Efficacy and safety of duloxetine in the treatment of generalized anxiety disorder: a flexible-dose, progressive-titration, placebo-controlled trial

Generalized anxiety disorder (GAD), a prevalent and chronic illness, is associated with dysregulation in both serotonergic and noradrenergic neurotransmission. Our study examined the efficacy, safety, and tolerability of duloxetine hydrochloride, a dual reuptake inhibitor of serotonin and norepinephrine, for short-term treatment of adults with GAD. In a 10-week, double-blind, progressive-titration, flexible-dose trial, 327 adult outpatients with a DSM-IV-defined GAD diagnosis were randomized to duloxetine 60-120 mg (DLX, N=168) or placebo (PLA, N=159) treatment. The primary efficacy measure was mean change from baseline to endpoint in Hamilton Anxiety Scale (HAMA) total score. Secondary outcome measures included response rate (HAMA total score reduction > or =50% from baseline), Clinician Global Impression-Improvement (CGI-I) scores, and Sheehan Disability Scale (SDS) scores. Patients who received duloxetine treatment demonstrated significantly greater improvement in HAMA total scores (P=.02); a higher response rate (P=.03), and greater improvement (P=.04) than patients who received placebo. Duloxetine-treated patients were also significantly more improved than placebo-treated patients on SDS global functional (P<.01) and work, social, and family/home impairment scores (P<.05). The rate of discontinuation due to adverse events (AEs) was higher for the duloxetine group compared with the placebo group (P=.002). The AEs most frequently associated with duloxetine were nausea, dizziness, and somnolence. Duloxetine was an efficacious, safe, and well-tolerated treatment that resulted in clinically significant improvements in symptom severity and functioning for patients with GAD.     

Neural mechanisms and predictors of SSRI and CBT treatment of anxiety: A randomized trial focused on emotion and cognitive processing

Anxiety disorders (ADs) are common and difficult to treat. While research suggests ADs are characterized by an imbalance between bottom-up and top-down attention processes and that effective treatments work by correcting this dysfunction, there is insufficient data to explain how and for whom treatments work. The late positive potential (LPP), an event-related potential reflecting elaborative processing of motivationally salient stimuli, is sensitive to both bottom-up and top-down processes. The present study examines the LPP in healthy controls (HC) and patients with ADs under low and high working memory (WM) load to assess its utility as a predictor and index of symptom reduction in patients who underwent cognitive behavioral therapy (CBT) or selective serotonin reuptake inhibitor (SSRI) treatment. The LPP when viewing negative and neutral distractor images and WM performance were assessed in 96 participants (40 HC, 32 CBT, 24 SSRI) during a letter recall task at Week 0 and in a subset of the study sample (23 CBT, 16 SSRI) at Week 12. Patients were randomly assigned to twelve weeks of CBT or SSRI treatment. Participants completed self-reported symptom measures at each time point. Greater Week 0 LPP to negative images under low WM load predicted greater symptom reduction in the SSRI, but not the CBT, group. Regression analyses examining the LPP to negative images as an index of symptom reduction revealed a smaller decrease in the LPP to negative images under low WM load was associated with less anxiety reduction across treatment modalities. Findings suggest the LPP during low WM load may serve as a cost-effective predictor and index of treatment outcome in ADs.Clinical Trials Registration: ClinicalTrials.gov (Identifier: NCT01903447)     

Improved EEG source analysis using low‐resolution conductivity estimation in a four‐compartment finite element head model

Bioelectric source analysis in the human brain from scalp electroencephalography (EEG) signals is sensitive to geometry and conductivity properties of the different head tissues. We propose a low‐resolution conductivity estimation (LRCE) method using simulated annealing optimization on high‐resolution finite element models that individually optimizes a realistically shaped four‐layer volume conductor with regard to the brain and skull compartment conductivities. As input data, the method needs T1‐ and PD‐weighted magnetic resonance images for an improved modeling of the skull and the cerebrospinal fluid compartment and evoked potential data with high signal‐to‐noise ratio (SNR). Our simulation studies showed that for EEG data with realistic SNR, the LRCE method was able to simultaneously reconstruct both the brain and the skull conductivity together with the underlying dipole source and provided an improved source analysis result. We have also demonstrated the feasibility and applicability of the new method to simultaneously estimate brain and skull conductivity and a somatosensory source from measured tactile somatosensory‐evoked potentials of a human subject. Our results show the viability of an approach that computes its own conductivity values and thus reduces the dependence on assigning values from the literature and likely produces a more robust estimate of current sources. Using the LRCE method, the individually optimized four‐compartment volume conductor model can, in a second step, be used for the analysis of clinical or cognitive data acquired from the same subject. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Differential effects of cathodal transcranial direct current stimulation of prefrontal,motor and somatosensory cortices on cortical excitability and pain perception – a double‐blind randomised sham‐controlled study

