Lamotrigine for cognitive deficits associated with neurofibromatosis type 1: A phase II randomized placebo-controlled trial.

AIM: To find proof-of-principle evidence for short-term treatment with lamotrigine to improve cognitive functioning of adolescents with neurofibromatosis type 1 (NF1). METHOD: This was a double-blind, parallel-group, randomized, placebo-controlled clinical trial (the NF1-EXCEL trial: Examining the Cognitive and Electrophysiological benefit of Lamotrigine in Neurofibromatosis type 1; Clinicaltrials.gov identifier NCT02256124), with the aim of enrolling 60 adolescents with NF1 aged 12 to 17 years 6 months. The short-term study intervention was 200 mg of lamotrigine taken orally for 26 weeks. The primary outcome was performance IQ tested with the Wechsler Intelligence Scale for Children, Third Edition, complemented with secondary outcomes for visuospatial learning efficacy, visual perception, visual sustained attention, fine motor coordination, attention-deficit/hyperactivity problems, and executive functioning. RESULTS: We screened 402 adolescents with NF1, of whom 31 (eight females) entered the study. Complete-case analysis showed no effect of lamotrigine on either performance IQ (-0.23, 95% CI -6.90 to 6.44) or most secondary outcomes. Visual sustained attention showed a trend towards better performance in the lamotrigine group (-0.81, 95% CI -1.67 to 0.04). INTERPRETATION: Lamotrigine did not improve cognitive functioning in adolescents with NF1. The small treatment effects make it unlikely that a larger sample size could have changed this conclusion.

Transcranial Direct Current Stimulation Targeting the Entire Motor Network Does Not Increase Corticospinal Excitability.

Transcranial direct current stimulation (tDCS) over the contralateral primary motor cortex of the target muscle (conventional tDCS) has been described to enhance corticospinal excitability, as measured with transcranial magnetic stimulation. Recently, tDCS targeting the brain regions functionally connected to the contralateral primary motor cortex (motor network tDCS) was reported to enhance corticospinal excitability more than conventional tDCS. We compared the effects of motor network tDCS, 2 mA conventional tDCS, and sham tDCS on corticospinal excitability in 21 healthy participants in a randomized, single-blind within-subject study design. We applied tDCS for 12 min and measured corticospinal excitability with TMS before tDCS and at 0, 15, 30, 45, and 60 min after tDCS. Statistical analysis showed that neither motor network tDCS nor conventional tDCS significantly increased corticospinal excitability relative to sham stimulation. Furthermore, the results did not provide evidence for superiority of motor network tDCS over conventional tDCS. Motor network tDCS seems equally susceptible to the sources of intersubject and intrasubject variability previously observed in response to conventional tDCS.

Cortical Inhibition and Plasticity in Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) is a severe psychiatric disorder that is associated with various cognitive impairments, including learning and memory deficits. As synaptic plasticity is considered an important mechanism underlying learning and memory, deficits in cortical plasticity might play a role in the pathophysiology of patients with MDD. We used Transcranial Magnetic Stimulation (TMS) to assess inhibitory neurotransmission and cortical plasticity in the motor cortex of MDD patients and controls. METHODS: We measured the cortical silent period (CSP) and short interval cortical inhibition (SICI), as well as intermittent theta-burst stimulation (iTBS), in 9 drug-free MDD inpatients and 18 controls. RESULTS: The overall response to the CSP, SICI, and iTBS paradigms was not significantly different between the patient and control groups. iTBS induction resulted in significant potentiation after 20 mins in the control group (t (17) = -2.8, p = 0.01), whereas no potentiation was observed in patients. CONCLUSIONS: Potentiation of MEP amplitudes was not observed within the MDD group. No evidence was found for medium-to-large effect size differences in CSP and SICI measures in severely depressed drug-free patients, suggesting that reduced cortical inhibition is unlikely to be a robust correlate of the pathophysiological mechanism in MDD. However, these findings should be interpreted with caution due to the high inter-subject variability and the small sample size. SIGNIFICANCE: These findings advance our understanding of neurophysiological functioning in drug-free severely depressed inpatients.

