Dynamic time warp analysis of individual symptom trajectories in individuals with bipolar disorder.

BACKGROUND: Manic and depressive mood states in bipolar disorder (BD) may emerge from the non-linear relations between constantly changing mood symptoms exhibited as a complex dynamic system. Dynamic Time Warp (DTW) is an algorithm that may capture symptom interactions from panel data with sparse observations over time. METHODS: The Young Mania Rating Scale and Quick Inventory of Depressive Symptomatology were repeatedly assessed in 141 individuals with BD, with on average 5.5 assessments per subject every 3-6 months. Dynamic Time Warp calculated the distance between each of the 27 × 27 pairs of standardized symptom scores. The changing profile of standardized symptom scores of BD participants was analyzed in individual subjects, yielding symptom dimensions in aggregated group-level analyses. Using an asymmetric time-window, symptom changes that preceded other symptom changes (i.e., Granger causality) yielded a directed network. RESULTS: The mean age of the BD participants was 40.1 (SD 13.5) years old, and 60% were female participants. Idiographic symptom networks were highly variable between subjects. Yet, nomothetic analyses showed five symptom dimensions: core (hypo)mania (6 items), dysphoric mania (5 items), lethargy (7 items), somatic/suicidality (6 items), and sleep (3 items). Symptoms of the "Lethargy" dimension showed the highest out-strength, and its changes preceded those of "somatic/suicidality," while changes in "core (hypo)mania" preceded those of "dysphoric mania." CONCLUSION: Dynamic Time Warp may help to capture meaningful BD symptom interactions from panel data with sparse observations. It may increase insight into the temporal dynamics of symptoms, as those with high out-strength (rather than high in-strength) could be promising targets for intervention.

Childhood trauma and anger in adults with and without depressive and anxiety disorders.

BACKGROUND: Childhood trauma (CT) is associated with severe sequelae, including stress-related mental health disorders that can perpetuate long into adulthood. A key mechanism in this relationship seems to be emotion regulation. We aimed to investigate (1) whether childhood trauma is associated with anger in adulthood, and, if so, (2) to explore which types of childhood trauma predominate in the prediction of anger in a cohort that included participants with and without current affective disorders. METHODS: In the Netherlands Study of Depression and Anxiety (NESDA), childhood trauma was assessed with a semi-structured Childhood Trauma Interview (CTI) at baseline, and analyzed in relation to anger as measured at a 4-year follow-up with the Spielberger Trait Anger Subscale (STAS), the Anger Attacks Questionnaire, and cluster B personality traits (i.e., borderline, antisocial) of the Personality Disorder Questionnaire 4 (PDQ-4), using analysis of covariance (ANCOVA) and multivariable logistic regression analyses. Post hoc analyses comprised cross-sectional regression analyses, using the Childhood Trauma Questionnaire-Short Form (CTQ-SF) also obtained at a 4-year follow-up. RESULTS: Participants (n = 2271) were on average 42.1 years (SD = 13.1), and 66.2% were female. Childhood trauma showed a dose-response association with all anger constructs. All types of childhood trauma were significantly associated with borderline personality traits, independently of depression and anxiety. Additionally, all types of childhood trauma except for sexual abuse were associated with higher levels of trait anger, and a higher prevalence of anger attacks and antisocial personality traits in adulthood. Cross-sectionally, the effect sizes were larger compared with the analyses with the childhood trauma measured 4 years prior to the anger measures. CONCLUSIONS: Childhood trauma is linked with anger in adulthood, which could be of particular interest in the context of psychopathology. Focus on childhood traumatic experiences and adulthood anger may help to enhance the effectiveness of treatment for patients with depressive and anxiety disorders. Trauma-focused interventions should be implemented when appropriate.

Understanding personalized dynamics to inform precision medicine: a dynamic time warp analysis of 255 depressed inpatients.

