Genetic variation in 5-hydroxytryptamine transporter expression causes adaptive changes in 5-HT₄ receptor levels

Genetic variation in 5-HT transporter (5-HTT) expression is a key risk factor for psychiatric disorder and has been linked to changes in the expression of certain 5-HT receptor subtypes. This study investigated the effect of variation in 5-HTT expression on 5-HT? receptor levels in both 5-HTT knockout (KO) and overexpressing (OE) mice using autoradiography with the selective 5-HT? receptor radioligand, [3H]SB207145. Compared to wild-type (5-HTT?/?) controls, homozygous 5-HTT KO mice (5-HTT?/?) had reduced 5-HT? receptor binding site density in all brain regions examined (35-65% of 5-HTT?/?). In contrast, the density of 5-HT? receptor binding sites was not significantly different between heterozygous 5-HTT KO mice (5-HTT?/?) and 5-HTT?/? mice. The 5-HT synthesis inhibitor p-chlorophenylalanine (250 mg/kg twice daily for 3 d) abolished the difference in 5-HT? binding between 5-HTT?/? and 5-HTT?/? mice in all brain regions. Compared to wild-type (WT) littermate controls, 5-HTT OE mice had increased 5-HT? binding density across all brain regions, except amygdala (118-164% of WT) and this difference between genotypes was reduced by the 5-HTT inhibitor, fluoxetine (20 mg/kg twice daily, 3 d). Together, these findings suggest that variation in 5-HTT expression causes adaptive changes in 5-HT? receptor levels which are directly linked to alterations in 5-HT availability.     

Language lateralization and cognitive control across the menstrual cycle assessed with a dichotic-listening paradigm

Lateralization has been shown to vary across the menstrual cycle, however, the underlying mechanisms are not fully understood, and results are inconsistent. Additionally, it has been suggested that estradiol enhances cognitive control. By modulating attention in a consonant-vowel dichotic listening test, the current study aims to investigate the effects of cycle-related changes on language lateralization (non-forced condition), as well as the effects of estradiol-modulated cognitive control (forced left condition) on the ear advantage. Fifteen women and fifteen men tested three times on the dichotic listening test, women once in menstrual, follicular, and luteal phase (verified by hormone assays). Whereas the results from the non-forced and forced-right condition remained stable, results from the forced left condition changed across the cycle, where women in the follicular phase compared to both menstrual and luteal phases showed a stronger left ear advantage, i.e. better cognitive control performance. The increase in performance from menstrual to follicular phase correlated negatively with increase in estradiol levels, indicating a shift from a stimulus-driven right ear advantage (indicating a left hemispheric asymmetry for language) when estradiol levels were low toward a cognitively controlled left ear advantage when estradiol levels were high. This finding strongly suggests an active role of estradiol on cognitive control. The study further suggests that the degree of cognitive control demands of a given task is important to consider when investigating lateralization across the menstrual cycle.     

Value of therapeutic drug monitoring in epilepsy

Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) has made it possible to study the individual variations in drug utilization, to reveal noncompliance in patients and for quality assurance aspects. Even if there is a shortage of data from randomized controlled studies concerning the effectiveness of using TDM as an aid to dosage adjustment, experience from nonrandomized investigations and long-lasting clinical experience have shown that TDM of both older and newer AEDs may be of clinical benefit if used appropriately. The main situations for TDM include: after starting treatment to provide a baseline steady-state concentration for further evaluation of an individual therapeutic concentration; after change in drug dosage, in particular when nonlinear kinetics apply; at therapeutic failure to sort out a pharmacokinetic explanation for uncontrolled seizures or side effects; in case of drug interactions; and when pharmacokinetic changes due to physiological or pathological changes are foreseen (e.g., age-dependent conditions [children, elderly], pregnancy, hepatic disease, renal disease or gastrointestinal conditions potentially affecting drug absorption) and change in drug formulation (brand name/generic). Recently, new terminology and definitions have been suggested by the International League Against Epilepsy. The reference range is a range of drug concentrations quoted by laboratories and is not a therapeutic range. Emphasis should be placed on the concept of an individual therapeutic concentration.     

