Levetiracetam as an Adjunctive Treatment for Mania: A Double-Blind, Randomized, Placebo-Controlled Trial

<b><i>Background:</i></b> Levetiracetam is an anticonvulsant with a low side effect profile and favorable properties for individuals with bipolar I disorder during their manic phase. Despite initial promising results until about 2008, it appears that this track of research has not been followed-up. To counter this, we tested the influence of adjuvant levetiracetam on acute mania, compared to placebo. More specifically, we performed a randomized, double-blind, placebo-controlled clinical trial among inpatients with bipolar disorder I during their acute phase of mania. <b><i>Methods:</i></b> A total of 72 inpatients (mean age: 33.98 years; 23.6% females) with diagnosed bipolar disorder I and during their acute manic phase were randomly assigned either to the adjuvant levetiracetam (250 mg to a maximum of 1,500 mg) or to the placebo condition. Standard medication was lithium at therapeutic dosages. At baseline, participants completed a series of self-rating questionnaires covering sociodemographic information and subjective sleep. Subjective sleep was re-assessed 24 days later at the end of the study. Experts rated participants’ acute state of mania with the Young Mania Rating Scale at baseline and at day 12 and day 24. Participants’ cognitive performance was assessed at baseline and at day 24 at the end of the study. <b><i>Results:</i></b> Over time, mania scores significantly decreased (large effect size), but more so in the levetiracetam condition, compared to the placebo condition (medium effect size). Likewise, over time, subjective sleep improved (large effect size), but more so in the levetiracetam condition, compared to the placebo condition (large effect size). Over time, cognitive performance improved (large effect size), irrespective of the study condition. <b><i>Conclusions:</i></b> Compared to placebo, adjuvant levetiracetam to lithium improved symptoms of mania, as rated by experts, and subjective sleep quality. Adjuvant levetiracetam had no further favorable (or detrimental) impact on cognitive performance.

Myofascial Tissue and Depression

Background The myofascial system plays a fundamental role in the mechanics of the body, in body tension regulation and the etiology of pathological states like chronic pain. Moreover, it contains contractile elements and preliminary evidence suggests that its properties are linked to psychological factors. The aim of the present research was to investigate characteristics of the myofascial tissue in patients with Major Depressive Disorder (MDD) and to examine whether the state of the myofascial tissue causally affects pathopsychological processes in MDD. Methods In Study 1, stiffness and elasticity of the myofascial tissue of 40 inpatients suffering from MDD measured with a tissue compliance meter were compared with those of 40 matched never-depressed participants. In Study 2, 69 MDD patients were randomly assigned to single-session self-myofascial release intervention (SMRI) or a placebo intervention. Effects on memory bias and affect were investigated. Results Results showed that MDD patients displayed heightened stiffness and reduced elasticity of the myofascial tissue and that patients in the SMRI group showed a reduced negative memory bias and more positive affect compared to patients in the placebo condition. Conclusions The preliminary results of our studies indicate that the myofascial tissue might be part of a dysfunctional body-mind dynamic that maintains MDD.

Great Expectations: Recommendations for improving the methodological rigor of psychedelic clinical trials

Rationale: Psychedelic research continues to garner significant public and scientific interest with a growing number of clinical studies examining a wide range of conditions and disorders. However, expectancy effects and effective condition masking have been raised as critical limitations to the interpretability of the research.Objective: In this article, we review the many methodological challenges of conducting psychedelic clinical trials and provide recommendations for improving the rigor of future research.Results: We found that although some challenges are shared with psychotherapy and pharmacology trials more broadly, psychedelic clinical trials have to contend with several unique sources of potential bias. The subjective effects of a high-dose psychedelic are often so pronounced that it is difficult to mask participants to their treatment condition; the significant hype from positive media coverage on the clinical potential of psychedelics influences participants’ expectations for treatment benefit; and participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects. Specific recommendations to increase the success of masking procedures and reduce the influence of participant expectancies concern study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, as well as the measurement of participant expectations and masking efficacy.Conclusion: Incorporating these design elements is intended to reduce the risk of bias in psychedelic clinical trials and thereby increase the ability to discern treatment-specific effects of psychedelic therapy

Oxytocin promotes social grooming in bonobos: testing the biobehavioural feedback loop hypothesis

Oxytocin has attracted research attention due to its role in promoting social bonding. One notable recent hypothesis is the biobehavioral feedback loop, which posits that the oxytocin system has evolved to support the formation and maintenance of social bonds through a positive feedback loop, where oxytocin promotes social behaviours which then cause oxytocin release themselves. In the two Pan species, humans’ closest relatives, oxytocin is known to be released following key behaviours related to social bonding, such as social grooming in chimpanzees and female-female sexual behaviour in bonobos. However, no experimental evidence has demonstrated that oxytocin promotes such socio-positive behaviours. To test this, we administered nebulized oxytocin or saline placebo to a group of female bonobos and subsequently observed the change in their gross behavior during free interaction. We found that bonobos groomed other group members significantly more frequently in the oxytocin compared to placebo condition. Other behavioural measures did not largely differ between conditions, except for a nonsignificant trend for reduction in abnormal regurgitation/reingestion behaviour. Overall, we found that oxytocin promoted socio-positive interaction in bonobos, providing support for the biobehavioural feedback loop hypothesis of oxytocin in bonobo social evolution.

