Anxious Major Depressive Disorder Research Articles

Prediction of anxious depression using multimodal neuroimaging and machine learning

Anxious depression is a common subtype of major depressive disorder (MDD) associated with adverse outcomes and severely impaired social function. It is important to clarify the underlying neurobiology of anxious depression to refine the diagnosis and stratify patients for therapy. Here we explored associations between anxiety and brain structure/function in MDD patients. A total of 260 MDD patients and 127 healthy controls underwent three-dimensional T1-weighted structural scanning and resting-state functional magnetic resonance imaging. Demographic data were collected from all participants. Differences in gray matter volume (GMV), (fractional) amplitude of low-frequency fluctuation ((f)ALFF), regional homogeneity (ReHo), and seed point-based functional connectivity were compared between anxious MDD patients, non-anxious MDD patients, and healthy controls. A random forest model was used to predict anxiety in MDD patients using neuroimaging features. Anxious MDD patients showed significant differences in GMV in the left middle temporal gyrus and ReHo in the right superior parietal gyrus and the left precuneus than HCs. Compared with non-anxious MDD patients, patients with anxious MDD showed significantly different GMV in the left inferior temporal gyrus, left superior temporal gyrus, left superior frontal gyrus (orbital part), and left dorsolateral superior frontal gyrus; fALFF in the left middle temporal gyrus; ReHo in the inferior temporal gyrus and the superior frontal gyrus (orbital part); and functional connectivity between the left superior temporal gyrus(temporal pole) and left medial superior frontal gyrus. A diagnostic predictive random forest model built using imaging features and validated by 10-fold cross-validation distinguished anxious from non-anxious MDD with an AUC of 0.802. Patients with anxious depression exhibit dysregulation of brain regions associated with emotion regulation, cognition, and decision-making, and our diagnostic model paves the way for more accurate, objective clinical diagnosis of anxious depression.

Efficacy of repeated intravenous esketamine in adolescents with anxious versus non-anxious depression

BackgroundPatients with anxious major depressive disorder (MDD) are more likely to have poorer outcomes than those with non-anxious MDD. However, the effect of esketamine on adolescents with anxious versus non-anxious...

Abnormal white matter integrity in Papez circuit in first-episode medication-naive adults with anxious depression: A combined voxel-based analysis and region of interest study

BackgroundAnxious depression is one of the subtypes of major depressive disorder (MDD), usually defined as “patients with MDD and high levels of anxiety symptoms”. Compared to non-anxious MDD (naMDD), patients with anxious MDD (aMDD) have more severe depressive symptoms and suicidal ideation, worse treatment outcomes and remission rates, and poorer prognosis. Current research suggests that the Papez circuit is an important brain structure closely related to emotion, memory, and cognition. This study applied DTI to explore the altered white matter integrity in Papez circuit of patients with aMDD. MethodsDTI data were acquired from 30 medication-naive outpatients with naMDD and 55 with aMDD and 88 demographically similar healthy control (HC) subjects. Voxel-based analysis (VBM) and region of interest (ROI) analysis were conducted to explore the significant difference of fractional anisotropy (FA) values among 3 groups. Pearson's correlations were performed to analyze the correlation between FA values and the score of HAMA-14 and HAMD-17. ResultsWe found that aMDD patients had significantly higher FA values in left fornix (belong to Papez circuit) and left posterior thalamic radiation and right anterior corona radiata (belong to limbic-thalamo-cortical circuitry) compared with HC. And there was variability in the white matter integrity in right posterior thalamic radiation (belong to limbic-thalamo-cortical circuitry) and left fornix (belong to Papez circuit) between aMDD and naMDD patients. LimitationsThe cross-sectional study and the population vary between aMDD group and naMDD group are limitations. ConclusionsAbnormal white matter integrity in Papez circuit and Limbic-Thalamo-Cortical circuitry may play an important role in the neuropathology of aMDD and might help to identify aMDD.

Association of Subclinical Hypothyroidism With Anxiety Symptom in Young First-Episode and Drug-Naïve Patients With Major Depressive Disorder.

