Rationale: 3,4-Methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD, particularly in treatment-resistant patients. However, given MDMA’s broad pharmacological profile, further investigation is warranted before moving to a complex clinical population. Objectives: We aimed to inform clinical research by providing a translational model of MDMA’s effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction. Methods: We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training. Results: MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA’s effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA’s effect by 5-HTT inhibition also downregulated 5-HT2A-mediated behavior, and 5-HT2Aantagonism disrupted MDMA’s effect on extinction. Conclusions: We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT2Areceptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.
Introduction: Throughout the world, anxiety disorders are 1.5-2 times more prevalent among women than men but the reasons for this gender disparity remain elusive. Despite frequent attribution to cultural roles of men and women, data regarding gendered risk factors in non-Western settings are scant. Aims: This study evaluated the role of gender as a moderator (effect modifier) of stressful life events (SLEs) and social support on the risk of anxiety in Nepal. A cross-sectional random sampling design was employed to recruit 316 persons in a rural community. The participants completed the Beck Anxiety Inventory (BAI), Stressful Life Events Rating Scale (SLERS), and a measure of social support. Results: The prevalence of anxiety differed by gender: 36.9% of women versus 20.4% of men endorsed anxiety symptoms above the validated cutoff for intervention (odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.4-3.8). The number of SLEs and levels of social support did not differ by gender, nor did gender moderate the relationship between SLEs and anxiety. Gender did moderate the relationship of social support with anxiety. Men who reported low social support had 3.5 times greater odds (95% CI = 1.4-10.7) of endorsing anxiety relative to men reporting high social support. Women exhibited no association of anxiety with social support. Conclusion: Women are at a greater risk of anxiety in Nepal. Social support moderates the risk of anxiety among men but not among women. Ethnography and mixed-methods research are needed to identify other forms of support that may be protective for women and such factors should be promoted in gender-focused mental health interventions.
Stroke is a leading cause of death that affects 15 million people worldwide each year. Increasing evidence suggests that stroke confers substantial risk for suicide and following a stroke, patients frequently develop poststroke depression, which is a well-established risk factor for suicide. In this overview of the current literature, we examined the association between suffering a stroke and subsequent risk for suicide and suicidal ideation. We performed a careful MedLine, Excerpta Medica, PsycLit, PsycInfo, and Index Medicus search to identify all articles and book chapters in English. We initially selected 31 articles published between 1990 and 2011; however, only 16 studies were included in this review. All articles identified stroke as a significant risk factor for suicide, especially among depressed patients, providing further support for poststroke depression and suicidality. The results also indicated that there were differences between patients who developed acute-onset suicidal plans and those who reported delayed-onset plans, which occurred more frequently. Many of the stroke patients who died by suicide suffered from depression prior to their death, suggesting that being diagnosed with a mood disorder contributes to an increased risk of suicide in this population. Suffering from a stroke increases the risk of dying by suicide and developing suicidal ideation, particularly in young adults and women. The factors found to confer the most risk for suicidality were depression, previous mood disorder, prior history of stroke, and cognitive impairment.
by
Sanjay J. Mathew;
Meena Vythilingam;
James W. Murrough;
Carlos A. Zarate;
Adriana Feder;
David A. Luckenbaugh;
Becky Kinkead;
Michael K. Parides;
David G. Trist;
Massimo S. Bani;
Paolo U. Bettica;
Emiliangelo M. Ratti;
Dennis S. Charney
The substance P-neurokinin-1 receptor (SP-NK1R) system has been extensively studied in experimental models of stress, fear, and reward. Elevated cerebrospinal fluid (CSF) SP levels were reported previously in combat-related PTSD. No medication specifically targeting this system has been tested in PTSD. This proof-of-concept randomized, double-blind, placebo-controlled trial evaluated the selective NK1R antagonist GR205171 in predominately civilian PTSD. Following a 2-week placebo lead-in, 39 outpatients with chronic PTSD and a Clinician-Administered PTSD Scale (CAPS) score ≥50 were randomized to a fixed dose of GR205171 (N=20) or placebo (N=19) for 8weeks. The primary endpoint was mean change from baseline to endpoint in the total CAPS score. Response rate (≥50% reduction in baseline CAPS) and safety/tolerability were secondary endpoints. CSF SP concentrations were measured in a subgroup of patients prior to randomization. There was significant improvement in the mean CAPS total score across all patients over time, but no significant difference was found between GR205171 and placebo. Likewise, there was no significant effect of drug on the proportion of responders [40% GR205171 versus 21% placebo (p=0.30)]. An exploratory analysis showed that GR205171 treatment was associated with significant improvement compared to placebo on the CAPS hyperarousal symptom cluster. GR205171 was well-tolerated, with no discontinuations due to adverse events. CSF SP concentrations were positively correlated with baseline CAPS severity. The selective NK1R antagonist GR205171 had fewer adverse effects but was not significantly superior to placebo in the short-term treatment of chronic PTSD.
