BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism

Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.     

Sex Modulates the Interactive Effect of the Serotonin Transporter Gene Polymorphism and Childhood Adversity on Hippocampal Volume

The common genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been related to depressive symptoms, in particular after stressful life events. Although it has been investigated in the past, results suggesting that the 5-HTTLPR genotype also affects hippocampal volume are often inconsistent and it remains unclear to what extent reduced hippocampal volume is influenced by the effect of stressful life events and 5-HTTLPR genotype. Moreover, sex, which is known to affect the prevalence of depression substantially, has not been taken into account when trying to disentangle the interactive effect of common genetic variation and environmental stressors on the hippocampus. We investigated this potentially relevant three-way interaction using an automatic magnetic resonance imaging (MRI)-based segmentation of the hippocampus in 357 healthy individuals. We determined the 5-HTTLPR genotype as a biallelic locus and childhood adversity (CA) using a standard questionnaire. An interaction for hippocampal volume was found between the factors sex, genotype, and severe CA (p=0.010) as well as an interaction between genotype and severe CA (p=0.007) in men only. Post hoc tests revealed that only male S''-allele carriers with severe CA had smaller hippocampi (p=0.002). Interestingly, there was no main effect of genotype in men, while female S''-allele carriers had smaller hippocampi than L''L'' carriers (p=0.023). Our results indicate that sex modulates the interactive effect of the 5-HTTLPR genotype and CA on hippocampal volume. While the S''-allele is associated with hippocampal volume independent of CA in women, men only have smaller hippocampi if they carry the risk allele and experienced severe CA.     

Systematic review and meta-analysis of serotonin transporter genotype and discontinuation from antidepressant treatment

There is evidence that 5-HTTLPR is associated with response following treatment from selective serotonin reuptake inhibitors (SSRIs). The short (S) allele has reduced serotonin transporter expression, compared to the long (L) allele, and has been reported to be associated with poorer response in Europeans, with the effect in other populations unclear. However the published literature is inconsistent. A systematic review and meta-analysis was performed to investigate the effect of 5-HTTLPR on discontinuation from antidepressant treatment. Data were obtained from 17 studies including 4309 participants. The principal outcome measure was the allelic odds ratio (OR) for the 5-HTTLPR S allele and discontinuation status. A random effects meta-analysis provided no evidence that the S allele was associated with increased odds of discontinuation from SSRIs in Europeans (OR 1.09, 95% CI 0.83–1.42, p=0.53; 10 studies, n=2504) but in East Asians there was evidence of a reduced odds of discontinuation (OR 0.28, 95% CI 0.12–0.64, p=0.002; 2 studies, n=136). There was a suggestion of small study bias (p=0.05). This meta-analysis provides no evidence of an association between 5-HTTLPR and discontinuation from antidepressant treatment in Europeans. The low number of studies in East Asian samples using SSRIs reduces confidence in our evidence that the S allele decreases the odds of discontinuation in this population. At present, there is no evidence of an association between 5-HTTLPR and discontinuation from SSRI treatment in a European population with further studies required to investigate its effects in different populations.     

Interaction Between 5-HTTLPR Genotype and Cognitive Stress Vulnerability on Sleep Quality: Effects of Sub-Chronic Tryptophan Administration

Background:

Abundant evidence suggests that allelic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR) influences susceptibility to stress and its affective consequences due to brain serotonergic vulnerability. Based on recent assumptions, the present study examined whether the 5-HTTLPR genotype may also interact with a vulnerability to chronic stress experience (conceptualized by trait neuroticism) in order to influence sleep quality and, additionally, whether this is influenced by brain serotonergic manipulations.

Methods:

In a well-balanced experimental design, homozygous S-allele (n = 57) and L-allele (n = 54) genotypes with high and low chronic stress vulnerability (neuroticism) were first assessed for general past sleep quality during a month before onset of the experiment. Then subjects were assessed for sleep quality following 7 days of tryptophan (3.0g/day) or placebo intake.

Results:

Although high neuroticism was significantly related to a higher frequency of stressful life events and daily hassles, it did not interact with the 5-HTTLPR genotype on general past sleep quality. However, as expected, a 7 day period of tryptophan administration was exclusively associated with better sleep quality scores in the S’/S’ genotype with high trait neuroticism.