Attention and Motor Learning in Adult Patients with Neurofibromatosis Type 1.

OBJECTIVE: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities, including attention and motor learning problems. These disabilities have been extensively studied in children with NF1 but limited studies have been performed in adults. METHOD: Attention, motor learning and intellectual performance were studied with neuropsychological tasks in 32 adults with NF1 and 32 controls. RESULTS: The NF1 and control group performed similarly on attention and motor learning tasks, although controls had shorter reaction times than adults with NF1 during the motor learning task (t[60] = -2.20, p = .03). Measures of attention or motor learning were not significantly associated with reduced intellectual performance in NF1. CONCLUSION: In contrast to many studies in children with NF1, our findings did not provide evidence for presence of attention or motor learning problems in adults with NF1 in neuropsychological tasks. Our observations may be of clinical importance to determine treatment focus in adults with NF1.

Oxytocin moderates the association between testosterone-cortisol ratio and trustworthiness: A randomized placebo-controlled study.

Oxytocin has been proposed to enhance feelings of trust, however, these findings have been difficult to replicate. Environmental or hormonal factors might influence this association. We studied whether oxytocin moderates the association between the testosterone-cortisol ratio, which is associated with risk taking behavior and aggression, and trustworthiness, while controlling for the general level of trust. A randomized double-blind placebo-controlled study with 53 healthy males was performed in which 32IU oxytocin (n = 27) or placebo (n = 26) was administered intranasally. Participants subsequently played the Trust Game in which they were allocated to the role of trustee. In the third phase of the Trust Game, we found a positive association between the testosterone-cortisol-ratio and the proportion of the amount that is returned to the investor (P=<0.01). However, administration of oxytocin reduced reciprocity in those with a high testosterone-cortisol ratio after reciprocity restoration (a significant interaction effect between administration of oxytocin and the testosterone-cortisol ratio in the third phase of the Trust Game, P = 0.015). The third phase of the Trust Game represents the restoration of reciprocity and trustworthiness, after this is violated in the second phase. Therefore, our data suggest that oxytocin might hinder the restoration of trustworthiness and diminish risk-taking behavior when trust is violated, especially in those who are hormonally prone to risk-taking behavior by a high testosterone-cortisol ratio.

No effect of anodal tDCS on motor cortical excitability and no evidence for responders in a large double-blind placebo-controlled trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) has emerged as a non-invasive brain stimulation technique. Most studies show that anodal tDCS increases cortical excitability. However, this effect has been found to be highly variable. OBJECTIVE: To test the effect of anodal tDCS on cortical excitability and the interaction effect of two participant-specific factors that may explain individual differences in sensitivity to anodal tDCS: the Brain Derived Neurotrophic Factor Val66Met polymorphism (BDNF genotype) and the latency difference between anterior-posterior and lateromedial TMS pulses (APLM latency). METHODS: In 62 healthy participants, cortical excitability over the left motor cortex was measured before and after anodal tDCS at 2 mA for 20 min in a pre-registered, double-blind, randomized, placebo-controlled trial with repeated measures. RESULTS: We did not find a main effect of anodal tDCS, nor an interaction effect of the participant-specific predictors. Moreover, further analyses did not provide evidence for the existence of responders and non-responders. CONCLUSION: This study indicates that anodal tDCS at 2 mA for 20 min may not reliably affect cortical excitability.

Motor cortical excitability and plasticity in patients with neurofibromatosis type 1.

