Predicting response to leuprolide of women with premenstrual dysphoric disorder by daily mood rating dynamics

Approximately 60-70 percent of women with premenstrual dysphoric disorder (PMDD) show symptomatic improvement in response to the GnRH agonist leuprolide acetate, which suppresses ovarian function. However, it has been very difficult to either predict or understand why some women respond, while others do not. We applied several complementary statistical methods to the dynamics of pre-treatment mood rating data to determine possible predictors of response for women with PMDD. We compared responders (n = 33) to nonresponders (n = 12) in clinical trials of leuprolide (three months in duration) as a treatment for PMDD, on the basis of pre-trial daily self-ratings of sadness, anxiety, and irritability. We analyzed both sequential irregularity (approximate entropy, ApEn) and a quantification of spikiness of these series, as well as a composite measure that equally weighted these two statistics. Both ApEn and Spikiness were significantly smaller for responders than nonresponders (P ≤ 0.005); the composite measure was smaller for responders compared with nonresponders (P ≤ 0.002) and discriminated between the subgroups with high sensitivity and specificity. In contrast, mean symptom levels were indistinct between the subgroups. Relatively regular and non-spiky pre-trial dynamics of mood ratings predict a positive response to leuprolide by women with PMDD with high probability, moreover based on typically less than 3 months of daily records. The statistical measures may have broad and direct applicability to behavioral studies for many psychiatric disorders, facilitating both accurate diagnosis and the prediction of response to treatment.     

Endocannabinoid system dysfunction in mood and related disorders

Ashton CH, Moore PB. Endocannabinoid system dysfunction in mood and related disorders. Objective: The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders. Method: An overview is presented of the literature focussed on the functions of the EC system, its dysfunction in mood disorders and the therapeutic potential of exogenous cannabinoids. Results: We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid‐1 receptor (CNR1) gene that codes for cannabinoid‐1(CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement. Conclusion: Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential.     

Differentiation of women with premenstrual dysphoric disorder, recurrent brief depression, and healthy controls by daily mood rating dynamics

Enhanced statistical characterization of mood-rating data holds the potential to more precisely classify and sub-classify recurrent mood disorders like premenstrual dysphoric disorder (PMDD) and recurrent brief depressive disorder (RBD). We applied several complementary statistical methods to differentiate mood rating dynamics among women with PMDD, RBD, and normal controls (NC). We compared three subgroups of women: NC (n=8); PMDD (n=15); and RBD (n=9) on the basis of daily self-ratings of sadness, study lengths between 50 and 120 days. We analyzed mean levels; overall variability, SD; sequential irregularity, approximate entropy (ApEn); and a quantification of the extent of brief and staccato dynamics, denoted 'Spikiness'. For each of SD, irregularity (ApEn), and Spikiness, we showed highly significant subgroup differences, ANOVA0.001 for each statistic; additionally, many paired subgroup comparisons showed highly significant differences. In contrast, mean levels were indistinct among the subgroups. For SD, normal controls had much smaller levels than the other subgroups, with RBD intermediate. ApEn showed PMDD to be significantly more regular than the other subgroups. Spikiness showed NC and RBD data sets to be much more staccato than their PMDD counterparts, and appears to suitably characterize the defining feature of RBD dynamics. Compound criteria based on these statistical measures discriminated diagnostic subgroups with high sensitivity and specificity. Taken together, the statistical suite provides well-defined specifications of each subgroup. This can facilitate accurate diagnosis, and augment the prediction and evaluation of response to treatment. The statistical methodologies have broad and direct applicability to behavioral studies for many psychiatric disorders, and indeed to similar analyses of associated biological signals across multiple axes.     