The effect of sleep–wake intraindividual variability in digital cognitive behavioral therapy for insomnia: a mediation analysis of a large-scale RCT

Study ObjectivesDigital cognitive behavioral therapy for insomnia (dCBT-I) is an effective treatment for insomnia. However, less is known about mediators of its benefits. The aim of the present study was to test if intraindividual variability in sleep (IIV) was reduced with dCBT-I, and whether any identified reduction was a mediator of dCBT-I on insomnia severity and psychological distress.MethodsIn a two-arm randomized controlled trial (RCT), 1720 adults with insomnia (dCBT-I = 867; patient education about sleep = 853) completed the Insomnia Severity Index (ISI), the Hospital Anxiety and Depression Scale (HADS) and sleep diaries, at baseline and 9-week follow-up. Changes in IIV were analyzed using linear mixed modeling followed by mediation analyses of ISI, HADS, and IIV in singular sleep metrics and composite measures (behavioral indices (BI-Z) and sleep disturbance indices (SI-Z)).ResultsdCBT-I was associated with reduced IIV across all singular sleep metrics, with the largest between-group effect sizes observed for sleep onset latency (SOL). Reduced IIV for SOL and wake after sleep onset had the overall greatest singular mediating effect. For composite measures, SI-Z mediated change in ISI (b = −0.74; 95% confidence interval (CI) −1.04 to −0.52; 13.3%) and HADS (b = −0.40; 95% CI −0.73 to −0.18; 29.2%), while BI-Z mediated minor changes.ConclusionReductions in IIV in key sleep metrics mediate significant changes in insomnia severity and especially psychological distress when using dCBT-I. These findings offer important evidence regarding the therapeutic action of dCBT-I and may guide the future development of this intervention.Clinical trials Name: Overcoming Insomnia: Impact on Sleep, Health and Work of Online CBT-I Registration number: NCT02558647 URL: https://clinicaltrials.gov/ct2/show/NCT02558647?cond=NCT02558647&draw=2&rank=1     

Quality-of-life outcomes following topical melatonin application against acute radiation dermatitis in patients with early breast cancer: A double-blind,randomized, placebo-controlled trial

The aim of this double-blind, placebo-controlled, randomized study was to investigate whether topical melatonin administered during radiation therapy could increase the quality of life in patients with primary breast cancer. Patients were followed from the first radiation fraction until 3 weeks after the last. The patients applied 1 g of cream to the irradiated area of the skin twice daily, consisting of either 25 mg/g melatonin and 150 mg/g dimethyl sulfoxide, or a placebo cream. Outcomes were the European Organisation for Research and Treatment of Cancer's quality-of-life questionnaires for breast cancer (QLQ-C30 and QLQ-BR23) on the last day of radiation therapy. As a secondary outcome, we evaluated the breast symptom (BS) scores over the entire duration of the trial in a repeated measures linear model. We included 65 patients and had 17 drop-outs, thus totaling 26 and 22 patients in the melatonin and placebo groups, respectively. BS scores on the last day of radiation did not differ between groups (p = .333). However, the linear model analyzing BS for the entire duration showed that melatonin significantly decreased the symptoms (p = .001). There was no difference in the BS score on the last day of radiation, however, we found that the patients in the melatonin group had significantly lower BS scores over the entire duration of the trial.     

Effects of opium tincture on the enteric and central nervous systems: A randomized controlled trial

Opioids change gut motility, and opium tincture has been used for treatment of chronic diarrhoea for centuries. However, the effects have never been documented in controlled trials. We aimed to investigate the effects of opium tincture on gastrointestinal transit and motility, frequency of bowel movements, stool consistency, gastrointestinal symptoms and sedation. Twenty healthy subjects were included in this randomized controlled trial. Opium tincture or placebo was each applied for 9 days. Gastrointestinal transit and motility were investigated with the 3D-transit system. Bowel movements and gastrointestinal symptoms were recorded daily. General cognition, reaction time, memory and electroencephalography were used to assess effects on the central nervous system. Opium tincture doubled colonic transit (49 vs. 23 h, p < 0.001), decreased antegrade colonic movements (p < 0.05), reduced daily bowel movements (0.7 vs. 1.2, p < 0.001) and increased stool consistency (Type 3 vs. Type 4, p < 0.001). No changes in general cognition, reaction time or memory were observed, and minor changes of power observed by electroencephalography did not indicate sedation. This study is the first to show that opium tincture has anti-propulsive properties in the healthy gut, while no sedative effects were seen. This indicates that opium tincture is a relevant and safe treatment option in chronic diarrhoea.