OBJECTIVE: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities. Based on studies involving animals, the hypothesized cause of these disabilities results from increased activity of inhibitory interneurons that decreases synaptic plasticity. We obtained transcranial magnetic stimulation (TMS)-based measures of cortical inhibition, excitability and plasticity in individuals with NF1. METHODS: We included 32 NF1 adults and 32 neurotypical controls. Cortical inhibition was measured with short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Excitability and plasticity were studied with intermittent theta burst stimulation (iTBS). RESULTS: The SICI and CSP response did not differ between NF1 adults and controls. The response upon iTBS induction was significantly increased in controls (70%) and in NF1 adults (83%). This potentiation lasted longer in controls than in individuals with NF1. Overall, the TMS response was significantly lower in NF1 patients (F(1, 41) = 7.552, p = 0.009). CONCLUSIONS: Individuals with NF1 may have reduced excitability and plasticity, as indicated by their lower TMS response and attenuation of the initial potentiated response upon iTBS induction. However, our findings did not provide evidence for increased inhibition in NF1 patients. SIGNIFICANCE: These findings have potential utility as neurophysiological outcome measures for intervention studies to treat cognitive deficits associated with NF1.

Urbanicity, biological stress system functioning and mental health in adolescents.

Growing up in an urban area has been associated with an increased chance of mental health problems in adults, but less is known about this association in adolescents. We examined whether current urbanicity was associated with mental health problems directly and indirectly via biological stress system functioning. Participants (n = 323) were adolescents from the Dutch general population. Measures included home and laboratory assessments of autonomic nervous system and hypothalamic-pituitary-adrenal axis functioning, neighborhood-level urbanicity and socioeconomic status, and mother- and adolescent self-reported mental health problems. Structural equation models showed that urbanicity was not associated with mental health problems directly. Urbanicity was associated with acute autonomic nervous system and hypothalamic-pituitary-adrenal axis reactivity such that adolescents who lived in more urban areas showed blunted biological stress reactivity. Furthermore, there was some evidence for an indirect effect of urbanicity on mother-reported behavioral problems via acute autonomic nervous system reactivity. Urbanicity was not associated with overall autonomic nervous system and hypothalamic-pituitary-adrenal axis reactivity or basal hypothalamic-pituitary-adrenal axis functioning. Although we observed some evidence for associations between urbanicity, biological stress reactivity and mental health problems, most of the tested associations were not statistically significant. Measures of long-term biological stress system functioning may be more relevant to the study of broader environmental factors such as urbanicity.

The Impact of Objective and Subjective Sleep Parameters on Depressive Symptoms during Pregnancy in Women with a Mental Disorder: An Explorative Study.

Poor sleep quality during pregnancy is associated with both antepartum and postpartum depression and adverse birth outcomes. This study evaluated both objective and subjective sleep quality and the effects on the subsequent course of antepartum depressive symptoms in psychiatric patients. This observational explorative study was embedded in an ongoing study focusing on pregnant women with a mental disorder and was performed in 18 patients (24-29 weeks pregnant). Depressive symptoms were assessed throughout pregnancy using the Edinburgh Postnatal Depression Scale (EPDS) with 5-week intervals. Sleep was assessed with actigraphy, the Pittsburgh Sleep Quality Index (PSQI) and sleep diaries at the start of the study. We studied correlations between sleep parameters and EPDS scores cross-sectionally using Spearman correlation. Next, we studied the course of antepartum EPDS scores over time per sleep parameter using generalized linear mixed modelling analysis. Objectively measured fragmentation index, total PSQI score and 4 PSQI subscales (sleep quality, sleep duration, sleep disturbances and daytime dysfunctions) were significantly correlated with EPDS scores when measured cross-sectionally at the start. Six objectively and subjectively measured sleep parameters had moderate to large effects on the course of depressive symptoms through the third trimester, but these effects were not statistically significant. More research is necessary to explore the causality of the direction between sleep problems and antepartum depressive symptoms we found in psychiatric patients.

Intranasal administration of oxytocin decreases task-related aggressive responses in healthy young males.