Sympathetic reactivity in agoraphobic patients with and without personality disorders

OBJECTIVE: To compare sympathetic activity in agoraphobic patients with and without personality disorders before and after 11 weeks inpatient treatment. METHODS: Agoraphobic patients (n=38), 84% with panic disorder and 47% with personality disorders underwent cold pressure test (CPT), mental stress test (MST), and a specific anxiety test (SAT). Psychological assessments were done by the Bodily Sensations Questionnaire (BSQ), the Agoraphobic Cognitions Questionnaire (ACQ), Spielberger STAI-1 and -2, and a Stress Test Anxiety (STA) questionnaire. Sympathetic activity was measured by blood pressure, heart rate, epinephrine, and norepinephrine. RESULTS: The sympathetic activity did not differ significantly between patient groups, and the reactivity to stress was very low. The sympathetic reactivity remained unchanged after treatment, whereas psychiatric symptoms decreased. Correlations between sympathetic activity and psychological distress were not significant. CONCLUSION: Interpretation of bodily signals seems to be more important than the actual sympathetic activity in agoraphobic patients.     

Psychiatric disorders are associated with hospital care utilization in persons with hypertension

Background  Psychiatric disorders and hypertension both independently increase risk for heart disease, cardiac events, and healthcare utilization. However, the contribution of specific psychiatric disorders to healthcare utilization in persons with hypertension is unknown. Objective  To evaluate associations between psychiatric disorders and receipt of hospital care in people with hypertension. Design  Cross-sectional epidemiologic survey. Subjects  A total of 8,812 hypertensive individuals drawn from a randomly selected sample of 43,093 US adults. Main outcomes  Participants were assessed in-person for a range of mental disorders (using the Diagnostic and Statistical Manual of Mental Disorders-IV), hypertension status (self-report), and past-year occurrence of emergency room treatment and overnight hospital stay (self-report). Results  After controlling for demographics and clinical variables, persons having any lifetime mood, anxiety, or personality disorders had increased likelihood of emergency room treatment [odds ratios (ORs) = 1.26, 1.18, and 1.47, respectively]. Persons having any mood or personality disorder had increased likelihood of overnight hospital stay (ORs  = 1.24 and 1.31, respectively). The specific disorders significantly associated with emergency room treatment were lifetime major depression, lifetime manic disorder, past-year major depression, past-year manic disorder, past-year panic disorder without agoraphobia, and paranoid, histrionic, antisocial, obsessive–compulsive personality disorders, with ORs ranging from 1.25 to 2.41. The specific disorders significantly associated with overnight hospital stay were lifetime dysthymia, lifetime manic disorder, past-year major depression, past-year manic disorder, and histrionic, antisocial, and paranoid personality disorders, with ORs ranging from 1.40 to 1.87. Conclusion  Results suggest that addressing mental health problems in persons with hypertension may decrease healthcare utilization.     

Self-assessed parental depressive problems are associated with blunted cortisol responses to a social stress test in daughters. The TRAILS Study

Depression runs in families and is considered a stress-related disorder. Familial risk for depression may be transmitted via deregulated psychophysiological stress responses from parent to child. In this study, we examined the association between self-assessed lifetime parental depressive problems (PDP) and adolescent offspring' cortisol responses to a social stress test. Data were collected as part of the third assessment wave of TRAILS (TRacking Adolescents' Individual Lives Survey), a large prospective population study of Dutch adolescents. Data of 330 adolescents (mean age 16.04; 40.9% girls) who participated in a laboratory session, including a standardized performance-related social stress task (public speaking and mental arithmetic) were examined. Four saliva cortisol samples were collected before, during and after the social stress task which were analyzed with repeated measures Analysis of Variance. Lifetime parental depressive problems were assessed by self-reports from both biological parents. PDP was associated with daughter' cortisol responses (F(3,133)=3.90, p=.02), but no association was found in sons (F(3,193)=0.27, p=.78). Girls whose parents ever experienced depressive symptoms displayed a blunted cortisol response to the standardized social stress test, while girls whose parents never had such problems displayed the characteristic curvilinear response pattern. This effect was not mediated by offspring stress history (age 0-16). Analyses were corrected for smoking behaviour and adolescent depressed mood. The fact that PDP were measured by self-report questionnaires and did not reflect clinical DSM-IV diagnosis could be considered a limitation of the study.     

Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress

Central endocannabinoid signaling is known to be responsive to stressful stimuli; however, there is no research to date characterizing the effects of stress on peripheral endocannabinoid content. The current study examined serum content of the endocannabinoid ligands N-arachidonylethanolamide (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), and the non-cannabinoid N-acyl ethanolamine (NAE) molecules palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) under basal conditions, immediately following the Trier Social Stress Test (TSST), and 30 min thereafter, in 15 medication-free women diagnosed with major depression, and 15 healthy matched controls. Basal serum concentrations of AEA and 2-AG, but not PEA or OEA, were significantly reduced in women with major depression relative to matched controls, indicating a deficit in peripheral endocannabinoid activity. Immediately following the TSST, serum 2-AG concentrations were increased compared to baseline; serum AEA concentration was unchanged at this time point. Serum concentrations of PEA and OEA were significantly lower than baseline 30 min following the cessation of the TSST. The magnitude of these responses did not differ between depressed and control subjects. These are the first data to demonstrate that the peripheral endocannabinoid/NAE system is responsive to exposure to stress.     

Increased stress reactivity is associated with cognitive deficits and decreased hippocampal brain-derived neurotrophic factor in a mouse model of affective disorders

Cognitive deficits are a common feature of major depression (MD), with largely unknown biological underpinnings. In addition to the affective and cognitive symptoms of MD, a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is commonly observed in these patients. Increased plasma glucocorticoid levels are known to render the hippocampus susceptible to neuronal damage. This structure is important for learning and memory, creating a potential link between HPA axis dysregulation and cognitive deficits in depression. In order to further elucidate how altered stress responsiveness may contribute to the etiology of MD, three mouse lines with high (HR), intermediate (IR), or low (LR) stress reactivity were generated by selective breeding.The aim of the present study was to investigate whether increased stress reactivity is associated with deficits in hippocampus-dependent memory tests. To this end, we subjected mice from the HR, IR, and LR breeding lines to tests of recognition memory, spatial memory, and depression-like behavior. In addition, measurements of brain-derived neurotrophic factor (BDNF) in the hippocampus and plasma of these animals were conducted.Our results demonstrate that HR mice exhibit hippocampus-dependent memory deficits along with decreased hippocampal, but not plasma, BDNF levels. Thus, the stress reactivity mouse lines are a promising animal model of the cognitive deficits in MD with the unique feature of a genetic predisposition for an altered HPA axis reactivity, which provides the opportunity to explore the progression of the symptoms of MD, predisposing genetic factors as well as new treatment strategies.     

Menstrual cycle‐related changes in amygdala morphology are associated with changes in stress sensitivity

Premenstrual increases in negative mood are thought to arise from changes in gonadal hormone levels, presumably by influencing mood regulation and stress sensitivity. The amygdala plays a major role in this context, and animal studies suggest that gonadal hormones influence its morphology. Here, we investigated whether amygdala morphology changes over the menstrual cycle and whether this change explains differences in stress sensitivity. Twenty‐eight young healthy women were investigated once during the premenstrual phase and once during the late follicular phase. T1‐weighted anatomical images of the brain were acquired using magnetic resonance imaging and analyzed with optimized voxel‐based morphometry. To measure mood regulation and stress sensitivity, negative affect was assessed after viewing strongly aversive as well as neutral movie clips. Our results show increased gray matter volume in the dorsal part of the left amygdala during the premenstrual phase when compared with the late follicular phase. This volume increase was positively correlated with the premenstrual increase in stress‐induced negative affect. This is the first study showing structural plasticity of the amygdala in humans at the macroscopic level that is associated with both endogenous gonadal hormone fluctuations and stress sensitivity. These results correspond with animal findings of gonadal hormone‐mediated neural plasticity in the amygdala and have implications for understanding the pathogenesis of specific mood disorders associated with hormonal fluctuations. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Duration of untreated illness and depression severity are associated with cognitive impairment in mood disorders

Abstract

Introduction: In this study we estimated the rate and the trajectory of cognitive impairment in a naturalistic sample of outpatients with major depressive disorder (MDD) and bipolar disorder (BD) and its correlation with different variables.

Materials and methods: An overall sample of 109 outpatients with MDD or BD was assessed for multiple clinical variables, including duration of untreated illness (DUI), and tested using the Montreal Cognitive Assessment (MoCA) during Major Depressive Episodes (MDE) and after remission. Correlations between MoCA scores and the clinical variables were then computed.