BackgroundsSubclinical hypothyroidism (SCH) was reported to be associated with depression; however, its role in coexisting anxiety symptom in young patients with major depressive disorder (MDD) remains unclear. The objective of this study was to explore the relationship between SCH and anxiety symptom in young first-episode and drug-naïve (FEDN) MDD patients.MethodsA total of 520 outpatients diagnosed as FEDN MDD with SCH were recruited in this study. Their socio-demographic, clinical data and thyroid function parameters were collected. The Hamilton Anxiety Rating Scale (HAMA) and the Hamilton Depression Rating Scale (HAMD) were employed to measure the severity of anxiety symptom and depressive symptom, respectively. Based on the HAMA scores, patients who scored ≥ 25 were defined as anxious major depressive disorder (A-MDD) while others as non-anxious major depressive disorder (NA-MDD).ResultsThe prevalence rate of A-MDD was 15.8% in young FEDN MDD patients with comorbid SCH. Moreover, serum thyroid stimulating hormone (TSH) levels were significantly higher in patients with A-MDD compared with those with NA-MDD (p < 0.001). Multivariate binary logistic regression analysis indicated that A-MDD was associated with serum TSH levels with an odds ratio (OR) of 1.602. Serum TSH level of 6.17 mIU/L was the critical value to distinguish A-MDD and NA-MDD, with sensitivity of 0.805 and specificity of 0.539. There were no statistically significant differences between NA-MDD and A-MDD patients in terms of socio-demographic variables, serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidases antibody (TPOAb) and anti-thyroglobulin (TgAb) levels.ConclusionsA-MDD patients presented higher serum TSH level. It is suggested that serum TSH level may be a potential biomarker for predicting moderate and severe anxiety symptoms in young FEDN MDD patients with SCH.

TRANSCRIPTOME-WIDE ASSOCIATION STUDY OF TREATMENT-RESISTANT DEPRESSION AND DEPRESSION SUBTYPES FOR DRUG REPURPOSING

Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20-30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.

Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing

Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20–30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.

Abnormal white matter integrity in Chinese young adults with first-episode medication-free anxious depression: a possible neurological biomarker of subtype major depressive disorder.

BackgroundAlmost half of patients with major depressive disorder (MDD) also have clinically meaningful levels of anxiety. Anxious depression is a distinct clinical subtype of MDD, which has poor response to pharmacotherapy; however, the neural mechanisms behind are largely unknown. In the present study, we explored the white matter (WM) integrity traits of anxious depression in first-episode and medication-free (medication-naïve and medication washout) Chinese young adult patients by detecting differences in diffusion tensor imaging (DTI) with the tract-based spatial statistics (TBSS) method.Subjects and methodsDTI was obtained from 39 first-episode, medication-free anxious depressive patients, 45 nonanxious depressive patients, and 50 demographically similar healthy controls. All subjects underwent clinical assessments. TBSS was carried out to investigate the difference in WM integrity among three groups within DTI parameter maps. WM integrity was measured using fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity (RD). The correlations between WM integrity and clinical features were also computed.ResultsWhen compared with nonanxious patients, lower FA values in anxious depressive patients were found in multiple regions of the brain, mainly involving left uncinate fasciculus (UF), superior longitudinal fasciculus (SLF), and forceps major and minor. Higher RD in forceps major and minor and SLF were also detected. The decreased FA values and increased RD values correlated with both anxiety level and depression level in the pooled depressive group.ConclusionThe anxious depressive patients had more abnormalities in WM integrity at the early phase than the nonanxious group. Alternations in WM integrity in fiber pathways, including SLF, UF, and forceps major and minor, may play a critical role in the neuropathology of anxious depression and might help to identify anxious MDD from nonanxious MDD. Further study with larger sample size, larger age range, and longitudinal design is needed to confer a robust inference to better understand the dynamic neurological change and neuropathology of WM integrity in anxious MDD.

O43. Cognitive and Emotional Biomarkers of Anxious Major Depressive Disorder: An iSPOT-D Report

Major depressive disorder (MDD) commonly co-occurs with one or more anxiety disorders or with clinically significant levels of anxiety symptoms. While evidence suggests these anxious forms of MDD present with more severe clinical profiles and are prognostic of poorer antidepressant treatment outcomes, little is known of their cognitive and emotional functioning. We compared cognitive and emotional functioning in various forms of anxious MDD and assessed whether functioning could predict antidepressant treatment outcome.

