Platelet Serotonin Signaling in Patients With Cardiovascular Disease and Comorbid Depression.

OBJECTIVE: Depression in patients with cardiovascular disease is associated with increased risk of adverse clinical outcomes. Investigators have searched for potential biobehavioral explanations for this increased risk. Platelet activation and response to serotonin is an attractive potential mechanism. The aim of the study was to examine platelet serotonin signaling in a group of patients with coronary artery disease (CAD) and comorbid depression to define the relationship between platelet serotonin signaling and cardiovascular complications. METHODS: A total of 300 patients with CAD were enrolled (145 with acute coronary syndrome and 155 with stable CAD). Depression was assessed using the Structured Clinical Interview for DSM-IV as well as Beck Depression Inventory II in a dichotomous and continuous manner. Platelet serotonin response was measured by serotonin augmented aggregation, direct platelet serotonin activation, platelet serotonin receptor density, and platelet serotonin uptake. Cardiovascular outcomes were assessed at 12-month follow-up. RESULTS: One third of enrolled participants had at least minimal depressive symptoms and 13.6% had major depressive disorder. Depressed cardiovascular patients had significantly higher incidence of major (odds ratio = 3.43, 95% confidence interval = 1.49-7.91, p = .004) and minor (odds ratio = 2.42, 95% confidence interval = 1.41-4.13, p = .001) adverse cardiac events. Platelet serotonin response was not significantly different in patients with depression. Participants with major depressive disorder had higher serotonin receptor density (997.5 ± 840.8 vs 619.3 ± 744.3 fmol/ug, p = .009) primarily found in ACS patients. Depressed patients with minor adverse cardiac events had increased platelet response to serotonin. CONCLUSIONS: Depressed cardiovascular patients had higher serotonin receptor density and significantly higher incidence of major and minor cardiac adverse events. Future studies with larger sample sizes including patients with more severe depression are needed to expand on the present hypothesis-generating findings.

Low-Frequency Right Repetitive Transcranial Magnetic Stimulation for the Treatment of Depression After Traumatic Brain Injury: A Randomized Sham-Controlled Pilot Study.

OBJECTIVE: Major depression is the most common psychiatric sequela of traumatic brain injury (TBI), but effective treatment continues to be a challenge, with few studies providing guidance. METHODS: In a pilot study, the authors evaluated the effect size of low-frequency right-sided (LFR) repetitive transcranial magnetic stimulation (rTMS), compared with sham treatment, over the right dorsolateral prefrontal cortex (DLPFC) in patients (N=30) with TBI depression and co-occurring neuropsychiatric symptoms, including suicidal thoughts, anxiety, posttraumatic stress disorder, sleep disturbance, behavioral problems, and cognitive dysfunction. Exploratory analyses of diffusion tensor imaging pre- and postintervention were performed to determine the effect size of LFR rTMS on white matter integrity. RESULTS: Small (Hedge's g=0.19) and highly variable effects of LRF rTMS over right DLPFC in TBI depression were observed. Similarly, the effect of LFR rTMS for treatment of comorbid neuropsychiatric symptoms varied from small to moderate. CONCLUSIONS: These findings suggest that the observed effects of LFR rTMS over the right DLPFC in TBI depression and co-occurring neuropsychiatric symptoms are small, at best, and, preliminarily, that low-frequency right DLPFC stimulation has limited potential in this patient population. However, studies employing different rTMS parameters (e.g., type, location, frequency, duration) or other participant characteristics (e.g., TBI severity, chronicity, comorbidity, concurrent treatment) may potentially yield different responses.

Pathological Laughter and Crying and Psychiatric Comorbidity After Traumatic Brain Injury.