Nx4 Reduced Susceptibility to Distraction in an Attention Modulation Task

Background: Stress adversely affects the attentional focus, the active concentration on stimuli, and increases susceptibility to distraction. To experimentally explore the susceptibility to distraction, the Attention Modulation by Salience Task (AMST) is a validated paradigm measuring reaction times (RT) for processing auditory information while presenting task-irrelevant visual distractors of high or low salience. We extended the AMST by an emotional dimension of distractors and an EEG-based evaluation. We then investigated the effect of the stress-relieving medication Neurexan (Nx4) on the participants' susceptibility to distraction.Methods: Data from a randomized, placebo-controlled, crossover trial (NEURIM study; ClinicalTrials.gov: NCT02602275) were exploratively reanalyzed post-hoc. In this trial, 39 participants received a single dose of placebo or Nx4 immediately before the AMST. Participants had to discriminate two different tone modulations (ascending or descending) while simultaneously perceiving task-irrelevant pictures of different salience (high or low) or valence (negative or positive) as distractors. Using EEG recordings, RT and the event-related potential (ERP) components N1, N2, and N3 were analyzed as markers for susceptibility to distraction.Results: In the placebo condition, we could replicate the previously reported task effects of salient distractors with longer RT for high salient distractors on the behavioral level. On the electrophysiological level, we observed significantly increased amplitudes of the N2 and N3 ERP components for positive emotional pictures. In terms of drug effect, we found evidence that Nx4 reduced distractibility by emotional distractors. The effect was shown by significantly reduced amplitudes of N2 and N3 ERP components and reduced RT for the positive valence domain under Nx4 compared to placebo. The Nx4 effects on RT and ERP components also showed a significant correlation.Conclusion: Emotional distractors in addition to the previously used salience distractors and the EEG based evaluation of ERPs valuably complement the AMST. Salient distractors were affecting attentional processes earlier, while valent distractors show modulatory effects later. Our results suggest that Nx4 has beneficial effects on attention by inhibiting the effect of task-irrelevant information and reducing susceptibility to emotionally distracting stimuli. The observation of a beneficial impact of Nx4 on attention regulation is supportive of Nx4's claim as a stress-relieving medication.

Zolpidem Maintains Memories for Negative Emotions Across a Night of Sleep

Zolpidem, a common medication for sleep complaints, also shows secondary, unexpected memory benefits. We previously found that zolpidem prior to a nap enhanced negative, highly arousing picture memory. As zolpidem is typically administered at night, how it affects overnight emotional memory processing is relevant. We used a double-blind, placebo-controlled, within-subject, cross-over design to investigate if zolpidem boosted negative compared to neutral picture memory. Subjects learned both pictures sets in the morning. That evening, subjects were administered zolpidem or placebo and slept in the lab. Recognition was tested that evening and the following morning. We found that zolpidem maintained negative picture memory compared to forgetting in the placebo condition. Furthermore, zolpidem increased slow-wave sleep time, decreased rapid eye movement sleep time, and increased the fast spindle range in NREM. Our results suggest that zolpidem may enhance negative memory longevity and salience. These findings raise concerns for zolpidem administration to certain clinical populations.

Prospective memory deficits following acute alcohol consumption

Background: Prospective memory is a critical neurocognitive capacity that refers to the ability to execute delayed intentions. To date, few studies have investigated the effects of acute alcohol consumption on prospective memory, and important questions remain about the mechanisms that might underpin acute alcohol-induced prospective memory impairment. Aims: The current study sought to clarify the nature and magnitude of prospective memory difficulties following acute alcohol consumption and to test the degree to which any problems with prospective remembering might be a secondary consequence of broader cognitive impairment. This study also investigated whether there were potential sex differences. Methods: In all, 124 healthy adult social drinkers were assigned to either the alcohol ( n = 61) or placebo ( n = 63) condition. Participants were administered a dose of 0.6 g/kg alcohol or a matched placebo drink and then asked to complete a measure of prospective memory. A broader neurocognitive test battery was also administered. Results: Relative to the placebo condition, acute alcohol intoxication led to significant impairment on all prospective memory tasks, with effects mostly large in magnitude. These difficulties could not be explained by broader problems in retrospective memory, executive function or episodic future thinking. In addition, females recorded a higher blood alcohol concentration than males; however, no sex differences in prospective memory performance were identified following acute alcohol use. Conclusion: The results show that acutely, even a moderate dose of alcohol substantially impairs prospective memory function. These findings have potentially important implications for understanding many of the maladaptive behaviours associated with acute alcohol consumption.