BACKGROUND: Major depressive disorder (MDD) shows large heterogeneity of symptoms between patients, but within patients, particular symptom clusters may show similar trajectories. While symptom clusters and networks have mostly been studied using cross-sectional designs, temporal dynamics of symptoms within patients may yield information that facilitates personalized medicine. Here, we aim to cluster depressive symptom dynamics through dynamic time warping (DTW) analysis. METHODS: The 17-item Hamilton Rating Scale for Depression (HRSD-17) was administered every 2 weeks for a median of 11 weeks in 255 depressed inpatients. The DTW analysis modeled the temporal dynamics of each pair of individual HRSD-17 items within each patient (i.e., 69,360 calculated "DTW distances"). Subsequently, hierarchical clustering and network models were estimated based on similarities in symptom dynamics both within each patient and at the group level. RESULTS: The sample had a mean age of 51 (SD 15.4), and 64.7% were female. Clusters and networks based on symptom dynamics markedly differed across patients. At the group level, five dynamic symptom clusters emerged, which differed from a previously published cross-sectional network. Patients who showed treatment response or remission had the shortest average DTW distance, indicating denser networks with more synchronous symptom trajectories. CONCLUSIONS: Symptom dynamics over time can be clustered and visualized using DTW. DTW represents a promising new approach for studying symptom dynamics with the potential to facilitate personalized psychiatric care.

Cognitive change after electroconvulsive therapy in mood disorders measured with the Montreal Cognitive Assessment.

OBJECTIVE: The Montreal Cognitive Assessment (MoCA) is a sensitive and clinically practical test but its usefulness in measuring long-term cognitive effects of ECT is unclear. Using the MoCA, we investigated short- and long-term global cognitive change in ECT-treated patients with a Major Depressive Episode (MDE). METHOD: We included 65 consecutive ECT-treated patients with MDE, in whom global cognitive functioning was assessed at baseline (T0); during ECT (before the third session; T1); and 1 week (T2), 3 months (T3), and 6 months (T4) after completion of the index course. Changes in MoCA (sub)scores were analyzed using linear mixed models and reliable change indices were computed to investigate individual changes in MoCA total scores. RESULTS: There was a significant effect of time on MoCA scores (F(4, 230.5) = 4.14, P = 0.003), with an improvement in global cognitive functioning from T3 compared to T1 and T2. At the individual level, 26% (n = 17) of patients showed a significantly worse cognitive functioning at T2 and 12% (n = 8) an improved cognitive functioning compared to T0. For T4, these percentages ameliorated to 8% and 18% respectively. CONCLUSION: No persistent global cognitive impairment induced by ECT was found at the group level using the MoCA. At the individual level, however, there was clear heterogeneity in the effects of ECT on cognitive functioning. The MoCA is a suitable tool to monitor short- and long-term global cognitive functioning in ECT-treated patients with MDE but in younger patients, potential ceiling effects must be taken into account.

Fatty acids and recurrence of major depressive disorder: combined analysis of two Dutch clinical cohorts.

OBJECTIVE: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) alterations in patients with major depressive disorder (MDD) have been shown to persist after remission. Whether these alterations are risk factors for MDD recurrence remains unknown. Here, we examined whether fatty acids predict time until MDD recurrence in remitted MDD patients. METHODS: Data were used from remitted MDD patients of the Netherlands Study of Depression and Anxiety (n = 356) and the Depression Evaluation Longitudinal Therapy Assessment studies (n = 118). Associations of FAs with time until MDD recurrence up to 8-year follow-up were analyzed using Cox regression analyses. Study-specific estimates were pooled using mega- and meta-analysis techniques. RESULTS: 27.5% (NESDA) and 56.8% (DELTA) participants had an MDD recurrence. Pooled results showed that no FA was significantly associated with time until MDD recurrence (n-3 PUFAs: hazard ratio (HR) = 1.17, 95% confidence interval (CI) = 0.98-1.41, P = 0.082; n-6 PUFAs: HR = 1.08, 95% CI = 0.84-1.38, P = 0.55). CONCLUSION: In remitted MDD patients, circulating PUFAs were not associated with prospective risk of MDD recurrence. Consequently, circulating PUFAs are unlikely to reflect a vulnerability marker for recurrence, so correcting n-3 PUFA 'deficits' through supplementation does not seem a promising option to prevent MDD recurrence.

[Nutrition and mental disorders during the life span: an overview of scientific evidence]. / Voeding bij psychische aandoeningen gedurende de levensloop; een overzicht van de evidentie.