Metabolomic biosignature differentiates melancholic depressive patients from healthy controls

BackgroundMajor depressive disorder (MDD) is a heterogeneous disease at the level of clinical symptoms, and this heterogeneity is likely reflected at the level of biology. Two clinical subtypes within MDD that have garnered interest are “melancholic depression” and “anxious depression”. Metabolomics enables us to characterize hundreds of small molecules that comprise the metabolome, and recent work suggests the blood metabolome may be able to inform treatment decisions for MDD, however work is at an early stage. Here we examine a metabolomics data set to (1) test whether clinically homogenous MDD subtypes are also more biologically homogeneous, and hence more predictiable, (2) devise a robust machine learning framework that preserves biological meaning, and (3) describe the metabolomic biosignature for melancholic depression.ResultsWith the proposed computational system we achieves around 80 % classification accuracy, sensitivity and specificity for melancholic depression, but only ~72 % for anxious depression or MDD, suggesting the blood metabolome contains more information about melancholic depression.. We develop an ensemble feature selection framework (EFSF) in which features are first clustered, and learning then takes place on the cluster centroids, retaining information about correlated features during the feature selection process rather than discarding them as most machine learning methods will do. Analysis of the most discriminative feature clusters revealed differences in metabolic classes such as amino acids and lipids as well as pathways studied extensively in MDD such as the activation of cortisol in chronic stress.ConclusionsWe find the greater clinical homogeneity does indeed lead to better prediction based on biological measurements in the case of melancholic depression. Melancholic depression is shown to be associated with changes in amino acids, catecholamines, lipids, stress hormones, and immune-related metabolites. The proposed computational framework can be adapted to analyze data from many other biomedical applications where the data has similar characteristics.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2953-2) contains supplementary material, which is available to authorized users.

A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression.

Patients with anxious major depressive disorder (AMDD) have more severe symptoms and poorer treatment response than patients with non-AMDD. Increasing evidence implicates the endogenous opioid system in the pathophysiology of depression. AZD2327 is a selective delta opioid receptor (DOR) agonist with anxiolytic and antidepressant activity in animal models. This double-blind, parallel group design, placebo-controlled pilot study evaluated the safety and efficacy of AZD2327 in a preclinical model and in patients with AMDD. We initially tested the effects of AZD2327 in an animal model of AMDD. Subsequently, 22 subjects with AMDD were randomized to receive AZD2327 (3 mg BID) or placebo for 4 weeks. Primary outcome measures included the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). We also evaluated neurobiological markers implicated in mood and anxiety disorders, including vascular endothelial growth factor (VEGF) and electroencephalogram (EEG). Seven (54 %) patients responded to active drug and three (33 %) responded to placebo. No significant main drug effect was found on either the HAM-D (p = 0.39) or the HAM-A (p = 0.15), but the HAM-A had a larger effect size. Levels of AZ12311418, a major metabolite of AZD2327, were higher in patients with an anti-anxiety response to treatment compared to nonresponders (p = 0.03). AZD2327 treatment decreased VEGF levels (p = 0.02). There was a trend (p < 0.06) for those with an anti-anxiety response to have higher EEG gamma power than nonresponders. These results suggest that AZD2327 has larger potential anxiolytic than antidepressant efficacy. Additional research with DOR agonists should be considered.

Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys.

To examine cross-national patterns and correlates of lifetime and 12-month comorbid DSM-IV anxiety disorders among people with lifetime and 12-month DSM-IV major depressive disorder (MDD). Nationally or regionally representative epidemiological interviews were administered to 74045 adults in 27 surveys across 24 countries in the WHO World Mental Health (WMH) Surveys. DSM-IV MDD, a wide range of comorbid DSM-IV anxiety disorders, and a number of correlates were assessed with the WHO Composite International Diagnostic Interview (CIDI). 45.7% of respondents with lifetime MDD (32.0-46.5% inter-quartile range (IQR) across surveys) had one of more lifetime anxiety disorders. A slightly higher proportion of respondents with 12-month MDD had lifetime anxiety disorders (51.7%, 37.8-54.0% IQR) and only slightly lower proportions of respondents with 12-month MDD had 12-month anxiety disorders (41.6%, 29.9-47.2% IQR). Two-thirds (68%) of respondents with lifetime comorbid anxiety disorders and MDD reported an earlier age-of-onset (AOO) of their first anxiety disorder than their MDD, while 13.5% reported an earlier AOO of MDD and the remaining 18.5% reported the same AOO of both disorders. Women and previously married people had consistently elevated rates of lifetime and 12-month MDD as well as comorbid anxiety disorders. Consistently higher proportions of respondents with 12-month anxious than non-anxious MDD reported severe role impairment (64.4 v. 46.0%; χ 2 1=187.0, p<0.001) and suicide ideation (19.5 v. 8.9%; χ 2 1=71.6, p<0.001). Significantly more respondents with 12-month anxious than non-anxious MDD received treatment for their depression in the 12 months before interview, but this difference was more pronounced in high-income countries (68.8 v. 45.4%; χ 2 1=108.8, p<0.001) than low/middle-income countries (30.3 v. 20.6%; χ 2 1=11.7, p<0.001). Patterns and correlates of comorbid DSM-IV anxiety disorders among people with DSM-IV MDD are similar across WMH countries. The narrow IQR of the proportion of respondents with temporally prior AOO of anxiety disorders than comorbid MDD (69.6-74.7%) is especially noteworthy. However, the fact that these proportions are not higher among respondents with 12-month than lifetime comorbidity means that temporal priority between lifetime anxiety disorders and MDD is not related to MDD persistence among people with anxious MDD. This, in turn, raises complex questions about the relative importance of temporally primary anxiety disorders as risk markers v. causal risk factors for subsequent MDD onset and persistence, including the possibility that anxiety disorders might primarily be risk markers for MDD onset and causal risk factors for MDD persistence.