Aggression and distrust are often challenging problems in mental health treatment. Converging evidence reveals that oxytocin increases trust in social interactions and decreases fear of social betrayal. However, oxytocin has also been associated with protective behavior and, as such, might increase defensive aggressive reactions. In this randomized double-blind, placebo-controlled study, the effects of intranasal oxytocin (32IU) on task-related aggressive responses were measured using the Point Subtraction Aggression Paradigm (PSAP). Fifty-seven healthy males were enrolled and randomized to oxytocin (N = 30) or placebo (n = 27). Salivary oxytocin, cortisol and testosterone were measured serially prior to the intervention, and then before and after the PSAP, to evaluate the effects of oxytocin administration on hormonal functioning in relation to aggression. In addition, oxytocin was measured in urine collected directly after the experimental task, reflecting the 2 h period after oxytocin or placebo administration. The proportion of aggressive responses to the PSAP was significantly lower in participants receiving oxytocin versus placebo (ß= -0.46, P = 0.01). No significant effect of oxytocin was found regarding defensive reactions. Urinary oxytocin was negatively associated with the proportion of aggressive responses to the PSAP in both the oxytocin and the placebo group (ß= -0.02, P < 0.01), suggesting that higher levels of urinary oxytocin corresponded with reduced aggressive responding. Our results indicate that oxytocin administration reduces aggressive behavior in healthy young men. Moreover, increased endogenous urinary oxytocin is associated with less aggressive responding. Taken together, these findings suggest that oxytocin signaling has a causal influence on aggressive behavior.

Differences in potential biomarkers of delirium between acutely ill medical and elective cardiac surgery patients.

BACKGROUND/AIMS: The pathophysiology of delirium is poorly understood. Increasing evidence suggests that different pathways might be involved in the pathophysiology depending on the population studied. The aim of the present study was to investigate potential differences in mean plasma levels of neopterin, amino acids, amino acid ratios and homovanillic acid between two groups of patients with delirium. METHODS: Data from acutely ill medical patients aged 65 years and older, and patients aged 70 years and older undergoing elective cardiac surgery, were used. Differences in biomarker levels between the groups were investigated using univariate ANOVA with adjustments for age, sex, comorbidities, C-reactive protein (CRP) and the estimated glomerular filtration rate (eGFR), where appropriate. Linear regression analysis was used to identify potential determinants of the investigated biochemical markers. RESULTS: Eighty patients with delirium were included (23 acutely ill medical patients and 57 elective cardiac surgery patients). After adjustment, higher mean neopterin levels (93.1 vs 47.3 nmol/L, P=0.001) and higher phenylalanine/tyrosine ratios (1.39 vs 1.15, P=0.032) were found in acutely ill medical patients when compared to elective cardiac surgery patients. CRP levels were positively correlated with neopterin levels in acutely ill medical patients, explaining 28.4% of the variance in neopterin levels. eGFR was negatively correlated with neopterin in elective cardiac surgery patients, explaining 53.7% of the variance in neopterin levels. CONCLUSION: In this study, we found differences in mean neopterin levels and phenylalanine/tyrosine ratios between acutely ill medical and elective cardiac surgery patients with delirium. Moreover, our findings may suggest that in acutely ill medical patients, neopterin levels are mainly determined by inflammation/oxidative stress whereas in elective cardiac surgery patients, neopterin levels are mainly driven by renal function/fluid status. These findings suggest that the markers and pathways that might be involved in the pathophysiology of delirium may differ between specific groups of patients.

Oxytocin, vasopressin and trust: Associations with aggressive behavior in healthy young males.