There are limited data regarding the incidence of pathological laughter and crying (PLC) after traumatic brain injury (TBI). This study aimed to identify the occurrence of PLC in the first year after TBI and to determine whether there is a relationship between PLC and other clinical features or demographics. Subjects who sustained a first-time TBI were recruited from acute trauma units and were assessed at 3, 6, and 12 months after TBI. Rates of PLC at 3, 6, and 12 months after TBI were 21.4%, 17.5%, and 15.5%, respectively. Patients with PLC had higher percentages of psychiatric diagnoses, including personality changes, depressive disorders, and mood disorders secondary to a general medical condition, as well as higher rates of posttraumatic stress disorder. Univariate logistic and linear regression analyses indicated a significant association between PLC and scores on the Clinical Anxiety Scale 3 months after TBI and on the Hamilton Depression Rating Scale 12 months after TBI. Individuals who have PLC during the first year after TBI are more likely to have any psychiatric diagnosis as well as higher rates of mood and anxiety symptoms. In addition, PLC in the early TBI period may serve as a predictor of depression and anxiety symptoms at 12 months after TBI.

Does acute TBI-related sleep disturbance predict subsequent neuropsychiatric disturbances?

PRIMARY OBJECTIVE: To determine whether sleep disturbance in the acute post-traumatic brain injury (TBI) period predicts symptoms of depression, anxiety or apathy measured 6 and 12 months after TBI. RESEARCH DESIGN: Longitudinal, observational study. METHODS AND PROCEDURES: First time closed-head injury patients (n = 101) were recruited and evaluated within 3 months of injury and followed longitudinally, with psychiatric evaluations at 6 and 12 months post-injury. Pre- and post-injury sleep disturbances were measured via the Medical Outcome Scale (MOS) for Sleep. Subjects were also assessed for anxiety, depression, apathy, medical comorbidity and severity of TBI. MAIN OUTCOMES AND RESULTS: Sleep disturbance in the acute TBI period was associated with increased symptoms of depression, anxiety and apathy 12 months post-injury. CONCLUSIONS: Sleep disturbances experienced soon after trauma (i.e. <3 months after injury) predicted neuropsychiatric symptoms 1 year after injury, raising two important clinical questions: (1) Is sleep disturbance soon after trauma a prognostic marker of subsequent neuropsychiatric symptoms? and (2) Can early treatment of sleep disturbance during the post-TBI period reduce subsequent development of neuropsychiatric symptoms? Future studies with larger sample sizes and appropriate control groups could help to answer these questions, using evidence-based methods for evaluating and treating sleep disturbances.

Studies of (±)-3,4-methylenedioxymethamphetamine (MDMA) metabolism and disposition in rats and mice: relationship to neuroprotection and neurotoxicity profile.

The neurotoxicity of (±)-3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") is influenced by temperature and varies according to species. The mechanisms underlying these two features of MDMA neurotoxicity are unknown, but differences in MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine whether the neuroprotective effect of hypothermia is related to inhibition of MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in MDMA metabolism and/or disposition in the two species. Rats and mice received single neurotoxic oral doses of MDMA at 25°C and 4°C, and body temperature, pharmacokinetic parameters, and serotonergic and dopaminergic neuronal markers were measured. Hypothermia did not alter MDMA metabolism in rats and only modestly inhibited MDMA metabolism in mice; however, it afforded complete neuroprotection in both species. Rats and mice metabolized MDMA in a similar pattern, with 3,4-methylenedioxyamphetamine being the major metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, respectively. Differences between MDMA pharmacokinetics in rats and mice, including faster elimination in mice, did not account for the different profile of MDMA neurotoxicity in the two species. Taken together, the results of these studies indicate that inhibition of MDMA metabolism is not responsible for the neuroprotective effect of hypothermia in rodents, and that different neurotoxicity profiles in rats and mice are not readily explained by differences in MDMA metabolism or disposition.

Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations.

Repeated doses of the popular recreational drug methylenedioxymethamphetamine (MDMA, 'Ecstasy') are known to produce neurotoxic effects on brain serotonin (5-HT) neurons but it is widely believed that typical single oral doses of MDMA are free of neurotoxic risk. Experimental and therapeutic trials with MDMA in humans are underway. The mechanisms by which MDMA produces neurotoxic effects are not understood but drug metabolites have been implicated. The aim of the present study was to assess the neurotoxic potential of a range of clinically relevant single oral doses of MDMA in a non-human primate species that metabolizes MDMA in a manner similar to humans, the squirrel monkey. A secondary objective was to explore the relationship between plasma MDMA and metabolite concentrations and lasting serotonergic deficits. Single oral doses of MDMA produced lasting dose-related serotonergic neurochemical deficits in the brains of squirrel monkeys. Notably, even the lowest dose of MDMA tested (5.7 mg/kg, estimated to be equivalent to 1.6 mg/kg in humans) produced significant effects in some brain regions. Plasma levels of MDMA engendered by neurotoxic doses of MDMA were on the order of those found in humans. Serotonergic neurochemical markers were inversely correlated with plasma concentrations of MDMA, but not with those of its major metabolites, 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine. These results suggest that single oral doses of MDMA in the range of those used by humans pose a neurotoxic risk and implicate the parent compound (MDMA), rather than one of its metabolites, in MDMA-induced 5-HT neural injury.

