Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Randomized controlled trial of two internet-based written therapies for world trade center workers and survivors with persistent PTSD symptoms.

Posttraumatic stress disorder (PTSD) remains prevalent among individuals exposed to the 9/11 World Trade Center (WTC) terrorist attacks. The present study compared an Internet-based, therapist-assisted psychotherapy for PTSD to an active control intervention in WTC survivors and recovery workers with WTC-related PTSD symptoms (n = 105; 75% syndromal PTSD). Participants were randomized to integrative testimonial therapy (ITT), focused on WTC-related trauma, or modified present-centered therapy (I-MPCT), each comprising 11 assigned written narratives. The primary outcome was baseline-to-post-treatment change in PTSD symptoms on the PTSD Checklist for DSM-5 (PCL-5). Secondary measures included PTSD symptom clusters, depressive/anxiety symptoms, functioning, and quality of life. A significant main effect of time was observed for the primary outcome (average "large" effect size improvement, d = 1.49). Significant and "moderate-to-large" main effects of time were also observed for all PTSD symptom clusters, depressive symptoms, quality of life, and mental health-related functioning (d range=0.62-1.33). Treatment and treatment-by-time interactions were not significant. In planned secondary analyses incorporating 3-month follow-up measures, ITT was associated with significantly greater reductions than I-MPCT in PTSD avoidance and negative alterations in cognitions and mood, anxiety, and mental health-related functioning. Both therapies significantly lowered PTSD symptoms, suggesting they may benefit hard-to-reach individuals with chronic WTC-related PTSD symptoms.

Provision of Cognitive Behavior Therapy for Depression and Anxiety Disorders by Medical Student Trainees.

OBJECTIVE: The purpose of the article is to evaluate an innovative education program in which medical students were trained in cognitive behavior therapy (CBT) and provided CBT treatments under supervision to uninsured individuals with depressive, anxiety, adjustment, and trauma-based disorders. METHODS: The authors assessed improvements in trainees' CBT knowledge using the Cognitive Therapy Awareness Scale before and after their didactic training. CBT supervisors rated trainees' clinical competencies utilizing standardized checklist evaluations based upon supervision reports. The authors employed mixed effects ANOVA and regression modeling to test the association between the addition of CBT to treatment as usual (TAU) and improvements in patients' depressive and anxious symptom severity. The authors collected feedback and self-assessment of functioning with a Psychotherapy Feedback Questionnaire. RESULTS: Medical students showed increases in CBT knowledge that were maintained six months later and demonstrated satisfactory competency in CBT techniques. The addition of CBT to TAU was associated with greater improvements in depressive, but not anxious, symptom severity. However, among the TAU + CBT group, there was an association between the number of CBT sessions received and the magnitude of improvement in anxious symptoms from baseline. Patients gave positive feedback to medical student CBT providers and reported improvements in broad domains of psychosocial functioning. CONCLUSIONS: Medical students can provide competent and clinically beneficial CBT treatments for depression and anxiety disorders. These findings have implications for medical training and support the use of medical students to deliver care for individuals with limited access to psychotherapy.

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders.

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Altered gene expression and PTSD symptom dimensions in World Trade Center responders.

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort using stratified random sampling, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N = 1016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with total highest lifetime CAPS score (FDR-corrected p < 0.05), and 31 genes associated with total past-month CAPS score. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our analyses with total CAPS scores. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and total lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were downregulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between total lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

Heart rate and respiratory response to doxapram in patients with panic disorder.

Panic disorder (PD) is characterized by anticipatory anxiety and panic, both causing physiological arousal. We investigated the differential responses between anticipatory anxiety and panic in PD and healthy controls (HC). Subjects (15 PD and 30 HC) received an injection of a respiratory stimulant, doxapram, with a high rate of producing panic attacks in PD patients, or an injection of saline. PD subjects had significantly higher scores in anxiety and panic symptoms during both conditions. Analysis of heart rate variability (HRV) indices showed higher sympathetic activity (LF) during anticipatory anxiety and panic states, an increase in the ratio of LF/HF during the anticipatory and panic states and a decrease in parasympathetic (HF) component in PD patients. During doxapram PD subjects increased their LF/HF ratio while HC had a reduction in LF/HF. Parasympathetic component of HRV was lower during anticipatory anxiety in PD. In general, PD showed greater sympathetic and psychological responses related to anxiety and sensations of dyspnea, reduced parasympathetic responses during anticipatory and panic states, but no differences in respiratory response. This confirms previous studies showing that PD patients do not have an intrinsic respiratory abnormality (either heightened or dysregulated) at the level of the brain stem but rather an exaggerated fear response.