Oxytocin enhances trust during social interactions and reduces the tendency for social betrayal. Animal studies have revealed that oxytocin is also an important factor in the establishment and regulation of aggression, for which social interaction is a critical precondition. In humans, however, the effects of oxytocin appear more nuanced and influenced by social context and personality traits. Moreover, the pro-social effects of oxytocin are not mirrored by vasopressin, despite their high chemical similarity. Rather, vasopressin has been associated with an increase of aggressive responses. Therefore, we sought to investigate the association of oxytocin and vasopressin with trust and aggressive behavior. Overnight urinary oxytocin and vasopressin levels were obtained from 62 healthy males (age range: 18-26 years) to compare with trait measures of trust and aggressive behavior. We found a significant interaction of oxytocin and trust on aggression in which low trait measures of trust, in combination with low levels of oxytocin, were associated with a history of aggressive behavior. Notably, we found no significant associations for vasopressin. Although both oxytocin and vasopressin have been shown to be important in the emergence of violent behavior, our study suggests that oxytocin may be particularly modified by affiliative behaviors. These findings provide insights into the neuropsychological influences of oxytocin, and highlights the potential for clinical translation regarding the treatment of patients who exhibit recurrent aggressive behavior.

TMS motor mapping: Comparing the absolute reliability of digital reconstruction methods to the golden standard.

BACKGROUND: Changes in transcranial magnetic stimulation motor map parameters can be used to quantify plasticity in the human motor cortex. The golden standard uses a counting analysis of motor evoked potentials (MEPs) acquired with a predefined grid. Recently, digital reconstruction methods have been proposed, allowing MEPs to be acquired with a faster pseudorandom procedure. However, the reliability of these reconstruction methods has never been compared to the golden standard. OBJECTIVE: To compare the absolute reliability of the reconstruction methods with the golden standard. METHODS: In 21 healthy subjects, both grid and pseudorandom acquisition were performed twice on the first day and once on the second day. The standard error of measurement was calculated for the counting analysis and the digital reconstructions. RESULTS: The standard error of measurement was at least equal using digital reconstructions. CONCLUSION: Pseudorandom acquisition and digital reconstruction can be used in intervention studies without sacrificing reliability.

The 5-HTTLPR genotype, early life adversity and cortisol responsivity to psychosocial stress in women.

BACKGROUND: The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has previously been associated with hypothalamus-pituitary-adrenal axis function. Moreover, it has been suggested that this association is moderated by an interaction with stressful life experiences. AIMS: To investigate the moderation of cortisol response to psychosocial stress by 5-HTTLPR genotype, either directly or through an interaction with early life stress. METHOD: A total of 151 women, 85 of which had personality psychopathology, performed the Trier Social Stress Test while cortisol responsivity was assessed. RESULTS: The results demonstrate a main effect of genotype on cortisol responsivity. Women carrying two copies of the long version of 5-HTTLPR exhibited stronger cortisol responses to psychosocial stress than women with at least one copy of the short allele (P = 0.03). However, the proportion of the variance of stress-induced cortisol responsivity explained by 5-HTTLPR genotype was not further strengthened by including early life adversity as a moderating factor (P = 0.52). CONCLUSIONS: Our results highlight the need to clarify gender-specific biological factors influencing the serotonergic system. Furthermore, our results suggest that childhood maltreatment, specifically during the first 15 years of life, is unlikely to exert a moderating influence of large effect on the relationship between the 5-HTTLPR genotype and cortisol responsivity to psychosocial stress. DECLARATION OF INTEREST: None.

The levonorgestrel-releasing intrauterine device potentiates stress reactivity.

