Prefrontal–Amygdala Dysregulation to Threat in Pediatric Posttraumatic Stress Disorder

Functional abnormalities in fear circuitry are likely to underlie the pathophysiology of pediatric posttraumatic stress disorder (PTSD), but the few studies to date have yielded conflicting findings. Furthermore, network level functional connectivity and age-related disruptions in fear circuitry have not been thoroughly explored. In a cross-sectional design, 24 healthy and 24 medication-free youth with severe PTSD completed an event-related emotion-processing task during functional MRI. Youth viewed threat and neutral images, half of which were paired with a neutral male face. Group- and age-related differences in brain activation were examined in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Amygdala functional connectivity was examined using a seed-based approach. PTSD youth showed hyperactivation of the dorsal anterior cingulate cortex (dACC) to threat images. In the dorsomedial PFC (dmPFC), age positively predicted activation in healthy youth but negatively predicted activation in PTSD youth. In the amygdala functional connectivity analysis, PTSD youth showed decreased amygdala–mPFC connectivity to threat images. Furthermore, age positively predicted amygdala–vmPFC connectivity in healthy youth, but negatively predicted connectivity in PTSD youth. Finally, dmPFC activation and amygdala–mPFC connectivity were inversely related to PTSD severity. Pediatric PTSD involves abnormal functional activation and connectivity in fear circuitry. Specifically, dACC hyperactivation is consistent with abnormal promotion of fear responses, whereas reduced amygdala–mPFC connectivity suggests impaired regulation of amygdala responses to threat. Importantly, age-dependent decreases in dmPFC activation and amygdala–vmPFC connectivity may indicate abnormal developmental processes in key emotion pathways in pediatric PTSD.     

Amygdala-prefrontal disconnection in borderline personality disorder.

Abnormal fronto-amygdala circuitry has been implicated in impulsive aggression, a core symptom of borderline personality disorder (BPD). We examined relative glucose metabolic rate (rGMR) at rest and after m-CPP (meta-chloropiperazine) with (18)fluorodeoxyglucose (FDG) with positron emission tomography (PET) in 26 impulsive aggressive (IED)-BPD patients and 24 controls. Brain edges/amygdala were visually traced on MRI scans co-registered to PET scans; rGMR was obtained for ventral and dorsal regions of the amygdala and Brodmann areas within the prefrontal cortex (PFC). Correlation coefficients were calculated between rGMR for dorsal/ventral amygdala regions and PFC. Additionally, amygdala volumes and rGMR were examined in BPD and controls. Correlations PFC/amygdala Placebo: Controls showed significant positive correlations between right orbitofrontal (OFC) and ventral, but not dorsal, amygdala. Patients showed only weak correlations between amygdala and the anterior PFC, with no distinction between dorsal and ventral amygdala. Correlations PFC/amygdala: m-CPP response: Controls showed positive correlations between OFC and amygdala regions, whereas patients showed positive correlations between dorsolateral PFC and amygdala. Group differences between interregional correlational matrices were highly significant. Amygdala volume/metabolism: No group differences were found for amygdala volume, or metabolism in the placebo condition or in response to meta-chloropiperazine (m-CPP). We demonstrated a tight coupling of metabolic activity between right OFC and ventral amygdala in healthy subjects with dorsoventral differences in amygdala circuitry, not present in IED-BPD. We demonstrated no significant differences in amygdala volumes or metabolism between BPD patients and controls.     