Effect of a Tobacco Cessation Intervention Incorporating Weight Management for Adults With Serious Mental Illness: A Randomized Clinical Trial.

Importance: Tobacco smoking drives markedly elevated cardiovascular disease risk and preventable death in persons with serious mental illness, and these risks are compounded by the high prevalence of overweight/obesity that smoking cessation can exacerbate. Guideline-concordant combined pharmacotherapy and behavioral smoking cessation treatment improves abstinence but is not routinely offered in community settings, particularly to those not seeking to quit smoking immediately. Objective: To determine the effectiveness of an 18-month pharmacotherapy and behavioral smoking cessation intervention incorporating weight management and support for physical activity in adults with serious mental illness interested in quitting smoking within 1 or 6 months. Design, Setting, and Participants: This was a randomized clinical trial conducted from July 25, 2016, to March 20, 2020, at 4 community health programs. Adults with serious mental illness who smoked tobacco daily were included in the study. Participants were randomly assigned to intervention or control, stratified by willingness to try to quit immediately (within 1 month) or within 6 months. Assessors were masked to group assignment. Interventions: Pharmacotherapy, primarily varenicline, dual-form nicotine replacement, or their combination; tailored individual and group counseling for motivational enhancement; smoking cessation and relapse prevention; weight management counseling; and support for physical activity. Controls received quitline referrals. Main Outcome and Measures: The primary outcome was biochemically validated, 7-day point-prevalence tobacco abstinence at 18 months. Results: Of the 298 individuals screened for study inclusion, 192 enrolled (mean [SD] age, 49.6 [11.7] years; 97 women [50.5%]) and were randomly assigned to intervention (97 [50.5%]) or control (95 [49.5%]) groups. Participants self-identified with the following race and ethnicity categories: 93 Black or African American (48.4%), 6 Hispanic or Latino (3.1%), 90 White (46.9%), and 9 other (4.7%). A total of 82 participants (42.7%) had a schizophrenia spectrum disorder, 62 (32.3%) had bipolar disorder, and 48 (25.0%) had major depressive disorder; 119 participants (62%) reported interest in quitting immediately (within 1 month). Primary outcome data were collected in 183 participants (95.3%). At 18 months, 26.4% of participants (observed count, 27 of 97 [27.8%]) in the intervention group and 5.7% of participants (observed count, 6 of 95 [6.3%]) in the control group achieved abstinence (adjusted odds ratio [OR], 5.9; 95% CI, 2.3-15.4; P < .001). Readiness to quit within 1 month did not statistically significantly modify the intervention's effect on abstinence. The intervention group did not have significantly greater weight gain than the control group (mean weight change difference, 1.6 kg; 95% CI, -1.5 to 4.7 kg). Conclusions and Relevance: Findings of this randomized clinical trial showed that in persons with serious mental illness who are interested in quitting smoking within 6 months, an 18-month intervention with first-line pharmacotherapy and tailored behavioral support for smoking cessation and weight management increased tobacco abstinence without significant weight gain. Trial Registration: ClinicalTrials.gov Identifier: NCT02424188.

Diffusion tensor imaging atlas-based analyses in major depression after mild traumatic brain injury.