Conclusions:

Current findings suggest that 5-HTTLPR does not directly interact with stress vulnerability in order to influence sleep quality. Instead, based on current and previous findings, it is suggested that the S’/S’ 5-HTTLPR genotype promotes the risk for stress-related sleep disturbances because of an increased susceptibility to the depressogenic consequences of stress. Accordingly, by way of reducing depressive symptomatology, tryptophan augmentation may particularly improve sleep quality in stress-vulnerable individuals carrying the 5-HTTLPR S-allele.     

Prefrontal serotonin transporter availability is positively associated with the cortisol awakening response

Stress sensitivity and serotonergic neurotransmission interact, e.g. individuals carrying the low-expressing variants (S and L_G) of the 5-HTTLPR promoter polymorphism of the serotonin transporter (SERT) gene are at higher risk for developing mood disorders when exposed to severe stress and display higher cortisol responses when exposed to psychosocial stressors relative to high expressing 5-HTTLPR variants. However, it is not clear how the relation between SERT and cortisol output is reflected in the adult brain. We investigated the relation between cortisol response to awakening (CAR) and SERT binding in brain regions considered relevant to modify the cortisol awakening response. Methods: thirty-two healthy volunteers underwent in vivo SERT imaging with [¹¹C]DASB-Positron Emission Tomography (PET), genotyping, and performed home-sampling of saliva to assess CAR. Results: CAR, defined as the area under curve with respect to increase from baseline, was positively coupled to prefrontal SERT binding (p=0.02), independent of adjustment for 5-HTTLPR genotype. Although S- and L_G-allele carriers tended to show a larger CAR (p=0.07) than L_A homozygous, 5-HTTLPR genotype did not modify the coupling between CAR and prefrontal SERT binding as tested by an interaction analysis (genotype×CAR). Conclusion: prefrontal SERT binding is positively associated with cortisol response to awakening. We speculate that in mentally healthy individuals prefrontal serotonergic neurotransmission may exert an inhibitory control on the cortisol awakening response.     

The effect of COMT Val158 Met genotype on decision-making and preliminary findings on its interaction with the 5-HTTLPR in healthy females

Poor decision-making is inherent to several psychiatric conditions for which a genetic basis may exist. We previously showed that healthy female volunteers homozygous for the short allele (s/s) of the serotonin transporter length polymorphic region (5-HTTLPR) chose more often cards from disadvantageous decks in the Iowa Gambling Task (IGT), which measures decision-making, than long (l) allele carriers. The 5-HTTLPR and catechol-O-methyltransferase (COMT) Val¹⁵⁸ Met polymorphism affect the same set of neuronal structures. Therefore, we explored the effect of the (COMT) Val¹⁵⁸ Met polymorphism on IGT performance and its interaction with the 5-HTTLPR in the same subjects in this study. We observed that subjects homozygous for methionine (Met/Met) chose more disadvantageously than subjects homozygous for valine (Val/Val). s/s-Met/Met-subjects appeared to show the poorest IGT performance of all possible combinations of 5-HTTLPR and COMT allelic variants. Using the Expectancy-Valence model, no differences were found for the three different 5-HTTLPR or COMT genotypes regarding (i) attention to wins versus losses, (ii) updating rate, or (iii) response consistency. However, subjects with at least one Met-allele were paying more attention to wins than subjects with no Met-alleles. We discuss whether a common neuronal mechanism relates to s- and Met-allele-related deficits in updating and/or processing of choice outcome to guide subsequent choices in this gamble-based test.     

Associations between coping,affect, and social support among low-income African American smokers

Objective

Previous research has documented disparities in smoking cessation between African Americans and Caucasians. Many low-income African American smokers face a range of circumstances that may inhibit effective coping during quit attempts, yet previous research has not considered factors that influence coping in this population. This study examined (a) affect (positive and negative) and (b) perceived social support in association with coping strategies.

Methods

The baseline assessment of African American smokers (N = 168) enrolled in a randomized controlled trial included the Positive and Negative Affect Schedule, the Multidimensional Scale of Perceived Social Support, and the Brief COPE. A factor analysis of the Brief COPE resulted in two factors, adaptive and maladaptive strategies.