BACKGROUND: Nutritional interventions are scarcely used in the prevention and treatment of mental disorders.
AIM: To summarize scientific evidence on the relation between nutrition and mental health, across the life span.
METHOD: An overview of the literature based on recent knowledge syntheses, meta-analyses and original studies.
RESULTS: Healthy dietary patterns are associated with a lower risk for depressive symptoms among adults and potentially also among children and adolescents. Dietary interventions can be effective in reducing depressive symptoms among high-risk groups and can have a beneficial effect in the treatment of depression. Meta-analyses of randomised studies have shown that omega-3 fatty acid supplements can be of added value in the treatment of adhd in children and of depression in adults.
CONCLUSION: Promotion of healthy dietary patterns in line with National guidelines for healthy diets is important in the entire spectrum from good mental health to a chronic disorder. More attention for improving healthy dietary patterns among patients with mental disorders can lead to important health gains.

Severity, course trajectory, and within-person variability of individual symptoms in patients with major depressive disorder.

BACKGROUND: Depression shows a large heterogeneity of symptoms between and within persons over time. However, most outcome studies have assessed depression as a single underlying latent construct, using the sum score on psychometric scales as an indicator for severity. This study assesses longitudinal symptom-specific trajectories and within-person variability of major depressive disorder over a 9-year period. METHODS: Data were derived from the Netherlands Study of Depression and Anxiety (NESDA). This study included 783 participants with a current major depressive disorder at baseline. The Inventory Depressive Symptomatology-Self-Report (IDS-SR) was used to analyze 28 depressive symptoms at up to six time points during the 9-year follow-up. RESULTS: The highest baseline severity scores were found for the items regarding energy and mood states. The core symptoms depressed mood and anhedonia had the most favorable course, whereas sleeping problems and (psycho-)somatic symptoms were more persistent over 9-year follow-up. Within-person variability was highest for symptoms related to energy and lowest for suicidal ideation. CONCLUSIONS: The severity, course, and within-person variability differed markedly between depressive symptoms. Our findings strengthen the idea that employing a symptom-focused approach in both clinical care and research is of value.

Metabolic and inflammatory markers: associations with individual depressive symptoms.

BACKGROUND: Literature has shown that obesity, metabolic syndrome and inflammation are associated with depression, however, evidence suggests that these associations are specific to atypical depression. Which of the atypical symptoms are driving associations with obesity-related outcomes and inflammation is unknown. We evaluated associations between individual symptoms of depression (both atypical and non-atypical) and body mass index (BMI), metabolic syndrome components and inflammatory markers. METHODS: We included 808 persons with a current diagnosis of depression participating in the Netherlands Study of Depression and Anxiety (67% female, mean age 41.6 years). Depressive symptoms were derived from the Composite International Diagnostic Interview and the Inventory of Depressive Symptomatology. Univariable and multivariable regression analyses adjusting for sex, age, educational level, depression severity, current smoking, physical activity, anti-inflammatory medication use, and statin use were performed. RESULTS: Increased appetite was positively associated with BMI, number of metabolic syndrome components, waist circumference, C-reactive protein and tumor necrosis factor-α. Decreased appetite was negatively associated with BMI and waist circumference. Psychomotor retardation was positively associated with BMI, high-density lipoprotein cholesterol and triglycerides, and insomnia with number of metabolic syndrome components. CONCLUSION: Increased appetite - in the context of a depressive episode - was the only symptom that was associated with both metabolic as well as inflammatory markers, and could be a key feature of an immuno-metabolic form of depression. This immuno-metabolic depression should be considered in clinical trials evaluating effectiveness of compounds targeting metabolic and inflammatory pathways or lifestyle interventions.

Testosterone in human studies: Modest associations between plasma and salivary measurements.

Testosterone is involved in many processes like aggression and mood disorders. As it may easily diffuse from blood into saliva, salivary testosterone is thought to reflect plasma free testosterone level. If so, it would provide a welcome noninvasive and less stressful alternative to blood sampling. Past research did not reveal consensus regarding the strength of the association, but sample sizes were small. This study aimed to analyse the association in a large cohort. In total, 2,048 participants (age range 18-65 years; 696 males and 1,352 females) were included and saliva (using cotton Salivettes) and plasma were collected for testosterone measurements. Levels were determined by enzyme-linked immunosorbent assay and radioimmunoassay respectively. Free testosterone was calculated by the Vermeulen algorithm. Associations were determined using linear regression analyses. Plasma total and free testosterone showed a significant association with salivary testosterone in men (adjusted ß = .09, p = .01; and ß = .15, p < .001, respectively) and in women (adjusted ß = .08, p = .004; and crude ß = .09, p = .002 respectively). The modest associations indicate that there are many influencing factors of both technical and biological origin.