Treating comorbid anxiety and depression: Psychosocial and pharmacological approaches.

Comorbid anxiety with depression predicts poor outcomes with a higher percentage of treatment resistance than either disorder occurring alone. Overlap of anxiety and depression complicates diagnosis and renders treatment challenging. A vital step in treatment of such comorbidity is careful and comprehensive diagnostic assessment. We attempt to explain various psychosocial and pharmacological approaches for treatment of comorbid anxiety and depression. For the psychosocial component, we focus only on generalized anxiety disorder based on the following theoretical models: (1) "the avoidance model"; (2) "the intolerance of uncertainty model"; (3) "the meta-cognitive model"; (4) "the emotion dysregulation model"; and (5) "the acceptance based model". For depression, the following theoretical models are explicated: (1) "the cognitive model"; (2) "the behavioral activation model"; and (3) "the interpersonal model". Integration of these approaches is suggested. The treatment of comorbid anxiety and depression necessitates specific psychopharmacological adjustments as compared to treating either condition alone. Serotonin reuptake inhibitors are considered first-line treatment in uncomplicated depression comorbid with a spectrum of anxiety disorders. Short-acting benzodiazepines (BZDs) are an important "bridging strategy" to address an acute anxiety component. In patients with comorbid substance abuse, avoidance of BZDs is recommended and we advise using an atypical antipsychotic in lieu of BZDs. For mixed anxiety and depression comorbid with bipolar disorder, we recommend augmentation of an antidepressant with either lamotrigine or an atypical agent. Combination and augmentation therapies in the treatment of comorbid conditions vis-à-vis monotherapy may be necessary for positive outcomes. Combination therapy with tricyclic antidepressants, gabapentin and selective serotonin/norepinephrine reuptake inhibitors (e.g., duloxetine) are specifically useful for comorbid chronic pain syndromes. Aripiprazole, quetiapine, risperidone and other novel atypical agents may be effective as augmentations. For treatment-resistant patients, we recommend a "stacking approach" not dissimilar from treatment of hypertension In conclusion, we delineate a comprehensive approach comprising integration of various psychosocial approaches and incremental pharmacological interventions entailing bridging strategies, augmentation therapies and ultimately stacking approaches towards effectively treating comorbid anxiety and depression.

Heart rate and blood pressure changes during autonomic nervous system challenge in panic disorder patients.

OBJECTIVE: To test the hypothesis that panic disorder (PD) patients have a heightened or deregulated autonomic nervous system at rest and during autonomic challenge compared with healthy controls (HC); and to test a second hypothesis that severity of illness differentiates patients'; sympathovagal balance both at rest and during orthostatic challenge. METHODS: Spectral analysis of heart rate (HR) and blood pressure was performed on 30 PD and 10 HC participants during an orthostatic challenge (head-up tilt). RESULTS: PD patients presented higher HR (p < .001), lower heart rate variability (HRV) (p < .015), higher mean diastolic blood pressure (p < .006), higher low-frequency component of HR (p < .001), and a higher ratio of low-frequency to high-frequency component of HR (LF/HF) (p < .022) than HC at baseline. During tilt, PD patients responded with higher HR (p < .039), lower HRV (p < .043), increased mean diastolic blood pressure (p < .028), and a mild increase in LF/HF, whereas controls responded with a five-fold increase in LF/HF (p < .022). Patients with higher illness severity ratings (Clinical Global Impression Scale) showed higher HR (p < .002), lower HRV (p < .026), and a lower total power of systolic blood pressure (p < .02) compared with less ill patients. CONCLUSION: These findings demonstrate a consistently higher or deregulated autonomic arousal in PD patients at rest and during orthostatic challenge compared with HC. These data also reveal a possible association between the level of anxiety illness severity and sympathovagal balance, which may imply greater cardiac risk.

Effect of medication and psychotherapy on heart rate variability in panic disorder.