There are currently no known early neuroanatomical markers predictive of the development of major depression or depressive symptoms after mild traumatic brain injury (mTBI). The authors conducted a 1-year longitudinal pilot study to determine whether diffusion tensor imaging (DTI) measures collected within 1 month of mTBI could predict incident depression. Of the 14 subjects who met study inclusion criteria, 4 (28.6%) developed major depression over the follow-up period. Compared with the nondepressed group, those who developed depression had white-matter abnormalities in the fronto-temporal regions measured by DTI. These preliminary results highlight the need for additional studies, including studies using a larger sample and appropriate controls.

Metabolism and disposition of 3,4-methylenedioxymethamphetamine ("ecstasy") in baboons after oral administration: comparison with humans reveals marked differences.

The baboon is potentially an attractive animal for modeling 3,4-methylenedioxymethamphetamine (MDMA) effects in humans. Baboons self-administer MDMA, are susceptible to MDMA neurotoxicity, and are suitable for positron emission tomography, the method most often used to probe for MDMA neurotoxicity in humans. Because pharmacokinetic equivalence is a key feature of a good predictive animal model, we compared the pharmacokinetics of MDMA in baboons and humans. Baboons were trained to orally consume MDMA. Then, pharmacokinetic profiles of MDMA and its major metabolites were determined after various oral MDMA doses using the same analytical method recently used to perform similar studies in humans. Results indicate that MDMA pharmacokinetics after oral ingestion differ markedly between baboons and humans. Baboons had little or no MDMA in their plasma but had high plasma concentrations of 3,4-dihydroxymethamphetamine (HHMA), pointing to much more extensive first-pass metabolism of MDMA in baboons than in humans. Other less prominent differences included less O-methylation of HHMA to 4-hydroxy-3-methoxymethamphetamine, greater N-demethylation of MDMA to 3,4-methylenedioxyamphetamine, and a shorter half-life of HHMA in the baboon. To our knowledge, this is the first study to characterize MDMA metabolism and disposition in the baboon. Differences in MDMA pharmacokinetics between baboons and humans suggest that the baboon may not be ideal for modeling human MDMA exposure. However, the unusually rapid conversion of MDMA to HHMA in the baboon may render this animal uniquely useful for clarifying the relative role of the parent compound (MDMA) versus metabolites (particularly HHMA) in the biological actions of MDMA.

Synthesis and neurotoxicity profile of 2,4,5-trihydroxymethamphetamine and its 6-(N-acetylcystein-S-yl) conjugate.

The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, "ecstasy"), or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), play a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined. A single intraventricular injection of THMA produced a significant lasting depletion of regional rat brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), consistent with previous reports that THMA harbors 5-HT neurotoxic potential. The lasting effect of THMA on brain 5-HT markers was blocked by the 5-HT uptake inhibitor fluoxetine, indicating that persistent effects of THMA on 5-HT markers, like those of MDMA, are dependent on intact 5-HT transporter function. Efforts to identify THMA in the brains of animals treated with a high, neurotoxic dose (80 mg/kg) of MDMA were unsuccessful. Inability to identify THMA in the brains of these animals was not related to the unstable nature of the THMA molecule because exogenous THMA administered intracerebroventricularly could be readily detected in the rat brain for several hours. The thioether conjugate of THMA, 6-NAC-THMA, led to no detectable lasting alterations of cortical 5-HT or 5-HIAA levels, indicating that it lacks significant 5-HT neurotoxic activity. The present results cast doubt on the role of either THMA or 6-NAC-THMA in the lasting serotonergic effects of MDMA. The possibility remains that different conjugated forms of THMA or oxidized cyclic forms (e.g., the indole of THMA) play a role in MDMA-induced 5-HT neurotoxicity in vivo.

Identifying the serotonin transporter signal in Western blot studies of the neurotoxic potential of MDMA and related drugs.

A number of published studies have questioned the serotonin neurotoxic potential of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and related drugs (fenfluramine, p-chloroamphetamine) based upon results from Western blot studies using a custom synthesized serotonin transporter (SERT) antibody that found no reduction in the abundance of a 50kDa protein after substituted amphetamine treatment. The purpose of this study was to collect Western blot data using the same SERT antibody used in those studies, but with positive and negative controls to identify the SERT protein signal. A 63-68 kDa band that had the regional distribution expected of rat brain SERT, was decreased by 5,7-DHT, and was absent in SERT KO animals was identified as the SERT protein. Significant, lasting decreases in the abundance of the 63-68 kDa band were evident in the rat brain after treatment with MDMA and related drugs (FEN, PCA). Thus, when the band corresponding to the SERT protein is identified in Western blots through the use of positive and negative controls, reduced abundance of the SERT protein can be readily demonstrated after substituted amphetamine treatment. These data provide further evidence of lasting loss of the SERT protein after exposure to MDMA and other substituted amphetamines.