Altered amygdala subregion-related circuits in treatment-naïve post-traumatic stress disorder comorbid with major depressive disorder

Individuals with both post-traumatic stress disorder and major depressive disorder (PTSD+MDD) often show greater social and occupational impairment and poorer treatment response than individuals with PTSD alone. Increasing evidence reveals that the amygdala, a brain region implicated in the pathophysiology of both of these conditions, is a complex of structurally and functionally heterogeneous nuclei. Quantifying the functional connectivity of two key amygdala subregions, the basolateral (BLA) and centromedial (CMA), in PTSD+MDD and PTSD-alone could advance our understanding of the neurocircuitry of these conditions. 18 patients with PTSD+MDD, 28 with PTSD-alone, and 50 trauma exposed healthy controls (TEHC), all from a cohort who survived the same large earthquake in China, underwent resting-state functional magnetic resonance imaging. Bilateral BLA and CMA functional connectivity (FC) maps were created using a seed-based approach for each participant. The analysis of covariance of FC was used to determine between-group differences. A significant interaction between amygdala subregion and diagnostic group suggested that differences in connectivity patterns between the two seeds were mediated by diagnosis. Post-hoc analyses revealed that PTSD+MDD patients showed weaker connectivity between right BLA and (a) left anterior cingulate cortex/supplementary motor area, and (b) bilateral putamen/pallidum, compared with PTSD-alone patients. Higher CMA connectivities left ACC/SMA were also observed in PTSD+MDD compared with PTSD-alone. An inverse relationship between the connectivity of right BLA with right putamen/pallidum and MDD symptoms was found in PTSD+MDD. These findings indicate a relationship between the neural pathophysiology of PTSD+MDD compared with PTSD-alone and TEHC and may inform future clinical interventions.     

Hydrocortisone impairs hippocampal-dependent trace eyeblink conditioning in post-traumatic stress disorder.

Trace eyeblink conditioning is a hippocampal-dependent associative learning task that could help evaluate hippocampal function in Post-traumatic stress disorder (PTSD). Since preclinical research has demonstrated that trace eyeblink conditioning can be pharmacologically manipulated by glucocorticoids, this task may shed light on glucocorticoid sensitivity in PTSD. This study assessed baseline and hydrocortisone-mediated changes in trace eyeblink conditioning in patients with PTSD and in healthy controls. A total of 12 patients with PTSD and 12 age- and sex-matched healthy controls participated in a trace eyeblink test 6 h following intravenous administration of 30 mg of hydrocortisone. Spontaneous blink rates were similar between PTSD patients and healthy controls. There was no significant difference in the mean conditioned response between PTSD subjects and healthy controls under placebo conditions. Following hydrocortisone administration, only the PTSD patients demonstrated a significant reduction in conditioned response in contrast to healthy subjects who did not demonstrate any change. Patients with PTSD had increased glucocorticoid sensitivity in the focal brain regions mediating trace eyeblink conditioning.     

Amygdala,Hippocampus, and Ventral Medial Prefrontal Cortex Volumes Differ in Maltreated Youth with and without Chronic Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is considered a disorder of recovery where individuals fail to learn and retain extinction of the traumatic fear response. In maltreated youth, PTSD is common, chronic, and associated with comorbidity. Studies of extinction-related structural volumes (amygdala, hippocampus, anterior cingulate cortex (ACC), and ventral medial prefrontal cortex (vmPFC)) and this stress diathesis, in maltreated youth were not previously investigated. In this cross-sectional study, neuroanatomical volumes associated with extinction in maltreated youth with PTSD (N=31), without PTSD (N=32), and in non-maltreated healthy volunteers (n=57) were examined using magnetic resonance imaging. Groups were sociodemographically similar. Participants underwent extensive assessments for strict inclusion/exclusion criteria and DSM-IV disorders. Maltreated youth with PTSD demonstrated decreased right vmPFC volumes compared with both maltreated youth without PTSD and non-maltreated controls. Maltreated youth without PTSD demonstrated larger left amygdala and right hippocampal volumes compared with maltreated youth with PTSD and non-maltreated control youth. PTSD symptoms inversely correlated with right and left hippocampal and left amygdala volumes. Confirmatory masked voxel base morphometry analyses demonstrated greater medial orbitofrontal cortex gray matter intensity in controls than maltreated youth with PTSD. Volumetric results were not influenced by psychopathology or maltreatment variables. We identified volumetric differences in extinction-related structures between maltreated youth with PTSD from those without PTSD. Alterations of the vmPFC may be one mechanism that mediates the pathway from PTSD to comorbidity. Further longitudinal work is needed to determine neurobiological factors related to chronic and persistent PTSD, and to PTSD resilience despite maltreatment.     