Results

Participants were mostly single (64%), women (61%), with ≥ 12 years of education (68%), and low-income. They were middle aged (M = 46.1, SD = 8.7), smoked 21.8 (SD = 13.3) cigarettes/day for 24.3 (SD = 11) years, and were moderately nicotine dependent. Results demonstrated that adaptive coping was positively correlated with positive affect and social support. Maladaptive coping was positively correlated with negative affect, and inversely related to positive affect and social support. Multivariate analyses revealed that positive affect and social support were independently associated with adaptive coping strategies. In contrast, maladaptive coping was independently associated with negative affect, but not social support.

Conclusions

Interventions that harness positive resources, such as social support and positive mood, may facilitate adaptive coping. Also, addressing negative affect among low-income African American smokers may be important to reduce maladaptive coping strategies.     

Smoking moderates association of 5-HTTLPR and in vivo availability of serotonin transporters

Although preclinical studies clearly indicate an effect of 5-HTTLPR genotype on 5-HT transporter (5-HTT) expression, studies in humans provided inconclusive results, hypothetically due to environmental factors and differences in individual behavior. For example, nicotine and other constituents of tobacco smoke elevate serotonin (5-HT) levels in the brain and may thereby cause homeostatic adaptations in 5-HTT availability that moderate effects of 5-HTTLPR genotype. To test whether 5-HTT availability in the midbrain is affected by smoking status and 5-HTTLPR genotype, we pooled data from prior studies on in vivo 5-HTT availability (BP_ND) measured with positron emission tomography (PET) and [¹¹C]DASB. In total, we reanalyzed 5-HTT availability in 116 subjects using ANCOVA statistics. ROI analysis revealed that current smokers and non-smokers do not differ in midbrain BP_ND. Interestingly, smoking status significantly interacted with 5-HTTLPR genotype: active smoking was associated with reduced 5-HTT availability only in LL subjects but not in carriers of the S-allele. From the perspective of genotype effects, non-smokers showed the expected association with 5-HTTLPR, i.e. higher 5-HTT availability in LL subjects compared to carriers of the S-allele, whereas this pattern was actually reversed for active smokers. Our study indicates that smoking status moderates the association of 5-HTTLPR genotype and 5-HTT expression, which may help to explain inconsistent findings in previous studies. Regarding the mechanism, we suggest that smoking may induce epigenetic processes such as methylation of SLC6A4, which can differ depending on its genetic constitution.     

Differential Effects of 5-HTTLPR Genotypes on Inhibition of Negative Emotional Information Following Acute Stress Exposure and Tryptophan Challenge

Previous data suggest that a polymorphism at the serotonin (5-HT) transporter gene (5-HTTLPR) may influence stress resilience and stress-related depression symptoms due to interactions between brain 5-HT dysfunction and stress exposure. Although attentional bias for emotional information has been reliably observed in depression, the interaction between 5-HT transporter-linked promoter region (5-HTTLPR), brain 5-HT vulnerability, and acute stress on affective information processing has not yet been investigated. This study examines the effects of tryptophan (TRP) augmentation (indicating 5-HT manipulation) on inhibition of negative emotional information under stress in mainly female S′/S′- vs L′/L′-allele carriers. A total of 15 female homozygotic short-allele 5-HTTLPR (S′/S′=S/S, S/L_G, L_G/L_G) and 13 female homozygotic long-allele 5-HTTLPR (L′/L′=L_A/L_A) subjects were tested for mood and inhibition of emotional information in a double-blind, placebo-controlled design before and after stress exposure following TRP manipulation. Stress exposure significantly impaired inhibition of negative affective information only in S′/S′ carriers, whereas L′/L′ carriers even showed increased inhibition of negative information. The S′/S′ allele 5-HTTLPR genotype increases cognitive-attentional bias for negative emotional information under acute stress. As this bias is an important component of depression, this may be a mediating mechanism making S′/S′-allele carriers more vulnerability for stress-induced depression symptoms. Moreover, current data suggest that L′/L′-allele genotypes are more resilient, even increasing cognitive emotional (inhibitory) control after stress.     