Inhibition of 3,4-methylenedioxymethamphetamine metabolism leads to marked decrease in 3,4-dihydroxymethamphetamine formation but no change in serotonin neurotoxicity: implications for mechanisms of neurotoxicity.

3,4-Methylenedioxymethamphetamine (MDMA)'s O-demethylenated metabolite, 3,4-dihydroxymethamphetamine (HHMA), has been hypothesized to serve as a precursor for the formation of toxic catechol-thioether metabolites (e.g., 5-N-acetylcystein-S-yl-HHMA) that mediate MDMA neurotoxicity. To further test this hypothesis, HHMA formation was blocked with dextromethorphan (DXM), which competitively inhibits cytochrome P450 enzyme-mediated O-demethylenation of MDMA to HHMA. In particular, rats were randomly assigned to one of four treatment groups (n = 9-12 per group): (1) Saline/MDMA; (2) DXM/MDMA; (3) DXM/Saline; (4) Saline/Saline. During drug exposure, time-concentration profiles of MDMA and its metabolites were determined, along with body temperature. One week later, brain serotonin (5-HT) neuronal markers were measured in the same animals. DXM did not significantly alter core temperature in MDMA-treated animals. A large (greater than 70%) decrease in HHMA formation had no effect on the magnitude of MDMA neurotoxicity. These results cast doubt on the role of HHMA-derived catechol-thioether metabolites in the mechanism of MDMA neurotoxicity.

Sleep disturbance after mild traumatic brain injury: indicator of injury?

Mild traumatic brain injury (mTBI) is a complex entity with no known objective diagnostic markers. To test the hypothesis that sleep disturbances in the acute mTBI period can serve as an indicator of brain injury, the authors compared sleep polysomnograms (PSG) and sleep EEG power spectra (PS) data in seven mTBI subjects with seven age- and race-matched healthy-control subjects. The two groups differed significantly on PS measures, suggesting that mTBI can result in a disruption of sleep microarchitecture and, in theory, could be of use as a marker for brain injury. These pilot findings need to be replicated on larger samples.

Racial differences in platelet serotonin polymorphisms in acute coronary syndrome.

INTRODUCTION: Genetic differences between races have been hypothesized to contribute to differences in outcome from acute coronary syndromes (ACS). Our objective was to assess racial differences in genetic variations in the platelet serotonin transporter (5HTT) and receptor in patients with ACS. MATERIALS AND METHODS: 127 consecutive patients, African Americans (AA) = 27; Caucasian (C) =100, admitted with ACS were evaluated for platelet function by serotonin (5HT) induced platelet activation. All patients were genotyped for two polymorphisms in the serotonin-transporter-linked polymorphic region (5-HTTLPR) S/L and LG/LA and one polymorphism of the serotonin 2A receptor (5-HT2A, T102C) gene. All patients were followed for major and minor adverse cardiac events at 12 months. RESULTS: AA when compared to C had a lower prevalence of the HTTLPR S allele (21% vs 45%, p = 0.0003) and a higher prevalence of the LG allele (24% vs 4.5%, p = 0.0001). Allelic frequency of the 5-HT2A T102C allele was not significantly different between the races. Platelet activation was lower in AA compared to C, median EC50 5HT was 12.08 µg vs 2.14 µg (p = 0.001). The 5-HTTLPR and the 5-HT2A polymorphisms were not associated with platelet functional responses to serotonin. There were no significant differences in major or minor adverse cardiac events in patients with serotonin transporter or receptor polymorphisms. CONCLUSION: We found a lower prevalence of the S allele and a higher prevalence of the G allele in AA with ACS. We also found decreased platelet activation in AA which did not correlate with serotonin-related platelet polymorphisms. It is unclear if other contributing factors may explain these platelet functional differences.