[Emotional scars: impact of childhood trauma on the development of depressive and anxiety disorders later in life]. / Emotionele littekens: langetermijn-gevolgen van jeugdtrauma voor angst- en depressieve stoornissen.

BACKGROUND: Childhood trauma and negative life events in childhood are risk factors for the development of anxiety and depressive disorders in adulthood.
AIM: To increase our understanding of the specific associations between trauma and negative life events in childhood and the development and course of anxiety and depressive disorders in adulthood.
METHOD: Our research findings are based on data from the Netherlands Study of Depression and Anxiety (NESDA). In our article we report on two cross-sectional and three prospective studies.
RESULTS: All domains of childhood trauma are risk factors for the development of anxiety and/or depressive disorders in adulthood. Emotional neglect is the main independent predictor of the occurrence and the course of anxiety and depressive disorders. Certain personality characteristics and more unfavorable clinical factors play an important role in mediating the relationship between childhood trauma and the course of anxiety and depressive disorders later in life.
CONCLUSION: Not only does childhood trauma increase an individual's vulnerability to the development of anxiety and depressive disorders, it is also associated with a more serious and more chronic course of these disorders. Our studies have provided new insights into the underlying mechanism that links childhood trauma and anxiety and later anxiety depressive disorders. Consequently, we feel justified in making some recommendations with regards to clinical practice and public health interventions.

[Successful amantadine treatment of a patient with ECT-resistant catatonia]. / Succesvolle behandeling met amantadine bij een patiënt met ECT-resistente maligne katatonie.

Catatonia is a common neuropsychiatric syndrome. There is a life-threatening subtype of this disease known as malignant catatonia. One of the hypotheses regarding the pathogenesis is an imbalance of multiple neurotransmitters (gaba, glutamate and dopamine). The first step in treatment is to administer benzodiazepines; if the response is insufficient, the treatment can be replaced by electroconvulsive therapy (ect). So far, there is no consensus with regard to the tertiary treatment step. On the basis of a case report we describe the beneficial effects of administering an nmda receptor antagonist, amantadine, as the tertiary step for treating a patient with treatment-resistant malignant catatonia.

The bidirectional impact of perceived and enacted support on mood in bipolar outpatients: A two-year prospective study.

Bipolar disorder (BD) is a chronic illness, and a great need has been expressed to elucidate factors affecting the course of the disease. Social support is one of the psychosocial factors that is assumed to play an important role in the course of BD, but it is largely unknown whether the depressive and/or manic symptoms also affect the patients' support system. Further, the perception of one's social support appears to have stronger effects on disease outcomes than one's enacted or received support, but whether this also applies to BD has not been investigated. The objective of this study is to examine temporal, bidirectional associations between mood states (depression and mania) and both enacted and perceived support in BD patients. The current study was conducted among 173 BD I and II outpatients, with overall light to mild mood symptoms. Severity of mood symptoms and social support (enacted as well as perceived) were assessed every 3months, for 2years (1146 data points). Multilevel regression analyses (linear mixed-models) showed that lower perceived support during 3months was associated with subsequent higher levels of depressive, but not of manic symptoms in the following 3months. Vice versa, depressive symptoms during 3months were associated with less perceived support in the following 3months. Further, manic symptoms during 3months were associated with less enacted support in the subsequent 3 months. The current study suggests that perceived, but not enacted, support is consistently related to depressive symptoms in a bidirectional way, while mania is specifically associated with a subsequent loss of enacted support. Clinical implications of the current findings are discussed.

(Patho)physiology of cross-sex hormone administration to transsexual people: the potential impact of male-female genetic differences.