BACKGROUND: Panic disorder (PD) patients have been shown to have reduced heart rate variability (HRV). Low HRV has been associated with elevated risk for cardiovascular disease. Our aim was to investigate the effects of treatment on heart rate (HR) in patients with PD through a hyperventilation challenge. METHODS: We studied 54 participants, 43 with Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) PD and 11 controls. Subjects lay supine with their heads in a plastic canopy chamber, resting for 15 min and then breathing at a rate of 30 breaths per minute for 10 min. HRV was sampled for spectral analysis. Clinical and behavioral measures of anxiety were assessed. Treatment was chosen by patients: either 12 weeks of CBT alone or CBT with sertraline. RESULTS: All patients showed significant decrease on clinical measures from baseline and 31 were treatment responders, 8 dropped out of the study before completion of the 12-week treatment phase and 4 were deemed nonresponders after 12 weeks of treatment. Although both treatments led to significant clinical improvement, only CBT alone demonstrated a significant reduction in HR and increase in HRV. CONCLUSIONS: Our study replicated the finding that increased HR and decreased HRV occur in PD patients. Given the evidence of cardiac risk related to HRV, CBT appears to have additional benefits beyond symptom reduction. The mechanisms of this difference between CBT and sertraline are unclear and require further study.

Predictors and time course of response among panic disorder patients treated with cognitive-behavioral therapy.

OBJECTIVE: Cognitive-behavioral therapy (CBT) is well documented as an efficacious treatment for panic disorder. We provided open CBT treatment to patients who subsequently participated in a maintenance treatment study. This article reports on predictors and trajectory of response in 381 participants who completed treatment at 4 sites. METHOD: Participants who met criteria for panic disorder with or without agoraphobia (N = 381) completed assessment and entered treatment. Of these, 256 completed 11 sessions of CBT delivered by trained and supervised research therapists. Raters trained to reliability obtained demographic data and administered structured diagnostic interviews and the Hamilton Rating Scales for Depression and Anxiety and the Panic Disorder Severity Scale (PDSS) measures at baseline and posttreatment. We obtained self-report (SR) measures of anxiety sensitivity and adult separation anxiety at baseline and posttreatment and PDSS-SR ratings weekly. The study was conducted between November 1999 and July 2002. RESULTS: Treatment response rate was 65.6% for completers and 44.1% for the intent-to-treat sample. Greater severity of panic disorder and lower levels of adult separation anxiety predicted response. Beginning at week 4, responders showed greater mean decreases in PDSS scores than non-responders and maintained the advantage throughout the treatment. By week 6, 76% of responders, compared to 36% of nonresponders, recorded PDSS scores at least 40% below baseline on 2 consecutive weeks (odds ratio = 5.42, 95% CI = 3.10 to 9.48). CONCLUSION: These results suggest that CBT is just as effective for more severe panic disorder patients as it is for those with less severe panic disorder, regardless of other comorbid disorders, including agoraphobia. However, patients experiencing adult separation anxiety disorder are less likely to respond. Our results further inform clinicians that many people who will respond to 11 weeks of treatment will have done so by the middle of the treatment.

The effect of doxapram on brain imaging in patients with panic disorder.

Administration of doxapram hydrochloride, a respiratory stimulant, is experienced by panic disorder patients to be similar to panic attacks but has reduced emotional effect in normal volunteers, thus providing a laboratory model of panic for functional imaging. Six panic patients and seven normal control subjects underwent positron emission tomography with (18)F-deoxyglucose imaging after a single-blinded administration of either doxapram or a placebo saline solution. Saline and doxapram were administered on separate days in counterbalanced order. Patients showed a greater heart rate increase on doxapram relative to saline than controls, indicating differential response. On the saline placebo day, patients had greater prefrontal relative activity than controls. In response to doxapram, patients tended to decrease prefrontal activity more than controls, and increased cingulate gyrus and amygdala activity more than controls. This suggests that panic disorder patients activate frontal inhibitory centers less than controls, a tendency that may lower the threshold for panic.

Comparison of attachment styles in borderline personality disorder and obsessive-compulsive personality disorder.

The intense, unstable interpersonal relationships characteristic of patients with borderline personality disorder (BPD) are thought to represent insecure attachment. The Reciprocal Attachment Questionnaire was used to compare the attachment styles of patients with BPD to the styles of patients with a contrasting personality disorder, obsessive-compulsive personality disorder (OCPD). The results showed that patients with BPD were more likely to exhibit angry withdrawal and compulsive care-seeking attachment patterns. Patients with BPD also scored higher on the dimensions of lack of availability of the attachment figure, feared loss of the attachment figure, lack of use of the attachment figure, and separation protest. The findings may be relevant for understanding the core interpersonal psychopathology of BPD and for managing therapeutic relationships with these patients.