Effects of Capsiate Supplementation on Maximal Voluntary Contraction in Healthy Men

This study aimed to investigate the effects of acute capsaicin analog (Capsiate - CAP) supplementation on maximal voluntary isometric contraction (MVIC) performance in healthy young men. Thirteen subjects (25.2±3.2 yrs) participated in the present study. In two different days separated by one week, the subjects ingested capsiate (12 mg) or placebo (starch: 12 mg) 45 minutes before a MVIC test. The MVIC test consisted of five 10-second knee extension maximal isometric contractions with 45 seconds of recovery between efforts. The peak force, mean force, minimum force, fatigue index, and area under the curve of each contraction were calculated. Main condition effect was found, with higher values of peak force (+4.83%, F=6.867, p=0.02), fatigue index (+8.96%, F=5.228, p=0.041), and area under the curve (+4.19%, F=4.774, p=0.04) for CAP compared to placebo, however, no interaction effect was found for any variable (F=0.090 to 1.356, p≥0.276). In summary, healthy young men produced higher maximal isometric force and delayed fatigue in the CAP condition compared to placebo condition (condition effect) but without significant difference between each effort.

Effects of the selective orexin-2 receptor antagonist JNJ-48816274 on sleep initiated in the circadian wake maintenance zone: a randomised trial

The effects of orexinergic peptides are diverse and are mediated by orexin-1 and orexin-2 receptors. Antagonists that target both receptors have been shown to promote sleep initiation and maintenance. Here, we investigated the role of the orexin-2 receptor in sleep regulation in a randomised, double-blind, placebo-controlled, three-period crossover clinical trial using two doses (20 and 50 mg) of a highly selective orexin-2 receptor antagonist (2-SORA) (JNJ-48816274). We used a phase advance model of sleep disruption where sleep initiation is scheduled in the circadian wake maintenance zone. We assessed objective and subjective sleep parameters, pharmacokinetic profiles and residual effects on cognitive performance in 18 healthy male participants without sleep disorders. The phase advance model alone (placebo condition) resulted in disruption of sleep at the beginning of the sleep period compared to baseline sleep (scheduled at habitual time). Compared to placebo, both doses of JNJ-48816274 significantly increased total sleep time, REM sleep duration and sleep efficiency, and reduced latency to persistent sleep, sleep onset latency, and REM latency. All night EEG spectral power density for both NREM and REM sleep were unaffected by either dose. Participants reported significantly better quality of sleep and feeling more refreshed upon awakening following JNJ-48816274 compared to placebo. No significant residual effects on objective performance measures were observed and the compound was well tolerated. In conclusion, the selective orexin-2 receptor antagonist JNJ-48816274 rapidly induced sleep when sleep was scheduled earlier in the circadian cycle and improved self-reported sleep quality without impact on waking performance.

The increase in urinary serotonin and decrease in salivary cortisol concentrations following direct inhalations of concentrated essential oils is not induced by non-specific effects

Objectives. The effectiveness of exogenously triggered serotonin (e.g., dietary supplements, drugs) increase is varied. However, since urinary serotonin concentrations were found to correlate with those in the cerebrospinal fluid, the olfactory system might be an efficient and testable pathway to quickly elevate serotonin levels due to its fast-acting central neurophysiological and peripheral pathways. However, little research has been devoted to investigate this assumption. This paper extends previous findings of parasympathetic activation of a specially designed essential oil inhaler (AromaStick® Balance) by experimentally testing its impact on urine serotonin and saliva cortisol excretion. Method. Two experiments involving healthy individuals were conducted to test the efficacy of essential oil application to the nose by employing different inhalation protocols and control conditions. Results. In the pilot study (n=8), serotonin urine excretion was increased after six inhalations (effect size Cohen’s d=0.7). In the second experiment (n=80), inhalations proved superior to both the natural control condition and the pseudo placebo condition after three and six inhalation cycles (0.6<d<1.8). In addition, there was a large reduction of cortisol saliva levels after three inhalations (d=0.9). Conclusion. Short and deep inhalations of essential oil scents directly delivered to the olfac-tory system appear to result in an enhanced serotonin and a reduced cortisol release in healthy individuals of both sexes.