BACKGROUND: The levonorgestrel-releasing intrauterine device (LNG-IUD) is currently recommended as a first-line contraceptive with an exclusively local intrauterine influence. However, recent clinical trials have identified side effects of LNG-IUD that appear to be systemically mediated, including depressed mood and emotional lability. METHODS: We performed two experimental studies and a cross-sectional study. For each study, women were included from three groups: LNG-IUD (0.02mg/24h), oral ethinylestradiol/levonorgestrel (0.03mg/0.15mg; EE30/LNG) and natural cycling (NC). Study 1-Salivary cortisol was measured at baseline and at defined intervals following the Trier Social Stress Test (TSST). Heart rate was monitored continuously throughout the TSST. Study 2-Salivary cortisol and serum total cortisol were evaluated relative to low-dose (1µg) adrenocorticotropic hormone (ACTH) administration. Study 3-Hair cortisol was measured as a naturalistic index of long-term cortisol exposure. RESULTS: Women using LNG-IUD had an exaggerated salivary cortisol response to the TSST (24.95±13.45 nmol/L, 95% CI 17.49-32.40), compared to EE30/LNG (3.27±2.83 nmol/L, 95% CI 1.71-4.84) and NC (10.85±11.03nmol/L, 95% CI 6.30-15.40) (P<0.0001). Heart rate was significantly potentiated during the TSST in women using LNG-IUD (P=0.047). In response to ACTH challenge, women using LNG-IUD and EE30/LNG had a blunted salivary cortisol response, compared to NC (P<0.0001). Women using LNG-IUD had significantly elevated levels of hair cortisol compared to EE30/LNG or NC (P<0.0001). CONCLUSIONS: Our findings suggest that LNG-IUD contraception induces a centrally-mediated sensitization of both autonomic and hypothalamic-pituitary-adrenal (HPA) axis responsivity. LNG-IUD sensitization of HPA axis responsivity was observed acutely under standardized laboratory conditions, as well as chronically under naturalistic conditions.

Adrenocorticotropic hormone elicits gonadotropin secretion in premenopausal women.

STUDY QUESTION: Does adrenocorticotropic hormone (ACTH) induce gonadotropin release in premenopausal women? SUMMARY ANSWER: Administration of ACTH stimulates gonadotropin release, most likely by stimulation of the production of cortisol, in premenopausal women. WHAT IS KNOWN ALREADY: In animal models, acute activation of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to induce gonadotropin release in the presence of sufficiently high estrogen levels. However, it is unknown whether the HPA axis has a similar influence on gonadotropin release in humans. STUDY DESIGN, SIZE, DURATION: This study had a mixed factorial design. A total of 60 healthy female participants participated in the experimental study. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study sample comprised three distinct hormonal-based populations according to their levels of progesterone (PROG) and estradiol (E2): (i) low-PROG-low-E2, (ii) low-PROG-high-E2 and (iii) high-PROG-high-E2 women. A low dose (1 µg) of ACTH was administered to all study participants. Serum steroid and gonadotropin concentrations were measured prior to, and at 30 and 90 minutes after, intravenous ACTH administration. MAIN RESULTS AND THE ROLE OF CHANCE: Mean serum cortisol levels increased significantly following ACTH administration in all groups (P < 0.001). Similarly, the serum levels of 17-OH-PROG, androstenedione, dehydroepiandrosterone and testosterone increased significantly in all groups (P < 0.01). The low-PROG-high-E2 and high-PROG-high-E2 groups exhibited a significant increase in LH and FSH levels (P < 0.001), whereas the low-PROG-low-E2 group demonstrated blunted LH and FSH responses to ACTH administration (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Testing was performed during the luteal phase of the natural menstrual cycle. Testing during the follicular phase might have elicited premature, or more pronounced, LH surges in response to ACTH administration. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest a novel mechanism by which the adrenal cortex functions as a mediator of gonadotropin release. These findings contribute to a greater understanding of the influence of acute stress on reproductive endocrinology. STUDY FUNDING/COMPETING INTERESTS: Funding was received from the Erasmus University Medical Center. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: EudraCT Number 2012-005640-14.

Borderline and cluster C personality disorders manifest distinct physiological responses to psychosocial stress.