There is a limited body of knowledge of desired and undesired effects of cross-sex hormones in transsexual people. Little attention has been given to the fact that chromosomal configurations, 46,XY in male-to-female transsexuals subjects (MtoF) and 46,XX in female-to-male transsexual subjects (FtoM), obviously, remain unchanged. These differences in their genomes cause sex differences in the functions of cells. This study reviews sex differences in metabolism/cardiovascular pathology, immune mechanisms, bone (patho)physiology and brain functions and examines whether they are, maybe partially, determined by genetic mechanisms rather than by (cross-sex) hormones. There do not appear to be major genetic impacts on the changes in bone physiology. Also immune functions are rather unaffected and the evidence for an increase of autoimmune disease in MtoF is preliminary. Brain functions of transsexuals may have differed from controls before cross-sex hormones; they do undergo shifts upon cross-sex hormone treatment, but there is no evidence for changes in sex-specific brain disease. The prevalence of cardiovascular disease is higher in MtoF receiving oestrogens than in FtoM receiving androgens. While type of oestrogen and route of administration might be significant, it is reasonable to speculate that nonhormonal/genetic factors play a role.

Men and women, so different, so similar: observations from cross-sex hormone treatment of transsexual subjects.

Sexual differentiation in mammals is largely driven by the presence of androgen in males and their absence in females. The presence of androgens induces a number of irreversible changes in males: prenatally, the genital differentiation; during puberty, the development of secondary sex characteristics - the larger facial bones, hand, feet and height in males. A large number of metabolic variables are influenced by sex hormones and consequently show difference between men and women, and this helps to explain differences in pathologies, such as cardiovascular disease, bone fractures and auto immune disease. There is some recent evidence that some sex differences in brain functions are not mediated by sex hormones, but by-products of genes located on the X and Y chromosomes. This communication reviews the results of administration of cross-sex hormone treatment to transsexual persons transitioning to the other sex. Natal males are treated with anti-androgens+oestrogens and natal females with testosterone. This provides a unique opportunity to study which metabolic functions are not irreversibly sex-differentiated but are determined by the prevailing milieu of sex steroids. The insights gained with these studies should lead to a better appreciation of the role of sex steroids in cardiovascular disease and diabetes mellitus which presently do not receive due attention.

[The Leiden Routine Outcome Monitoring Study: mood, anxiety and somatoform disorders in patients attending a day clinic]. / De Leiden Routine Outcome Monitoring Studie: beloop van stemmings-, angst- en somatoforme stoornissen in de poliklinische praktijk.

BACKGROUND: Routine outcome monitoring (rom) is a method for the systematic monitoring of treatment-progression. Because rom data are collected regularly and systematically, we believe it should be possible to use these data in clinical epidemiological research. AIM: To describe, on the basis of publications of the Leiden Routine Outcome Monitoring Study, a number of potential research topics in which rom data can play a role. METHOD: We used rom data of patients referred, between 2004 and 2009, to secondary or tertiary care for treatment of a mood, anxiety or somatoform disorder. RESULTS: We describe three cross-sectional studies and one prospective study in which we aimed to identify predictors of outcome. CONCLUSION: These studies demonstrate clearly that it is feasible to use rom data to supplement clinical epidemiological research done on patients. Together these findings can be a useful addition to data derived from randomised clinical trials.

A healthy dietary pattern is associated with microbiota diversity in recently diagnosed bipolar patients: The Bipolar Netherlands Cohort (BINCO) study.

BACKGROUND: Diet largely impacts the gut microbiota, and may affect mental and somatic health via the gut-brain axis. As such, the relationship between diet and the microbiota in Bipolar Disorder (BD) could be of importance, but has not been studied before. The aim was therefore to assess whether dietary quality is associated with the gut microbiota diversity in patients with recently diagnosed BD, and whether changes occur in dietary quality and microbiota diversity during their first year of treatment. METHODS: Seventy recently (<1 year) diagnosed patients with BD were included in the "Bipolar Netherlands Cohort" (BINCO), and a total of 45 participants were assessed after one year. A 203-item Food Frequency Questionnaire (FFQ) data yielded the Dutch Healthy index (DHD-15), and the microbiota composition and diversity of fecal samples were characterized by 16S rRNA gene amplicon sequencing at baseline and 1-year follow-up. Associations and changes over time were analyzed using multivariate regression analyses and t-tests for paired samples. RESULTS: Included patients had a mean age of 34.9 years (SD ± 11.2), and 58.6 % was female. Alpha diversity (Shannon diversity index), richness (Chao1 index) and evenness (Pielou's Evenness Index) were positively associated with the DHD-15 total score, after adjustment for sex, age and educational level (beta = 0.55; P < 0.001, beta = 0.39; P = 0.024, beta = 0.54; P = 0.001 respectively). The positive correlations were largely driven by the combined positive effect of fish, beans, fruits and nuts, and inverse correlations with alcohol and processed meats. No significant changes were found in DHD-15 total score, nor in microbiota diversity, richness and evenness indexes during one year follow-up and regular treatment. CONCLUSION: A healthy and varied diet is associated with the diversity of the microbiota in BD patients. Its potential consequences for maintaining mood stability and overall health should be studied further.