The primary aim of this study was to assess the effects of cathodal transcranial direct current stimulation (c‐tDCS) over cortical regions of the pain neuromatrix, including the primary motor (M1), sensory (S1) and dorsolateral prefrontal (DLPFC) cortices on M1/S1 excitability, sensory (STh), and pain thresholds (PTh) in healthy adults. The secondary aim was to evaluate the placebo effects of c‐tDCS on induced cortical and behavioural changes. Before, immediately after and 30 min after c‐tDCS the amplitude of N20–P25 components of somatosensory evoked potentials (SEPs) and peak‐to‐peak amplitudes of motor evoked potentials (MEPs) were measured under four different experimental conditions. STh and PTh for peripheral electrical and mechanical stimulation were also evaluated. c‐tDCS of 0.3 mA was applied for 20 min. A blinded assessor evaluated all outcome measures. c‐tDCS of M1, S1 and DLPFC significantly decreased the corticospinal excitability of M1 (P < 0.05) for at least 30 min. Following the application of c‐tDCS over S1, M1 and DLPFC, the amplitude of the N20–P25 component of SEPs decreased for at least 30 min (P < 0.05). Compared with baseline values, significant STh and PTh increases were observed after c‐tDCS of these three sites. Decreasing the level of S1 and M1 excitability, following S1, M1 and DLPFC stimulation, confirmed the functional connectivities between these cortical sites involved in pain processing. Furthermore, increasing the level of STh/PTh after c‐tDCS of these sites indicated that stimulation of not only M1 but also S1 and DLPFC could be considered a technique to decrease the level of pain in patients.     

Ketamine effects on default mode network activity and vigilance: A randomized,placebo‐controlled crossover simultaneous fMRI/EEG study

In resting‐state functional connectivity experiments, a steady state (of consciousness) is commonly supposed. However, recent research has shown that the resting state is a rather dynamic than a steady state. In particular, changes of vigilance appear to play a prominent role. Accordingly, it is critical to assess the state of vigilance when conducting pharmacodynamic studies with resting‐state functional magnetic resonance imaging (fMRI) using drugs that are known to affect vigilance such as (subanesthetic) ketamine. In this study, we sought to clarify whether the previously described ketamine‐induced prefrontal decrease of functional connectivity is related to diminished vigilance as assessed by electroencephalography (EEG). We conducted a randomized, double‐blind, placebo‐controlled crossover study with subanesthetic S‐Ketamine in N = 24 healthy, young subjects by simultaneous acquisition of resting‐state fMRI and EEG data. We conducted seed‐based default mode network functional connectivity and EEG power spectrum analyses. After ketamine administration, decreased functional connectivity was found in medial prefrontal cortex whereas increased connectivities were observed in intraparietal cortices. In EEG, a shift of energy to slow (delta, theta) and fast (gamma) wave frequencies was seen in the ketamine condition. Frontal connectivity is negatively related to EEG gamma and theta activity while a positive relationship is found for parietal connectivity and EEG delta power. Our results suggest a direct relationship between ketamine‐induced functional connectivity changes and the concomitant decrease of vigilance in EEG. The observed functional changes after ketamine administration may serve as surrogate end points and provide a neurophysiological framework, for example, for the antidepressant action of ketamine (trial name: 29JN1556, EudraCT Number: 2009‐012399‐28).     

Fluoxetine versus sertraline in the treatment of patients with undifferentiated somatoform disorder: a randomized, open-label, 12-week, parallel-group trial

The present study was conducted to compare the effectiveness and tolerability of fluoxetine and sertraline in the treatment of undifferentiated somatoform disorder (USD), using the Patient Health Questionnaire (PHQ-15), which was specifically designed for assessing the severity of somatic symptoms. A randomized, 12-week, open-label trial of fluoxetine (10-60 mg/d) and sertraline (25-350 mg/d) in patients with USD was conducted. Six visits, at baseline and weeks 1, 2, 4, 8, and 12, were scheduled. Assessments for effectiveness and tolerability were conducted at each visit. The primary effectiveness measure was the mean change in PHQ-15 total score, from baseline to the end of treatment. Secondary effectiveness measures were the mean changes in total scores on the Beck Depression Inventory (BDI) and the 12-item General Health Questionnaire (GHQ-12), from baseline to the end of treatment. A total of 45 subjects were enrolled; of them, 28 were randomly assigned to receive fluoxetine and 17 to receive sertraline. The total score on the PHQ-15 from baseline to the end of treatment significantly decreased in the fluoxetine (-10.7, p<0.0001) and sertraline (-10.3, p<0.0001) treatment groups, with no between-group difference (F=0.0701, p=0.7924). Overall, both treatments were well tolerated and no serious adverse event was reported. This study suggests that both agents may have a potential role in the treatment of USD. A double-blind, placebo-controlled trial and/or head-to-head comparison study with larger samples are required to draw more definite conclusions.     