Testosterone and dehydroepiandrosterone sulfate in female anxious and non-anxious major depression

Objectives. Major Depression with severe anxiety has been proposed as a distinct clinical variant of Major Depressive Disorder (MDD). This proposal invites the investigation of the differential biological correlates of the anxious versus non-anxious MDD. One such research area might be their possible differential associations with androgens. Methods. Plasma total testosterone and dehydroepiandrosterone were assessed in adequately matched female inpatients with anxious MDD, non-anxious MDD and normal controls. Results. Androgen levels were significantly lower in both patient groups compared to those of controls. Moreover, they were significantly lower in anxious MDD patients compared to those of their non-anxious MDD counterparts. The limitations of this study were cross-sectional design of the study, the small sample size of the study sample and the outpatient status of the control group. In addition, free testosterone levels were not measured. Conclusions. Our findings indicate that female major depression is associated with lower androgen levels, a deficiency aggravated by the severity of their concomitant anxiety.

Testing anxious depression as a predictor and moderator of symptom improvement in major depressive disorder during treatment with escitalopram

The purpose of this analysis was to explore the potential role of anxious MDD as a treatment predictor and moderator in major depressive disorder (MDD) using a large escitalopram clinical trial dataset. Individual patient-level data from 13 double-blinded, randomized, controlled trials in patients with MDD were pooled. Both univariate, last observation carried forward (LOCF) analyses and repeated measurements analyses without imputation (MMRM) were carried out for change in symptom scores, response and remission rates. Of 3,919 patients, 48.0% were classified as having anxious MDD depression (HAMD) somatization/anxiety subscale score ≥7 at baseline. Patients with anxious MDD were less likely to report symptom improvement on some outcome measures than patients without anxious MDD (predictor analysis). Specifically, the difference in response rates for patients with vs. patients without anxious MDD according to the MADRS (55.6% vs. 57.7%, respectively) was not statistically different. However, the difference in remission rates for patients with versus without anxious MDD according to the MADRS (37.6% vs. 44.1%, respectively) was statistically significant. Escitalopram was more effective than placebo, and as effective as the SSRIs and SNRIs, in the treatment of anxious MDD. The present analysis provides some evidence that the presence of an anxious MDD subtype is a predictor of poor response. There was no difference in the response to treatment of patients with or without anxious MDD to escitalopram, SSRIs, or SNRIs. The present analysis did not support the notion that SNRIs are more effective than escitalopram in the treatment of anxious MDD, nor was there evidence to support treatment moderating effects for anxious MDD.

Fluoxetine-clonazepam cotherapy for anxious depression: an exploratory, post-hoc analysis of a randomized, double blind study