Results: About 50% of patients with MDD and BD showed mild cognitive impairment during MDE. Improvement of cognitive function between depression and remission was significant, even though residual symptoms were observed especially in the most impaired patients. Of note, cognitive performance during depression was negatively associated with depression severity and DUI.

Discussion: Present findings confirm available evidence about patterns of cognitive impairment in mood disorders, in terms of prevalence and persistence beyond remission in most severe cases. Moreover, a longer DUI was associated with worse cognitive performance during depression, and consequently with poorer outcome, underlining the importance of prompt treatment of these disorders also in light of a cognitive perspective.

• Keypoints

• Although distinct entities, unipolar and bipolar depression determine similar patterns of cognitive impairment in terms of severity and types of altered domains.

• Depression (but not anxiety) severity is associated with cognitive performance in depression.

• Prolonged duration of untreated illness is associated with more severe cognitive impairment during depression, particularly but not specifically in bipolar disorder.

     

Peripheral psychophysiological reactivity to mental tasks in children with psychiatric disorders

Summary Peripheral psychophysiological reactivity (skin conductance and heart rate changes) to mental activity tasks (imagery and listening to music) was examined in child psychiatric day or in-patients with conduct and emotional disorders. Children with predominant antisocial symptomatology showed higher electrodermal than cardiovascular reactivity to the experimental tasks, whilst children with predominant neurotic symptoms showed more marked cardiovascular reactivity. No statistical differences between the groups emerged in response to listening to music, but antisocials were more responsive (with higher skin conductance level increases) to imagining pleasant situations, whereas neurotics were more reactive (increased heart rate levels and decreases in skin conductance) to imagining unpleasant situations. The results are compatible with an enhanced biological responsiveness by antisocials to reward and with neurotics experiencing an unusually marked sense of threat and withdrawal to aversive stimuli.     

Disordered eating behaviour is associated with blunted cortisol and cardiovascular reactions to acute psychological stress

Research suggests a potential dysregulation of the stress response in individuals with bulimia nervosa. This study measured both cardiovascular and cortisol reactions to a standardised laboratory stress task in individuals identified as showing disordered eating behaviour to determine whether dysregulation of the stress response is characteristic of the two branches of the stress response system. Female students (N=455) were screened using two validated eating disorder questionnaires. Twelve women with disordered eating, including self-induced vomiting, and 12 healthy controls were selected for laboratory stress testing. Salivary cortisol and cardiovascular activity, via Doppler imaging and semi-automatic blood pressure monitoring, were measured at resting baseline and during and after exposure to a 10-min mental arithmetic stress task. Compared to controls the disordered eating group showed blunted cortisol, cardiac output, heart rate, and stroke volume reactions to the acute stress, as well as an attenuated vasodilatory reaction. These effects could not be accounted for in terms of group differences in stress task performance, subjective task impact/engagement, age, BMI, neuroticism, cardio-respiratory fitness, or co-morbid exercise dependence. Our findings suggest that disordered eating is characterised by a dysregulation of the autonomic stress-response system. As such, they add further weight to the general contention that blunted stress reactivity is characteristic of a number of maladaptive behaviours and states.     

Serum levels of second-generation antipsychotics are associated with cognitive function in psychotic disorders

Objectives: Antipsychotics are effective in treating psychosis and mood episodes; however, the effect on cognition is less known. We investigated the association between serum levels of second-generation antipsychotics (SGAs) and cognitive performance in psychosis spectrum disorders in a naturalistic setting.

Methods: A total of 495 patients with a DSM-IV Schizophrenia and Other Psychotic Disorders (SCZ, n?=?373) or Bipolar Disorder (BD, n?=?122) diagnosis treated with olanzapine, quetiapine, aripiprazole or risperidone were tested neuropsychologically with concurrent measurement of the serum concentration of the drug. Linear regression was used for association analyses.

Results: Attention was positively associated with the olanzapine concentration (standardised beta (β) coefficient =?0.19, P?=?.006), and short-term verbal memory and verbal fluency were negatively associated with the quetiapine (β?=?–0.24, P?=?.004) and risperidone (β?=?–0.37, P?=?.007) concentrations respectively.