Phenomenology of depression in older compared with younger adults: meta-analysis.

BACKGROUND: Late-life depression may differ from early-life depression in its phenomenology. AIMS: To investigate the effect of age on the phenomenology of major depression. METHOD: A systematic search was conducted in PubMed, Embase and PsycINFO for all studies examining the relation between age and phenomenology of major depression according to RDC, DSM and ICD criteria. Studies were included only if the age groups were compared at the single-item level using the 17-, 21- or 24-item versions of the Hamilton Rating Scale for Depression; a meta-analysis was done for each item of the 17-item scale. RESULTS: Eleven papers met the inclusion criteria. Older depressed adults, compared with younger depressed adults, demonstrated more agitation, hypochondriasis and general as well as gastrointestinal somatic symptoms, but less guilt and loss of sexual interest. CONCLUSIONS: The phenomenology of late-life depression differs only in part from that of early-life depression. Major depression in older people may have a more somatic presentation, whereas feelings of guilt and loss of sexual function may be more prevalent in younger people.

No effects of n-3 fatty acid supplementation on serum total testosterone levels in older men: the Alpha Omega Trial.

The intake of the n-3 fatty acids alpha-linolenic acid (ALA), acid (EPA) and docosahexaenoic acid (DHA) has been related to testosterone levels in epidemiological analyses. The aim of this study was to assess whether the n-3 fatty acids affects testosterone levels in post-myocardial infarction (MI) patients, who are at risk of testosterone deficiency. In a double-blind, placebo-controlled trial of low-dose supplementation of n-3 fatty acids, we included 1850 male post-MI patients aged 60-80 years who participated in the Alpha Omega Trial. Patients were randomly allocated to margarines that provided 400 mg/day of EPA-DHA (n = 453), 2 mg/day of ALA (n = 467), EPA-DHA plus ALA (n = 458), or placebo (n = 472). Serum testosterone levels were assessed at baseline and after 41 months using whole day blood samples obtained at the subjects' home or at the hospital. Subjects were on average age of 68.4 (SD 5.3) years old and had baseline mean serum total testosterone of 14.8 (SD 5.6) nmol/L. The four randomized groups did not differ for baseline characteristics. ALA, EPA-DHA, and EPA-DHA plus ALA supplementation did not affect serum total testosterone compared to placebo. Moreover, n-3 fatty acid supplementation did not affect the risk of incident testosterone deficiency (n = 76 with total testosterone <8.0 nmol/L). We conclude that n-3 fatty acids supplementation did not affect serum total testosterone in men who had had a MI.

Impact of childhood life events and trauma on the course of depressive and anxiety disorders.

OBJECTIVE: Data on the impact of childhood life events and childhood trauma on the clinical course of depressive and anxiety disorders are limited. METHOD: Longitudinal data were collected from 1209 adult participants in the Netherlands Study of Depression and Anxiety (NESDA). Childhood life events and trauma at baseline were assessed with a semi-structured interview and the clinical course after 2 years with a DSM-IV-based diagnostic interview and Life Chart Interview. RESULTS: At baseline, 18.4% reported at least one childhood life event and 57.8% any childhood trauma. Childhood life events were not predictive of any measures of course trajectory. Emotional neglect, psychological and physical abuse, but not sexual abuse, were associated with persistence of both depressive and comorbid anxiety and depressive disorder at follow-up. Emotional neglect and psychological abuse were associated with a higher occurrence of a chronic course. Poor course outcomes were mediated mainly through a higher baseline severity of depressive symptoms. CONCLUSION: Childhood trauma, but not childhood life events, was associated with an increased persistence of comorbidity and chronicity in adults with anxiety and/or depressive disorders. More unfavourable clinical characteristics at baseline mediate the relationship between childhood trauma and a poorer course of depressive and anxiety disorders.