The impact of sleep and psychiatric symptoms on alcohol consequences among young adults

ObjectiveIndependent lines of research have documented links between psychiatric symptoms and poor sleep quality, psychiatric symptoms and alcohol use, and alcohol use and poor sleep quality. The current study examined the synergistic effect of poor sleep quality and psychiatric symptoms on alcohol-related consequences in heavy-drinking young adults.MethodMatriculating college students reporting at least one heavy drinking episode over the first nine weeks of the semester (N = 385, 52% female) were categorized as experiencing ‘good’ (n = 280) versus ‘poor’ sleep quality (n = 105) and screening ‘positive’ (n = 203) or ‘negative’ (n = 182) for a psychiatric disorder. Sleep quality was assessed using the Pittsburgh Sleep Quality Index; psychiatric diagnosis was assessed using the Psychiatric Diagnostic Screening Questionnaire; and alcohol-related consequences were assessed using the Brief Young Adult Alcohol Consequences Questionnaire. General linear models were used to examine the main effects and interaction between sleep quality and psychiatric symptoms on alcohol-related consequences.ResultsSleep quality moderated the association between psychiatric screen and alcohol-related consequences among heavy-drinking college students, such that psychiatric symptoms were associated with more alcohol-related consequences in the context of poor sleep quality.ConclusionsThe combination of poor sleep quality and psychiatric symptoms is associated with increased alcohol-related consequences among heavy-drinking college students. Given the significant interaction between these symptoms, healthcare providers are encouraged to screen for the presence of sleep and psychiatric disorders among heavy-drinking young adults and to provide empirically-supported treatments as appropriate.     

Three-way interaction effect of 5-HTTLPR,BDNF Val66Met,and childhood adversity on depression: A replication study

Both the serotonin transporter linked promoter region (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms have been shown to interact with unfavourable environment in relation to depression symptoms and to depression diagnosis. Several attempts have been made to study a three-way interaction effect of these factors on depression, however with contradictory results. We aimed to test the hypothesis of a three-way interaction effect and to attempt at replication in an independent population-based sample. Family maltreatment, sexual abuse and depression were self-reported by an adolescent population-based cohort (N=1393) from the county of Västmanland, Sweden. DNA was isolated from saliva, and used for genotyping of the 5-HTTLPR and BDNF Val66Met polymorphisms. Neither 5-HTTLPR or BDNF genotypes separately, nor in interaction with each other had any relation to depression, however in an environment adjusted model a two-way interaction and a three-way interaction effect was found. Both 5-HTTLPR and BDNF Val66Met interacted with unfavourable environment in relation to depressive symptoms (Adj R²=0.19). Depressive symptoms and depression were more common among carriers of either the ss/sl+Val/Val or the ll+Met genotypes in the presence of early-life adversities. This three-way effect was more pronounced among girls. The current study, with a virtually similar set-up compared to previous studies, can partially confirm previous findings and their generalizability. The study also shows the importance of genetic plasticity in individuals with different environmental exposure, for different phenotypic expression.     

BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: A prospective study

Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val⁶⁶Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val⁶⁶Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val⁶⁶Met and 5-HTTLPR genotype.     

Evidence of a role for the 5-HTTLPR genotype in the modulation of motor response to antidepressant treatment

Rationale Serotonergic mechanisms are thought to play an important role in the regulation of mood, motor activity and sleep patterns. Serotonin reuptake is controlled by the serotonin transporter (5-HTT) and by a common functional insertion/deletion polymorphism in the corresponding genes promoter region (5-HTTLPR). Homozygosity for the long variant may confer a favourable response to treatment with serotonin reuptake inhibitors (SSRIs), and to sleep deprivation.Objectives The study assessed the role of the 5-HTTLPR genotype in determining motor side effects of antidepressant medication.Methods Motor activity patterns of 62 patients with major depression who were being treated with either SSRIs or tricyclic antidepressants (TCAs) were monitored over a 24-h period using a wrist-actograph. Additionally, motor activity was rated in a semi-structured interview using the motor agitation and retardation scale (MARS).Results Night-time motor activity was significantly increased in homozygous carriers of the long 5-HTTLPR allele (LL-genotype) who were being treated with SSRIs in comparison to short allele carriers (LS-genotype and SS-genotype), regardless of the type of antidepressant treatment (P<0.001). It was also significantly increased in comparison to patients with the LL-genotype who were being treated with TCAs (P<0.01). Differences in actographic motor activity were most prominent between 11 p.m. and 4 a.m. Clinical ratings of motor activity also showed a trend toward higher agitation scores in patients with the LL-genotype who received SSRI treatment.Conclusions Homozygosity for the long variant of the 5-HTTLPR may cause a predisposition to increased night-time motor activity in conjunction with SSRI treatment.     