Conclusions: The present results suggest that SGA serum concentration is associated with better attention (small effect size), and worse verbal memory (small effect size) and verbal fluency (medium effect size). These findings are in line with the notion that SGAs affect aspects of cognitive function, and suggest careful dosing in patients with severe memory and executive problems.     

Undiagnosed sleep-related breathing disorders are associated with focal brainstem atrophy in the elderly

Background: Sleep‐related breathing disorders (SRBDs) affect as many as 40% of elderly people. The association of SRBDs with structural brain abnormalities remains unclear. In this observational study, we evaluated gray matter changes in the brain associated with sleep abnormalities in volunteers and their relationship with the severity of SRBDs. Methods: One hundred fifty two healthy subjects aged 66.0 ± 0.6 years‐old underwent tridimensional brain MRI and nocturnal polygraphic recording during which apnea/hypopnea index (AHI) and the oxyhemoglobin desaturation index (ODI) were measured. Using voxel‐based morphometry, we investigated the presence of gray matter abnormalities in association with AHI and ODI. Findings: Seventy‐six subjects (50%) had SRBDs defined by an AHI ≥ to 15 and 25 subjects (16%) SRBDs defined by an ODI ≥ 15, in the absence of systematic excessive daytime sleepiness. A significant symmetrical loss of gray matter in the intermediate reticular zone of the bulbopontine area was found to correlate with both AHI and ODI (P < 0.05 corrected for multiple comparisons for cluster significance). Interpretation: This gray matter volume decrease in brain regions involved in breathing/autonomic functions, as well as their correlation with the severity of the disorder, suggests a pathophysiological link between structural changes and SRBDs. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Human hypothalamus-pituitary-adrenal axis responses to acute psychosocial stress in laboratory settings

Cumulative acute psychosocial stress is thought to promote the development of a range of disorders which suggests that biomarkers for the physiological response may become valuable tools for biomedical research and development. The search for these biomarkers has been aided by the development of a standardised protocol for inducing psychosocial stress that combines social-evaluative threat and uncontrollability, i.e., the Trier Social Stress Test (TSST). Among other biological markers of acute stress, this test induces significant changes of the hypothalamus-pituitary-adrenal axis (HPAA), which is thought to play a pivotal role in the generation of stress-associated pathologies. The HPAA responses show differences between patients and healthy subjects as well as between pathologies. Moreover, gender, age, personality traits, social environment, and genotype can also shape the individual's acute stress response triggered by the TSST. Characterization of the roles and interactions of these factors in generating a dysregulation of the neuroendocrine responses to acute psychosocial stress await longitudinal studies.     

Asymmetry between salivary cortisol and alpha-amylase reactivity to stress: relation to aggressive behavior in adolescents

This study used a multiple physiological systems measurement approach to test the hypothesis that asymmetry between the major components of the psychobiology of stress is associated with atypical behavior in youth [Bauer, A.M., Quas, J.A., Boyce, W.T., 2002. Associations between physiological reactivity and children's behavior: advantages of a multisystem approach. J. Dev. Behav. Pediatr. 23, 102-113]. Adolescents (N=67; ages 10-14; 52% male) provided 2 saliva samples before, and 4 samples after, a modified Trier Social Stress Test (TSST; Kirschbaum, C., Pirke, K., Hellhammer, D.H., 1993. The "Trier Social Stress Test": a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 28, 76-81). Samples were assayed for cortisol (C) and alpha-amylase (A-A), a surrogate marker of sympathetic nervous system (SNS) activity. Parents/guardians and adolescents reported on adolescents' aggressive behavior. Both salivary A-A and C increased in response to the TSST, with a peak response for A-A immediately post-TSST and for C 10 min post-TSST. A-A and C stress reactivity were estimated using area under the curve (AUC). Asymmetrical C and A-A reactivity accounted for 7% of the variance in parent-reported adolescent aggression. At lower levels of A-A reactivity, lower C reactivity corresponded to higher aggression ratings, but at high A-A reactivity levels, C reactivity was not related to aggression. These results support the hypothesis of Bauer et al. and underscore the importance of a multiple systems measurement approach in biosocial models of adolescent aggression.