Sleep deprivation differentially impairs cognitive performance in abstinent methylenedioxymethamphetamine ("Ecstasy") users.

Methylenedioxymethamphetamine (MDMA; "Ecstasy") is a popular recreational drug and brain serotonin (5-HT) neurotoxin. Neuroimaging data indicate that some human MDMA users develop persistent deficits in brain 5-HT neuronal markers. Although the consequences of MDMA-induced 5-HT neurotoxicity are not fully understood, abstinent MDMA users have been found to have subtle cognitive deficits and altered sleep architecture. The present study sought to test the hypothesis that sleep disturbance plays a role in cognitive deficits in MDMA users. Nineteen abstinent MDMA users and 21 control subjects participated in a 5 d inpatient study in a clinical research unit. Baseline sleep quality was measured using the Pittsburgh Sleep Quality Inventory. Cognitive performance was tested three times daily using a computerized cognitive battery. On the third day of admission, subjects began a 40 h sleep deprivation period and continued cognitive testing using the same daily schedule. At baseline, MDMA users performed less accurately than controls on a task of working memory and more impulsively on four of the seven computerized tests. During sleep deprivation, MDMA users, but not controls, became increasingly impulsive, performing more rapidly at the expense of accuracy on tasks of working and short-term memory. Tests of mediation implicated baseline sleep disturbance in the cognitive decline seen during sleep deprivation. These findings are the first to demonstrate that memory problems in MDMA users may be related, at least in part, to sleep disturbance and suggest that cognitive deficits in MDMA users may become more prominent in situations associated with sleep deprivation.

Dopamine is not essential for the development of methamphetamine-induced neurotoxicity.

It is widely believed that dopamine (DA) mediates methamphetamine (METH)-induced toxicity to brain dopaminergic neurons, because drugs that interfere with DA neurotransmission decrease toxicity, whereas drugs that increase DA neurotransmission enhance toxicity. However, temperature effects of drugs that have been used to manipulate brain DA neurotransmission confound interpretation of the data. Here we show that the recently reported ability of L-dihydroxyphenylalanine to reverse the protective effect of alpha-methyl-para-tyrosine on METH-induced DA neurotoxicity is also confounded by drug effects on body temperature. Further, we show that mice genetically engineered to be deficient in brain DA develop METH neurotoxicity, as long as the thermic effects of METH are preserved. In addition, we demonstrate that mice genetically engineered to have unilateral brain DA deficits develop METH-induced dopaminergic deficits that are of comparable magnitude on both sides of the brain. Taken together, these findings demonstrate that DA is not essential for the development of METH-induced dopaminergic neurotoxicity and suggest that mechanisms independent of DA warrant more intense investigation.

Further studies on the role of metabolites in (+/-)-3,4-methylenedioxymethamphetamine-induced serotonergic neurotoxicity.

The mechanism by which the recreational drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals. We also further evaluated the neurotoxic potential of 5-(N-acetylcystein-S-yl)-HHMA (5-NAC-HHMA), an MDMA metabolite recently implicated in 5-HT neurotoxicity. Lasting serotonergic deficits correlated strongly with pharmacokinetic parameters of MDMA (C(max) and area under the concentration-time curve), more weakly with those of MDA, and not at all with those of HHMA or HMMA (total amounts of the free analytes obtained after conjugate cleavage). HHMA and HMMA could not be detected in the brains of animals with high brain MDMA concentrations and high plasma HHMA and HMMA concentrations, suggesting that HHMA and HMMA do not readily penetrate the blood-brain barrier (either in their free form or as sulfate or glucuronic conjugates) and that little or no MDMA is metabolized to HHMA or HMMA in the brain. Repeated intraparenchymal administration of 5-NAC-HHMA did not produce significant lasting serotonergic deficits in the rat brain. Taken together, these results indicate that MDMA and, possibly, MDA are more important determinants of brain 5-HT neurotoxicity in the rat than HHMA and HMMA and bring into question the role of metabolites (including 5-NAC-HHMA) in MDMA neurotoxicity.