Effects of caffeinated vs. non-caffeinated alcoholic beverage on next-day hangover incidence and severity,perceived sleep quality,and alertness

Aims

Beliefs about the effects of mixing caffeine and alcohol on hangover or sleep may play a role in motivation to consume these mixtures; therefore, information is needed about actual effects. We investigated whether intoxication with caffeinated vs. non-caffeinated beer differentially affected perceived sleep quality, sleepiness, and hangover incidence and severity the next morning.

Methods

University students (89%) and recent graduate drinkers were randomized to receive: (1) beer with the equivalent of 69 mg caffeine/12 oz glass of regular beer (n = 28) or (2) beer without caffeine (n = 36), in sufficient quantity to attain a BrAC of 0.12 g%. After an 8-h supervised sleep period, participants completed measures of hangover, sleep quality, sleep latency and time asleep, and sleepiness.

Results

While caffeinated beer improved perceived sleep quality, effect sizes were greater for morning alertness than for quality while sleeping, with no effect on sleep latency or total sleep time. No effects were seen on hangover incidence or severity.

Conclusions

Mixing caffeine and alcohol does not significantly impair amount of sleep or sleep latency, hangover, or sleepiness the morning after drinking to intoxication in this population.     

Affect and craving: Positive and negative affect are differentially associated with approach and avoidance inclinations

Background

Research on reactivity to alcohol and drug cues has either ignored affective state altogether or has focused rather narrowly on the role of negative affect in craving. Moreover, until recently, the relevant analyses of affect and craving have rarely addressed the ambivalence often associated with craving itself. The current study investigated how both negative and positive affect moderate approach and avoidance inclinations associated with cue-elicited craving in a clinical sample diagnosed with substance use disorders.

Methods

One hundred forty-four patients (age range of 18–65, mean 42.0; n = 92 males) were recruited from an inpatient detoxification unit for substance abuse. Participants completed a baseline assessment of both positive and negative affect prior to completing a cue-reactivity paradigm for which they provided self-report ratings of inclinations to approach (use) and avoid (not use) alcohol, cigarettes, and non-psychoactive control substances (food and beverages).

Results

Participants with elevated negative affect reported significantly higher approach ratings for cigarette and alcohol cues, whereas those high in positive affect showed significantly higher levels of avoidance inclinations for both alcohol and cigarette cues and also significantly lower approach ratings for alcohol cues, all relative to control cues.

Conclusions

Results for negative affect are consistent with previous cue reactivity research, whereas results for positive affect are unique and call attention to its clinical potential for attenuating approach inclinations to substance use cues. Further, positive affect was related to both approach and avoidance inclinations, underscoring the utility of a multidimensional conceptualization of craving in the analysis.     

Sex differences in sleep and sleep-dependent learning in abstinent cocaine users

Sleep and sleep-dependent learning are impaired in male cocaine users during abstinence, but for female users little is known. Cocaine dependent men (n = 12) and women (n = 14), and control participants (n = 19) participated in this study of sleep and sleep-dependent learning. Cocaine users were assessed at 3, 10 and 20 days of abstinence and controls were studied over one night. Total sleep time, sleep efficiency and overnight motor learning were the main outcome measures. Cocaine dependent men compared to women exhibited deteriorations in sleep time, sleep efficiency, and overnight learning as abstinence progressed from 3 to 20 days. At abstinence day 3, cocaine dependent men and women were no different than control participants in the main outcomes. However, there were significant differences between cocaine men at abstinence day 20 and controls in sleep time and sleep-dependent learning, but no differences between controls and cocaine dependent women. There is growing evidence that sleep disturbances are associated with cocaine abuse and abstinence and have functional consequences that may be relevant to the development of effective treatments. The absence of sleep disturbances in women suggests a need to understand the mechanisms underlying these differences, as such knowledge could lead to novel therapies in cocaine dependence.     

Effect of diazepam and fosazepam (a soluble derivative of diazepam) on sleep in man

1 The effect of diazepam (5 mg and 10 mg), and fosazepam (60 mg and 80 mg), a soluble derivative of diazepam, on sleep was studied in six healthy adult males using electroencephalography for sleep measures, and analogue scales for subjective assessments of well-being and sleep quality. The effect of diazepam was limited to the night of ingestion, but the effect of fosazepam was carried over to the next night and so modified sleep for about 30 h after ingestion.

