzed by deconvolution microscopy. Selected areas (insets) were enhanced and visualized in xy and yz dimensions. Images represent 0.2 µm slices of from a deconvolved image stack. Scale bars represent 5 µm (1 µm in the insets).</p

EFhd2 expression in adult mouse brain determined by <i>lacZ</i> reporter gene expression.

<p>(<i>A</i>) Replacement of the murine <i>efhd2</i> locus by a <i>lacZ</i> reporter gene cassette. E1-4: Exons. Black: coding regions in exons. (<i>B</i>) Lysates of brains of wild-type (+/+), heterozygous (+/−) or EFhd2-deficient mice (−/−) were subjected to western blot analysis with antibodies indicated on the right. (<i>C</i>) Whole mount <i>lacZ</i> reporter gene staining of brains of adult mice. (<i>D</i>) Coronal sections of anterior and posterior parts of whole mount stained brains from adult EFhd2^+/+, EFhd2^+/− andEFhd2^−/− mice.</p

EFhd2 protein expression in embryonic and adult brain regions as well as in cortical neurons.

<p>(<i>A</i>) Embryonic (E18) and adult brains (P150) of wildtype mice were dissected into indicated regions. These regions as well as spleens from adult EFhd2^−/−, ^−/+ and ^+/+ mice were lysed and lysates were subjected to 10% SDS-PAGE, followed by western blotting with polyclonal antibodies indicated on the right. Molecular mass standards are indicated on the left (kDa). Optical densities of EFhd2 bands were normalized to actin bands. Representative of three experiments. (<i>B</i>) Cultures of E16 cortical neurons were cultured for the indicated days <i>in vitro</i> (DIV) and lysed. Each time point is represented by two lanes showing two independent cultures. Lysates were subjected to 10% SDS-PAGE, followed by western blotting with antibodies indicated on the right. Molecular mass standards are indicated on the left (kDa). Optical densities of synapsin1a/b, tau and EFhd2 bands were normalized to actin (n = 8 from 4 experiments; one representative experiment is shown). Data are represented as mean −/+ SEM.</p

Inhibitory effects of EFhd2 on microtubule motor mediated transport in cellular and cell-free systems.

<p>(A) Primary hippocampal neurons of EFhd2^+/+ and EFhd2^−/− mice were transfected to express synaptophysin-EGFP. The velocity of vesicles marked with synaptophysin-EGFP was determined and is plotted both against the relative frequency and as normalized velocity (EFhd2^+/+ = 1; mean −/+ SEM). The average velocities are 59.98−/+16.76 nm/s (EFhd2^−/−; 25 kymographs) vs. 47.06−/+12.73 nm/s (EFhd2^+/+; 10 kymographs) (mean−/+ SD; p = 0.0063, two tailed t-test). Results represent 4 experiments. (<i>B</i>) Primary hippocampal neurons of EFhd2^+/+ and EFhd2^−/− mice were transfected to express synaptophysin-EGFP. The number and pausing times of moving vesicles marked with synaptophysin-EGFP were quantified and data of 4 experiments was represented as mean ± SEM (*** <i>P</i><0.001; two tailed student's t-test). (<i>C</i>) Purified KIF5A₅₆₀ was coated to glass slides and incubated with polymerized MTs in the absence or presence of GST or increasing amounts GST-EFhd2. The gliding velocity was determined and is shown as % of the buffer control that was set as 100% (corresponding to a gliding velocity of 1.3 um/sec). Data are represented as mean ± SD of five independent experiments. In every experiment, gliding velocities of 10–15 microtubules were measured for each experimental condition. *** <i>P</i><0.001; one way ANOVA followed by a Dunett's multiple comparisons test.</p

Synaptic localization of EFhd2 is not required for synapse function in primary hippocampal neurons.

<p>(<i>A</i>) Crude synaptosomes were purified from pooled brains and centrifuged. Equal amounts of the supernatant (S2) and the crude synaptosome fraction (STS; P2) were subjected to 10% SDS-PAGE, followed by Western Blotting, Ponceau S staining of the membrane and incubation with antibodies as indicated on the right. The relative distribution of a cytosolic protein (β3-tubulin), a synaptic marker (synaptophysin) and EFhd2 in synaptosomes was calculated by OD measurement. (<i>B</i>) Equal amounts of protein were obtained from each of the separated synaptosomal (S) fractions (Cyt: cytosolic fraction, PM: plasma membrane, SV: synaptic vesicles) and subjected to 10% SDS-PAGE, followed by western blotting with antibodies indicated on the right. β3-tubulin is a marker protein for the cytosolic fraction (Cyt), synaptophysin is a marker protein for synaptic vesicle (SV) fractions and SNAP25 is a marker for plasma membrane (PM) and synaptic vesicle fractions. Molecular mass standards are indicated on the left (kDa). Representative of two independent experiments performed with each three EFhd2^+/+ and three EFhd2^−/− mice. (<i>C</i>) Normalized fluorescence intensity profiles of synapto-phluorin transfected primary neurons of EFhd2^+/+ and EFhd2^−/− mice. Neurons were stimulated with 200 pulses at 10 Hz. Insets show exemplary fluorescence images. Error bars indicate SD. Scale bar, 10 µm. n = 6 transfections.</p