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Amitai Abramovitch;
Lauren S. Hallion;
Hannah E. Reese;
Douglas W. Woods;
Alan Peterson;
John T. Walkup;
John Piacentini;
Lawrence Scahill;
Thilo Deckersbach;
Sabine Wilhelm
Tourette's disorder (TS) and chronic tic disorder (CTD) are neurodevelopmental disorders characterized by involuntary vocal and motor tics. Consequently, TS/CTD have been conceptualized as disorders of cognitive and motor inhibitory control. However, most neurocognitive studies have found comparable or superior inhibitory capacity among individuals with TS/CTD relative to healthy controls. These findings have led to the hypothesis that individuals with TS/CTD develop increased inhibitory control due to the constant need to inhibit tics. However, the role of cognitive control in TS/CTD is not yet understood, particularly in adults. To examine the role of inhibitory control in TS/CTD, the present study investigated this association by assessing the relationship between inhibitory control and treatment response in a large sample of adults with TS/CTD. As part of a large randomized trial comparing behavior therapy versus supportive psychotherapy for TS/CTD, a battery of tests, including tests of inhibitory control was administered to 122 adults with TS/CTD at baseline. We assessed the association between neuropsychological test performance and change in symptom severity, as well as compared the performance of treatment responders and non-responders as defined by the Clinical Global Impression Scale. Results indicated that change in symptoms, and treatment response were not associated with neuropsychological performance on tests of inhibitory control, intellectual ability, or motor function, regardless of type of treatment. The finding that significant change in symptom severity of TS/CTD patients is not associated with impairment or change in inhibitory control regardless of treatment type suggests that inhibitory control may not be a clinically relevant facet of these disorders in adults.
Depression and psychostimulant addiction are co-morbid conditions; depression is a significant risk factor for psychostimulant abuse, and the rate of depression in drug addicts is higher than in the general population. Despite the prevalence of this comorbidity, there are few animal models examining psychostimulant abuse behaviors in depression. We have shown previously that while rats selectively bred for depression-like phenotypes (SwLo) have blunted mesolimbic dopamine (DA) signaling and locomotor responses to dopaminergic drugs, they voluntarily administer excessive amounts of psychostimulants compared to normal or depression-resistant (SwHi) rats in oral consumption paradigms. To determine whether this increased drug intake by depression-sensitive rats extends to operant self-administration, we assessed fixed ratio-1, progressive ratio, extinction, and reinstatement responding for cocaine and amphetamine in SwLo and SwHi rats. Contrary to the oral consumption results, we found that the SwHi rats generally responded more for both cocaine and amphetamine than the SwLo rats in several instances, most notably in the progressive ratio and reinstatement tests. Food-primed reinstatement of food seeking was also elevated in SwHi rats. These results provide further insight into the neurobiology of depression and addiction comorbidity and caution that oral and operant psychostimulant self-administration paradigms can yield different, and this case, opposite results.
Background: While the impact of active maternal smoking during pregnancy on child health has been well investigated, the association between maternal passive smoking, or environmental tobacco smoke (ETS), or second-hand smoke, and behavioral development of offspring is less clear. This study examines the association between maternal ETS exposure during pregnancy and child behavior problems. Methods: Cross-sectional data of 646 mother-child pairs from the Jintan China Cohort Study were used in the analyses. Mother's exposure to tobacco smoking at home, the workplace, and other places during pregnancy (for the determination of maternal ETS exposure) and children's behaviors (via Child Behavior Checklist) were assessed when the children were 5-6 years old. Logistic regression models were constructed to examine associations between maternal exposure to ETS during pregnancy and internalizing and externalizing behavior problems, adjusting for potential cofounders including child sex and parental characteristics. Results: 37% of mothers reported ETS during pregnancy. Children of mothers exposed to ETS during pregnancy had higher scores for externalizing and total behavior problems, with 25% of children whose mothers were exposed to ETS compared to 16% of children of unexposed mothers. After adjusting for potential confounders, ETS exposure was associated with a higher risk of externalizing behavior problems in offspring of exposed mothers (OR = 2.08, 95% confidence interval [CI] 1.27-3.43). Analysis after multiple imputations and sensitivity analysis further verified the association, but no dose-response relationship was found. ETS exposure, however, was not associated with internalizing or total behavior problems. Conclusion: This study suggests that maternal ETS exposure during pregnancy may impact child behavioral development, particularly externalizing behaviors.