2 Effects on total sleep time were limited to the night of ingestion. There were increases with diazepam (10 mg) (P = 0.05), and with fosazepam (60 mg and 80 mg) (P = 0.001). For the night of ingestion sleep onset latencies were shortened, and awakenings were reduced by both drugs. The latency to stage 3 was shortened by fosazepam (60 mg and 80 mg) (P = 0.05).

3 The low and high dose of each drug reduced the duration (min) of stage 0 sleep (P = 0.01), but fosazepam also reduced the duration (min) of stage 1 sleep (P = 0.001), and there was an increase in stage 2 sleep (P = 0.01). With fosazepam there were carry over effects to the next night with reduction of stage 1 sleep (P = 0.05). There were no effects on the duration of stage 3, but there was evidence that stage 4 activity was reduced during the recovery night after ingestion of fosazepam (80 mg). No effects were observed on REM sleep.

4 Subjects reported an improved sense of well-being during the day after ingestion of diazepam and fosazepam, and with fosazepam they reported improved sleep. Correlations were calculated for sleep measures and subjective assessments.

     

Comparative effects of duloxetine and desipramine on sleep EEG in healthy subjects

Rationale Antidepressants are known to modify human sleep patterns.Objectives Duloxetine is a new antidepressant with a mechanism of action involving reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE). In this study, the effects of two dosing regimens of duloxetine on sleep electroencephalography (EEG) were investigated at steady-state plasma concentrations in young, healthy, male subjects.Methods Placebo (n=12), desipramine (50 mg BID; n=12) and two regimens of duloxetine (80 mg QD, n=6; or 60 mg BID, n=6) were compared in a randomized, double-blind, three-period crossover study, each treatment being administered from day 1 to day 7. Sleep polygraphic recordings took place at baseline (day –1) and day 6 of each period. The Leeds sleep evaluation questionnaire (LSEQ) was also administered on the morning of day 7.Results Both regimens of duloxetine produced a significant increase in the onset latency of REM sleep as well as a significant mean decrease in total REM sleep duration. Desipramine exhibited comparable effects. When compared to placebo, sleep continuity was significantly reduced with desipramine and duloxetine 60 mg BID whereas a significant improvement was observed with duloxetine 80 mg QD. On the LSEQ, duloxetine 80 mg QD produced a significant improvement in the getting to sleep subscale compared to placebo, whereas desipramine demonstrated a significant reduction (worsening) in the quality of sleep score versus placebo.Conclusions The two dose regimens of duloxetine (80 mg QD and 60 mg BID) produced a REM sleep pattern comparable to that of most antidepressant medications. Duloxetine 80 mg QD appeared to exhibit less impact upon sleep quality than duloxetine 60 mg BID in healthy subjects.     

Topiramate treatment for alcoholic outpatients recently receiving residential treatment programs: A 12-week,randomized, placebo-controlled trial

Background

Initiation of a relapse prevention medication is crucial at the end of alcohol detoxification. This study aimed to examine the efficacy and safety of topiramate for alcoholism in patients receiving a residential treatment program of alcohol detoxification and post-acute treatment.

Methods

This was a 12-week, randomized, double-blind, placebo-controlled trial of topiramate for alcoholism in patients receiving a residential treatment program. Individuals with DSM-IV alcohol dependence with minimal withdrawal were enrolled. Participants were randomly assigned to receive either 100–300 mg/day of topiramate or placebo. Primary outcomes were given as percentages of heavy drinking days and time to first day of heavy drinking. Other drinking outcomes, craving, and health-related quality of life were evaluated.

Results

A total of 106 participants were randomized to receive topiramate (n = 53) or placebo (n = 53). Twenty-eight participants of the topiramate group (52.8%) and 25 participants of the placebo group (47.2%) completed the study. Averaged over the trial period, there was no significant difference between groups on the mean percentages of heavy drinking days [1.96 (−1.62 to 5.54), p = .28]. Log rank survival analysis found no difference of time to first day of heavy drinking between topiramate and placebo groups (61.8 vs. 57.5 days, respectively; χ² = 0.61, d.f. = 1, p = .81). Other secondary outcomes were not significantly different between groups.

Conclusions

By using a conservative model for data analysis, we could not detect the effectiveness of topiramate in this particular population. As the sensitivity analysis showed a trend of its benefit, further studies in larger sample sizes are still warranted.