BACKGROUND: Maladaptive emotional control is a defining feature of personality disorders. Yet little is known about the underlying physiological dynamics of emotional reactivity to psychosocial stress across distinct personality disorders. The current study compared subjective emotional responses with autonomic nervous system and HPA axis physiological responses to psychosocial stress in women with cluster C personality disorder (CPD) and borderline personality disorder (BPD). METHODS: Subjective mood ratings, salivary cortisol, heart rate (HR), and skin conductance level (SCL) were assessed before, during, and after exposure to a standardized psychosocial stress paradigm (Trier Social Stress Test, TSST) in 26 women with BPD, 20 women with CPD, and 35 healthy female controls. Subjects were free of any medication including hormonal contraceptives, had a regular menstrual cycle, and were tested during the luteal phase of their menstrual cycle. RESULTS: Both CPD and BPD patients reported a similar burden of subjective mood disturbance. However, only BPD patients demonstrated reduced baseline cortisol levels with a blunted cortisol and HR reactivity to the TSST. In addition, BPD patients exhibited a generalized increase of SCL. No significant differences in baseline or TSST reactivity of cortisol, HR, or SCL were observed between CPD patients and healthy controls. CONCLUSION: These findings indicate that patients with BPD have significant alterations in their physiological stress reactivity, which is notably distinct from patients with CPD and those of healthy controls.

Stress Reactivity as a Prospective Predictor of Risky Substance Use During Adolescence.

OBJECTIVE: Youth who report risky substance use and who have a familial history of substance use disorders (SUDs) are at increased risk for developing SUDs themselves later in life. Physiological stress reactivity may be a potential biological mechanism underlying this increased risk. In the current study, we examined (a) whether physiological stress reactivity to a psychosocial stressor was prospectively related to risky substance use later in adolescence and (b) whether this relation was moderated by a familial history of SUDs. METHOD: Youth from the general population (n = 220) and the children of a parent/parents with an SUD (CPSUDs; n = 60) participated in a psychosocial stress procedure at Time 1. Cortisol and heart rate reactivity were measured during the procedure. Four years later, on average, risky substance use was self-reported (Time 2). RESULTS: Logistic regression analyses showed that youth who had lower cortisol reactivity at Time 1 were more likely to report risky substance use at Time 2. Heart rate reactivity was not related to risky substance use at Time 2, and the relation between stress reactivity and risky substance use was not more pronounced in CPSUDs compared with youth from the general population. These analyses were controlled for alcohol use at Time 1. CONCLUSIONS: The present findings suggest hyporeactivity of the hypothalamic-pituitary-adrenal axis in youth who are more likely to engage in risky substance use later in adolescence. These individuals may be inherently hypoaroused, which leads them to seek out substances in order to achieve a more normalized level of arousal.

Stress reactivity predicts symptom improvement in children with anxiety disorders.

BACKGROUND: We examined the longitudinal associations of autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis rest and reactivity measures with anxiety and depressive symptoms at one-year follow-up in children with anxiety disorders. METHODS: In a clinical sample of 152 children with a primary DSM-IV anxiety disorder, aged 8 to 12 years, anxiety and depressive symptoms were assessed with the Multidimensional Anxiety Scale for Children and the Children's Depression Inventory at pre-treatment baseline and one year later, after treatment with cognitive behavioral therapy. At baseline, children participated in a 70min stress task. Salivary cortisol was measured directly prior to and 20min post stress task. Skin conductance level (SCL), heart rate and high frequency heart rate variability (HRV) were continuously measured during rest and the stress task. To investigate if rest or reactivity measures predicted anxiety and depressive symptoms at one year follow-up, linear regression analyses were conducted for rest and reactivity measures of SCL, heart rate, HRV and cortisol separately. RESULTS: Higher SCL reactivity predicted less decrease of anxiety symptoms at one-year follow-up. Cortisol reactivity showed a weak association with depressive symptoms at one-year follow-up: lower cortisol reactivity predicted less decrease in depressive symptoms. LIMITATIONS: Only self-reported anxiety and depressive symptoms were used. However, all predictors were objective biological measures, hence there is no risk of shared method variance bias. CONCLUSIONS: These findings suggest that pre-treatment HPA and ANS responsiveness to stress are predictive biomarkers for a lack of symptom improvement in children with a clinical anxiety disorder.