Pallidal deep brain stimulation improves quality of life in segmental and generalized dystonia: Results from a prospective,randomized sham‐controlled trial

As part of the first randomized, sham‐timulation controlled trial on deep brain stimulation (DBS) in primary segmental or generalized dystonia, health‐related quality of life (HRQoL) was assessed by SF‐36. After the 3‐month sham‐controlled phase, significant HRQoL improvement occurred only in the active‐stimulation group. The open‐label extension phase resulted in a significant improvement in all SF‐36 domains following 6 months of neurostimulation. These results demonstrate a favorable impact of DBS on HRQoL in primary dystonia. © 2007 Movement Disorder Society     

Effects of pain treatment on sleep in nursing home patients with dementia and depression: A multicenter placebo‐controlled randomized clinical trial

Objective

To investigate the effects of pain treatment on sleep in nursing home (NH) patients with dementia and depression.

Methods

A multicenter, 2‐armed, double‐blinded, placebo‐controlled, randomized clinical trial conducted between August 2014 and September 2016. One hundred six long‐term patients from 47 NHs in Norway with dementia and depression according to the Mini‐Mental State Examination and the Cornell Scale for Depression in Dementia were included. Patients received stepwise pain treatment in which those who did not use analgesics were randomized to receive either paracetamol (3 g/day) or placebo tablets; those who already used pain treatment were allocated to buprenorphine transdermal system (max. 10 μg/h/7 days) or placebo transdermal patches. Sleep was assessed continuously for 14 days by actigraphy, 1 week of baseline measurement, and 1 week of ongoing treatment. The following sleep parameters were evaluated: total sleep time, sleep efficiency (SE), sleep onset latency (SOL), wake after sleep onset, early morning awakening (EMA), and number of wake bouts.

Results

In the intervention group (paracetamol/buprenorphine), SE (70%‐72%), SOL (32‐24 min), and EMA (50‐40 min) improved compared with the control group (SE, 70%‐67%; SOL, 47‐60 min; EMA, 31‐35 min). Treatment effects were significant (P < .01, P < .05, and P < .05, respectively).

Conclusion

Compared with placebo, pain treatment improved sleep as measured with actigraphy. This implies that sleep, pain, and depression in NH patients should be critically evaluated and that pain treatment should be considered to be a potentially beneficial treatment.     

Differential localization of γ‐aminobutyric acid type a and glycine receptor subunits and gephyrin in the human pons,medulla oblongata and uppermost cervical segment of the spinal cord: An immunohistochemical study

Gephyrin is a multifunctional protein responsible for the clustering of glycine receptors (GlyR) and γ‐aminobutyric acid type A receptors (GABA_AR). GlyR and GABA_AR are heteropentameric chloride ion channels that facilitate fast‐response, inhibitory neurotransmission in the mammalian brain and spinal cord. We investigated the immunohistochemical distribution of gephyrin and the major GABA_AR and GlyR subunits in the human light microscopically in the rostral and caudal one‐thirds of the pons, in the middle and caudal one‐thirds of the medulla oblongata, and in the first cervical segment of the spinal cord. The results demonstrate a widespread pattern of immunoreactivity for GlyR and GABA_AR subunits throughout these regions, including the spinal trigeminal nucleus, abducens nucleus, facial nucleus, pontine reticular formation, dorsal motor nucleus of the vagus nerve, hypoglossal nucleus, lateral cuneate nucleus, and nucleus of the solitary tract. The GABA_AR α₁ and GlyR α₁ and β subunits show high levels of immunoreactivity in these nuclei. The GABA_AR subunits α₂, α₃, β_2,3, and γ₂ present weaker levels of immunoreactivity. Exceptions are intense levels of GABA_AR α₂ subunit immunoreactivity in the inferior olivary complex and high levels of GABA_AR α₃ subunit immunoreactivity in the locus coeruleus and raphe nuclei. Gephyrin immunoreactivity is highest in the first segment of the cervical spinal cord and hypoglossal nucleus. Our results suggest that a variety of different inhibitory receptor subtypes is responsible for inhibitory functions in the human brainstem and cervical spinal cord and that gephyrin functions as a clustering molecule for major subtypes of these inhibitory neurotransmitter receptors. J. Comp. Neurol. 518:305–328, 2010. © 2009 Wiley‐Liss, Inc.