Anxious depression, defined as major depressive disorder (MDD) accompanied by high levels of anxiety, seems to be both common and difficult to treat, with antidepressant monotherapy often yielding modest results. We sought to examine the relative benefits of antidepressant-anxiolytic cotherapy versus antidepressant monotherapy for patients with anxious depression versus without anxious depression. We conducted a post-hoc analysis of an existing dataset (N=80), from a 3-week, randomized, double-blind trial which demonstrated cotherapy with fluoxetine and clonazepam to result in superior efficacy than fluoxetine monotherapy in MDD. The present analysis involved examining whether anxious depression status served as a predictor and moderator of symptom improvement. Anxious depression status was not found to predict symptom improvement, or serve as a moderator of clinical improvement to cotherapy versus monotherapy. However, the advantage in remission rates in favor of cotherapy versus monotherapy was, numerically, much larger for patients with anxious depression (32.2%) than it was for patients without anxious MDD (9.7%). The respective number needed to treat statistic for these two differences in response rates were, approximately, one in three for patients with anxious depression versus one in 10 for patients without anxious depression. The efficacy of fluoxetine-clonazepam cotherapy compared with fluoxetine monotherapy was numerically but not statistically enhanced for patients with anxious depression than those without anxious depression.

What Clinical and Symptom Features and Comorbid Disorders Characterize Outpatients with Anxious Major Depressive Disorder: A Replication and Extension

We previously found that 46% of the first 1450 outpatients with depression participating in the multicentre Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project qualified for the designation of anxious depression. This study was designed to replicate and extend our initial findings in a subsequent, larger cohort of outpatient STAR*D participants with nonpsychotic major depressive disorder (MDD). Baseline clinical and sociodemographic data were collected on 2337 consecutive STAR*D participants. A baseline 17-item Hamilton Depression Rating Scale Anxiety-Somatization factor score of 7 or higher was designated as anxious depression. We identified concurrent Axis I disorders with the Psychiatric Diagnostic Screening Questionnaire (PDSQ), using a 90% specificity threshold. Depressive symptoms were assessed by clinical telephone interview with the 30-item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C30). The prevalence of anxious depression in this population was 45.1%. Patients with anxious MDD were significantly more likely to be in primary care settings and to be women, nonsingle, unemployed, Hispanic, less educated, and suffering from severe depression, both before and after adjustment for overall depression severity. Patients with anxious depression were significantly more likely to meet PDSQ thresholds for generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, agoraphobia, hypochondriasis, and somatoform disorder, both before and after adjusting for baseline depression severity. Individuals with anxious depression were also significantly less likely to endorse IDS-C30 items concerning atypical features and were significantly more likely to endorse items concerning melancholic-endogenous depression features, both before and after adjusting for baseline depression severity. This study clearly replicates our previous STAR*D findings and supports the notion that anxious depression may be a valid diagnostic subtype of MDD, with distinct psychiatric comorbidities and clinical and sociodemographic features.

Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D

Anxious depression, defined as Major Depressive Disorder (MDD) with high levels of anxiety symptoms, may represent a relatively common depressive subtype, with distinctive features. The objective of this study was to determine the prevalence of anxious depression and to define its clinical correlates and symptom patterns. Baseline clinical and sociodemographic data were collected on 1450 subjects participating in the STAR*D study. A baseline Hamilton Rating Scale for Depression (HAM-D) Anxiety/ Somatization factor score of > or =7 was considered indicative of anxious depression. The types and degree of concurrent psychiatric symptoms were measured using the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items endorsed by study participants for each diagnostic category. MDD symptoms were assessed by clinical telephone interview with the 30-item Inventory of Depressive Symptomatology (IDS-C30). The prevalence of anxious depression in this population was 46 %. Patients with anxious MDD were significantly more likely to be older, unemployed, less educated, more severely depressed, and to have suicidal ideation before and after adjustment for severity of depression. As far as concurrent psychiatric symptoms are concerned, patients with anxious depression were significantly more likely to endorse symptoms related to generalized anxiety, obsessive compulsive, panic, post-traumatic stress, agoraphobia, hypochondriasis, and somatoform disorders before and after adjustment for severity of depression. Anxious-depression individuals were also significantly less likely to endorse IDS-C30 items concerning atypical features, and were significantly more likely to endorse items concerning melancholic/endogenous depression features. This study supports specific clinical and sociodemographic correlates of MDD associated with high levels of anxiety (anxious depression).

Comparison of major depressive patients with a predominantly sad versus anxious mood

One hundred and seventy-seven patients with major depressive disorder (MDD) experienced a mood disturbance that could be characterized as predominantly sad (55%), anxious (31%) or mixed (14%). Patients that had a predominantly sad mood were likely to be hypersomnic, anhedonic, younger and seen in an outpatient setting. Predominantly anxious MDD patients were more likely to have been hospitalized, agitated, psychotic, incapacitated, insomnic, and to have had higher post-dexamethasone cortisol levels.