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning,but Ketamine Abolishes those Effects

Witnessing pain and distress in others can cause psychological trauma and increase odds of developing PTSD in the future, on exposure to another stressful event. However, the underlying synaptic process remains unknown. Here we report that mice exposed to a conspecific receiving electrical footshocks exhibited enhanced passive avoidance (PA) learning when trained 24 h after the exposure. The exposure activated neurons in the dorsomedial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) and altered synaptic transmission from dmPFC to BLA. It increased amplitude, slowed decay of NMDA receptor-mediated currents, and generated silent synapses. Administration of sub-anesthetic ketamine immediately after the exposure prevented the enhancement of PA learning and silent synapse formation. These findings suggest that ketamine can prevent pathophysiological consequences of psychological trauma.     

Abnormal Structure of Fear Circuitry in Pediatric Post-Traumatic Stress Disorder

Structural brain studies of adult post-traumatic stress disorder (PTSD) show reduced gray matter volume (GMV) in fear regulatory areas including the ventromedial prefrontal cortex (vmPFC) and hippocampus. Surprisingly, neither finding has been reported in pediatric PTSD. One possibility is that they represent age-dependent effects that are not fully apparent until adulthood. In addition, lower-resolution MRI and image processing in prior studies may have limited detection of such differences. Here we examine fear circuitry GMV, including age-related differences, using higher-resolution MRI in pediatric PTSD vs healthy youth. In a cross-sectional design, 3 T anatomical brain MRI was acquired in 27 medication-free youth with PTSD and 27 healthy non-traumatized youth of comparable age, sex, and IQ. Voxel-based morphometry was used to compare GMV in a priori regions including the medial prefrontal cortex and amygdala/hippocampus. Compared with healthy youth, PTSD youth had reduced GMV but no age-related differences in anterior vmPFC (BA 10/11, Z=4.5), which inversely correlated with PTSD duration. In contrast, although there was no overall group difference in hippocampal volume, a group × age interaction (Z=3.6) was present in the right anterior hippocampus. Here, age positively predicted hippocampal volume in healthy youth but negatively predicted volume in PTSD youth. Within the PTSD group, re-experiencing symptoms inversely correlated with subgenual anterior cingulate cortex (sgACC, Z=3.7) and right anterior hippocampus (Z=3.5) GMV. Pediatric PTSD is associated with abnormal structure of the vmPFC and age-related differences in the hippocampus, regions important in the extinction and contextual gating of fear. Reduced anterior vmPFC volume may confer impaired recovery from illness, consistent with its role in the allocation of attentional resources. In contrast, individual differences in sgACC volume were associated with re-experiencing symptoms, consistent with the role of the sgACC in fear extinction. The negative relationship between age and hippocampal volume in youth with PTSD may suggest an ongoing neurotoxic process over development, which further contributes to illness expression. Future studies employing a longitudinal design would be merited to further explore these possibilities.     

Trauma treatment for veterans in buprenorphine maintenance treatment for opioid use disorder