Approach-avoidance coping conflict in a sample of burn patients at risk for posttraumatic stress disorder.

BACKGROUND: Following an acute burn injury, higher distress is consistently observed among individuals exhibiting a conflict between approach coping (e.g., processing) and avoidance coping (e.g., suppression) relative to those individuals who use only one of these methods. Study objectives were to determine if contradictory coping messages would lead to such approach-avoidance coping conflict and to determine if experiment-induced coping conflict is also associated with higher distress. METHODS: Participants (n=59 adults hospitalized with acute burn injuries) were assigned randomly to experimental conditions differing in the order in which training was provided in two ways of coping with posttrauma re-experiencing symptoms (i.e., process-then-suppress versus suppress-then-process). The primary dependent variable was coping behavior during the 24-hr posttraining period. Coping behavior was categorized as approach coping (processing), avoidance coping (suppressing), or approach-avoidance coping conflict (both) on the basis of median splits on subscales assessing these behaviors. Secondary analyses examined the relationship between this experiment-induced coping conflict and re-experiencing symptoms. RESULTS: Results indicated that participants in the process-then-suppress condition, relative to the suppress-then-process condition, were significantly more likely to exhibit approach-avoidance coping conflict (i.e., above median split on both processing and suppressing) during the next 24 hr. Furthermore, approach-avoidance coping conflict was associated with greater re-experiencing symptoms assessed via self-report and by blinded coding of recorded speech. CONCLUSIONS: It is concluded that the order of coping skill training can influence treatment outcome, success of coping methods, and overall levels of distress. therefore, training in stabilizing and calming methods should precede training in active processing following stressful life events.

Direct comparison of (+/-) 3,4-methylenedioxymethamphetamine ("ecstasy") disposition and metabolism in squirrel monkeys and humans.

The present study compared the disposition and metabolism of the recreational drug (+/-) 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in squirrel monkeys and humans because the squirrel monkey has been extensively studied for MDMA neurotoxicity. A newly developed liquid chromatography-mass spectrometric procedure for simultaneous measurement of MDMA, 3,4-dihydroxymethamphetamine, 4-hydroxy-3-methoxymethamphetamine, and 3,4-methylenedioxyamphetamine was employed. In both humans and squirrel monkeys, a within-subject design permitted testing of different doses in the same subjects. Humans and squirrel monkeys were found to metabolize MDMA in similar, but not identical, pathways and proportions. In particular, amounts of 3,4-dihydroxymethamphetamine (after conjugate cleavage) and 3,4-methylenedioxyamphetamine were similar in the 2 species, but formation of 4-hydroxy-3-methoxymethamphetamine was greater in squirrel monkeys than in humans. Both species demonstrated nonlinear MDMA pharmacokinetics at comparable plasma MDMA concentrations (125-150 ng/mL and above). The elimination half-life of MDMA was considerably shorter in squirrel monkeys than in humans (2-3 versus 6-9 hours). In both species, there was substantial individual variability. These results suggest that the squirrel monkey may be a useful model for predicting outcomes of MDMA exposure in humans, although this will also depend on the degree to which MDMA pharmacodynamics in the squirrel monkey parallels that in humans.

Repetitive TMS combined with exposure therapy for PTSD: a preliminary study.

Treatment for anxiety and post-traumatic stress disorder (PTSD) includes exposure therapy and medications, but some patients are refractory. Few studies of repetitive transcranial magnetic stimulation (rTMS) for anxiety or PTSD exist. In this preliminary report, rTMS was combined with exposure therapy for PTSD. Nine subjects with chronic, treatment-refractory PTSD were studied in a placebo-controlled, crossover design of imaginal exposure therapy with rTMS (1Hz) versus sham. PTSD symptoms, serum and 24h urine were obtained and analyzed. Effect sizes for PTSD symptoms were determined using Cohen's d. Active rTMS showed a larger effect size of improvement for hyperarousal symptoms compared to sham; 24-h urinary norepinephrine and serum T4 increased; serum prolactin decreased. Active rTMS with exposure may have symptomatic and physiological effects. Larger studies are needed to confirm these preliminary findings and verify whether rTMS plus exposure therapy has a role in the treatment of PTSD.