IntroductionOpioid use disorder (OUD) rates are high among veterans. PTSD is also prevalent among veterans; those with comorbidity have worse outcomes than those without comorbidity. This study assessed buprenorphine retention rates in veterans initiating OUD treatment, comparing veterans without PTSD to veterans with PTSD who were receiving versus not receiving concurrent trauma treatment.MethodsThis retrospective chart review examined consecutive referrals to buprenorphine maintenance (N = 140). PTSD diagnosis was identified by chart review and retention was defined as continuous buprenorphine maintenance 6-months post-admission. Logistic regression analyses compared buprenorphine retention for veterans without PTSD and PTSD-diagnosed veterans who received concurrent trauma treatment to a reference group of PTSD-diagnosed veterans who did not receive trauma treatment. Models adjusted for opioid type, age, and service-connected status.ResultsSixty-seven (47.9%) buprenorphine-seeking veterans carried a PTSD diagnosis; only 31.3% (n = 21) received trauma treatment while in buprenorphine maintenance, with 11.9% (n = 8) receiving evidence-based psychotherapy for PTSD. Among PTSD-diagnosed veterans who received trauma treatment, 90.5% (n = 19/21) were in buprenorphine maintenance at 6-months, compared to 23.9% (n = 11/46) of PTSD-diagnosed veterans without trauma treatment, and 46.6% (n = 34/73) of veterans without PTSD. In the full model, veterans with trauma treatment had 43.36 times greater odds of remaining in buprenorphine treatment than the reference group.ConclusionsMost PTSD-diagnosed veterans in buprenorphine treatment were not receiving trauma treatment. Those receiving concurrent trauma treatment had better retention, suggesting OUD and trauma can be simultaneously addressed. Future clinical trials should investigate trauma-focused treatment for veterans with comorbid PTSD who are seeking buprenorphine for OUD.     

Effects of intranasal oxytocin on distraction as emotion regulation strategy in patients with post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is characterized by difficulty down-regulating emotional responses towards trauma-reminders. The neuropeptide oxytocin may enhance treatment response in PTSD, by dampening excessive fear and improving fear regulation. However, oxytocin effects on (neural correlates of) cognitive emotion regulation abilities have never been investigated in PTSD patients. Therefore, we investigated behavioral and neural effects of intranasal oxytocin administration (40IU) on distraction as emotion regulation strategy in male and female police officers with and without PTSD (n?=?76), using a randomized placebo-controlled cross-over fMRI study. The distraction condition consisted of a working memory task while negative affective pictures were presented. Under placebo, male PTSD patients showed decreased right striatal activity during distraction compared to male trauma-exposed controls, which was unaffected by oxytocin. After oxytocin administration, left thalamus activity during distraction was enhanced in all participants, independent of PTSD status or sex. Although left thalamus activity during distraction did not differ between PTSD patients and controls under placebo, it was negatively correlated with error rates within PTSD patients. Furthermore, oxytocin administration increased functional connectivity between the left thalamus and amygdala in PTSD patients and male trauma-exposed controls. Upregulation of thalamus activity during distraction by oxytocin may enhance cognitive emotion regulation abilities during psychotherapy in PTSD, although this should still be investigated in a clinical setting. Our findings open an important research avenue into oxytocin effects on cognitive emotion regulation in PTSD and other psychiatric disorders characterized by deficient emotion regulation abilities. Registered in the Netherlands Trial Registry, registration number: NTR3516     

Positron tomographic emission study of olfactory induced emotional recall in veterans with and without combat-related posttraumatic stress disorder

OBJECTIVE: Memory for odors is often associated with highly emotional experiences, and odors have long been noted by clinicians to be precipitants of trauma symptoms in posttraumatic stress disorder (PTSD). Primitive brain systems involved in fear responsivity and survival also mediate smell, including the olfactory cortex and amygdala. The purpose of this study was to measure neural correlates of olfaction in PTSD. METHODS: We exposed male combat veterans with PTSD (N = 8) and without PTSD (N = 8) to a set of smells, including diesel (related to traumatic memories of combat), and three other types of smells: odorless air, vanilla/coconut, and hydrogen sulfide (H2S) (respectively, a neutral, positive, and negative hedonic nontraumatic smell) in conjunction with PET imaging of cerebral blood flow and assessment of psychophysiological and behavioral symptoms. All subjects also underwent a baseline of olfactory acuity. RESULTS: PTSD patients rated diesel as unpleasant and distressing, resulting in increased PTSD symptoms and anxiety in PTSD versus combat controls. Exposure to diesel resulted in an increase in regional blood flow (rCBF) in amygdala, insula, medial prefrontal cortex, and anterior cingulate cortex, and decreased rCBF in lateral prefrontal cortex in PTSD in comparison to combat controls. Combat controls showed less rCBF changes on any smell, and did not show amygdala activation upon diesel exposure. CONCLUSIONS: These data support the hypothesis that in PTSD trauma-related smells can serve as strong emotional reminders. The findings indicate the involvement of a neural circuitry that shares olfactory elements and memory processing regions when exposed to trauma-related stimuli.     

Larger dentate gyrus volume as predisposing resilience factor for the development of trauma-related symptoms

Early interventions to improve resilience require the identification of objective risk biomarkers for PTSD symptom development. Although altered hippocampal and amygdala volumes are consistently observed in PTSD, it remains currently unknown whether they represent a predisposing vulnerability factor for PTSD symptom development or an acquired consequence of trauma exposure and/or the disorder. We conducted a longitudinal, prospective study in 210 police recruits at high risk for trauma exposure (56 females(26.7%); mean[SD] age = 24.02[5.19]). Structural MRI scans and trauma-related symptom severity were assessed at pre-trauma baseline and at 16-month follow-up. Between assessments, police recruits were exposed to various potentially traumatic events during their police training. Police recruits reported a significant increase in police-related trauma exposure and stress-related symptoms between assessments. Smaller hippocampal left dentate gyrus (DG) volumes at baseline predicted increase in self-reported PTSD symptoms (B[SE] = −0.21[0.08], p = 0.011), stress symptoms (B[SE] = −0.16[0.07], p = 0.024) and negative affect (B[SE] = −0.21[0.07], p = 0.005) upon trauma exposure. Amount of police-related trauma exposure between assessments was positively associated with an increase in left basal amygdala nucleus volume (B[SE] = 0.11[0.05], p = 0.026). Taken together, smaller DG-volumes pre-trauma may represent a predisposing neurobiological vulnerability factor for development of trauma-related symptoms. On the other hand, amount of trauma exposure between assessments was positively associated with increased amygdala basal nucleus volume, suggesting acquired neural effects. These findings suggest that preventive interventions for PTSD aimed at improving resilience could be targeted at increasing DG-volume and potentially its functioning.Subject terms: Stress and resilience, Predictive markers, Risk factors     

Stress and hippocampal abnormalities in psychiatric disorders.

The hippocampus plays a main role in regulating stress response in humans, but is itself highly sensitive to neurotoxic effects of repeated stressful episodes. Hippocampal atrophy related to experimental stress has been reported in laboratory studies in animals. Several controlled brain imaging studies have also shown hippocampal abnormalities in psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and borderline personality disorder (BPD). This paper reviews the physiological role of the hippocampus in stress circuitry and the effects of stress on cognitive functions mediated by the hippocampus. We also review brain imaging studies investigating hippocampus in PTSD, MDD, and BPD. This literature suggests that individuals with PTSD, MDD, and BPD may suffer hippocampal atrophy as a result of stressors associated with these disorders. Prospective, longitudinal studies will be needed in high-risk offspring and first-episode subjects to explore the relationship between stress and hippocampal atrophy in these neuropsychiatric illnesses.     

Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study

Neurobiological markers of future susceptibility to posttraumatic stress disorder (PTSD) may facilitate identification of vulnerable individuals in the early aftermath of trauma. Variability in resting-state networks (RSNs), patterns of intrinsic functional connectivity across the brain, has previously been linked to PTSD, and may thus be informative of PTSD susceptibility. The present data are part of an initial analysis from the AURORA study, a longitudinal, multisite study of adverse neuropsychiatric sequalae. Magnetic resonance imaging (MRI) data from 109 recently (i.e., ~2 weeks) traumatized individuals were collected and PTSD and depression symptoms were assessed at 3 months post trauma. We assessed commonly reported RSNs including the default mode network (DMN), central executive network (CEN), and salience network (SN). We also identified a proposed arousal network (AN) composed of a priori brain regions important for PTSD: the amygdala, hippocampus, mamillary bodies, midbrain, and pons. Primary analyses assessed whether variability in functional connectivity at the 2-week imaging timepoint predicted 3-month PTSD symptom severity. Left dorsolateral prefrontal cortex (DLPFC) to AN connectivity at 2 weeks post trauma was negatively related to 3-month PTSD symptoms. Further, right inferior temporal gyrus (ITG) to DMN connectivity was positively related to 3-month PTSD symptoms. Both DLPFC-AN and ITG-DMN connectivity also predicted depression symptoms at 3 months. Our results suggest that, following trauma exposure, acutely assessed variability in RSN connectivity was associated with PTSD symptom severity approximately two and a half months later. However, these patterns may reflect general susceptibility to posttraumatic dysfunction as the imaging patterns were not linked to specific disorder symptoms, at least in the subacute/early chronic phase. The present data suggest that assessment of RSNs in the early aftermath of trauma may be informative of susceptibility to posttraumatic dysfunction, with future work needed to understand neural markers of long-term (e.g., 12 months post trauma) dysfunction. Furthermore, these findings are consistent with neural models suggesting that decreased top-down cortico-limbic regulation and increased network-mediated fear generalization may contribute to ongoing dysfunction in the aftermath of trauma.Subject terms: Amygdala, Predictive markers, Human behaviour     

The Dissociative Subtype of Posttraumatic Stress Disorder: Unique Resting-State Functional Connectivity of Basolateral and Centromedial Amygdala Complexes

Previous studies point towards differential connectivity patterns among basolateral (BLA) and centromedial (CMA) amygdala regions in patients with posttraumatic stress disorder (PTSD) as compared with controls. Here we describe the first study to compare directly connectivity patterns of the BLA and CMA complexes between PTSD patients with and without the dissociative subtype (PTSD+DS and PTSD−DS, respectively). Amygdala connectivity to regulatory prefrontal regions and parietal regions involved in consciousness and proprioception were expected to differ between these two groups based on differential limbic regulation and behavioral symptoms. PTSD patients (n=49) with (n=13) and without (n=36) the dissociative subtype and age-matched healthy controls (n=40) underwent resting-state fMRI. Bilateral BLA and CMA connectivity patterns were compared using a seed-based approach via SPM Anatomy Toolbox. Among patients with PTSD, the PTSD+DS group exhibited greater amygdala functional connectivity to prefrontal regions involved in emotion regulation (bilateral BLA and left CMA to the middle frontal gyrus and bilateral CMA to the medial frontal gyrus) as compared with the PTSD−DS group. In addition, the PTSD+DS group showed greater amygdala connectivity to regions involved in consciousness, awareness, and proprioception—implicated in depersonalization and derealization (left BLA to superior parietal lobe and cerebellar culmen; left CMA to dorsal posterior cingulate and precuneus). Differences in amygdala complex connectivity to specific brain regions parallel the unique symptom profiles of the PTSD subgroups and point towards unique biological markers of the dissociative subtype of PTSD.     

Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a psychiatric disease that seriously affects brain function. Currently, selective serotonin reuptake inhibitors (SSRIs) are used to treat PTSD clinically but have decreased efficiency and increased side effects. In this study, nasal cannabidiol inclusion complex temperature-sensitive hydrogels (CBD TSGs) were prepared and evaluated to treat PTSD. Mice model of PTSD was established with conditional fear box. CBD TSGs could significantly improve the spontaneous behavior, exploratory spirit and alleviate tension in open field box, relieve anxiety and tension in elevated plus maze, and reduce the freezing time. Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex, amygdala, and hippocampus CA1. CBD TSGs could reduce the level of tumor necrosis factor-α caused by PTSD. Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1A receptor. Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration, as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs. Overall, nasal CBD TSGs are safe and effective and have controlled release. There are a novel promising option for the clinical treatment of PTSD.KEY WORDS: Post-traumatic stress disorder, Cannabidiol, Hydroxypropyl-β-cyclodextrin, Inclusion complex, Hydrogels, Brain targeting, Blood‒brain barrier, Intranasal administration     

A Randomized,Double-Blind,Placebo-Controlled Trial of Pregnenolone for Bipolar Depression

Depression in bipolar disorder (BPD) is challenging to treat. Therefore, additional medication options are needed. In the current report, the effect of the neurosteroid pregnenolone on depressive symptoms in BPD was examined. Adults (n=80) with BPD, depressed mood state, were randomized to pregnenolone (titrated to 500 mg/day) or placebo, as add-on therapy, for 12 weeks. Outcome measures included the 17-item Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology—Self-Report (IDS-SR), Hamilton Rating Scale for Anxiety (HRSA), and Young Mania Rating Scale (YMRS). Serum neurosteroid levels were assessed at baseline and week 12. Data were analyzed using a mixed model ANCOVA with a between factor of treatment assignment, a within factor (repeated) of visit, and the baseline value, as well as age and gender, as covariates. In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.025), but not IDS-SR, was observed. Depression remission rates were greater in the pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ²(1)=3.99, p=0.046), but not the HRSD. Large baseline-to-exit changes in neurosteroid levels were observed in the pregnenolone group but not in the placebo group. In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=−0.43, p=0.036) and pregNANolone (r(22)=−0.48, p=0.019) levels. Pregnenolone was well tolerated. The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered.     

High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: Interplay between clinical and animal studies

High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below. In this preliminary study, 25 patients with acute stress symptoms were administered a single intravenous bolus of high-dose hydrocortisone (100–140 mg) or placebo within 6 h of a traumatic event in a prospective, randomized, double-blind, placebo-controlled pilot study. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as expressed by the reduced risk of the development of PTSD post-trauma. In parallel, a comparative study of morphological arborization in dentate gyrus and its modulating molecules was performed in stress-exposed animals treated with high-dose hydrocortisone. Steroid-treated stressed animals displayed significantly increased dendritic growth and spine density, with increased levels of brain-derived neurotrophic factor (BDNF) and obtunded postsynaptic density-95 (PSD-95) levels. The animal study provided insights into the potential mechanism of this intervention, as it identified relevant morphological and biochemical associations to the clinical observations. Thus, evidence from clinical and animal studies suggests that there is a “window of opportunity” in the early aftermath of trauma to help those who are vulnerable to the development of chronic PTSD.     

Dopaminergic Influences on Emotional Decision Making in Euthymic Bipolar Patients

We recently reported that the D2/D3 agonist pramipexole may have pro-cognitive effects in euthymic patients with bipolar disorder (BPD); however, the emergence of impulse-control disorders has been documented in Parkinson''s disease (PD) after pramipexole treatment. Performance on reward-based tasks is altered in healthy subjects after a single dose of pramipexole, but its potential to induce abnormalities in BPD patients is unknown. We assessed reward-dependent decision making in euthymic BPD patients pre- and post 8 weeks of treatment with pramipexole or placebo by using the Iowa Gambling Task (IGT). The IGT requires subjects to choose among four card decks (two risky and two conservative) and is designed to promote learning to make advantageous (conservative) choices over time. Thirty-four BPD patients completed both assessments (18 placebo and 16 pramipexole). Baseline performance did not differ by treatment group (F=0.63; p=0.64); however, at week 8, BPD patients on pramipexole demonstrated a significantly greater tendency to make increasingly high-risk, high-reward choices across the five blocks, whereas the placebo group''s pattern was similar to that reported in healthy individuals (treatment × time × block interaction, p<0.05). Analyses of choice strategy using the expectancy valence model revealed that after 8 weeks on pramipexole, BPD patients attended more readily to feedback related to gains than to losses, which could explain the impaired learning. There were no significant changes in mood symptoms over the 8 weeks, and no increased propensity toward manic-like behaviors were reported. Our results suggest that the enhancement of dopaminergic activity influences risk-associated decision-making performance in euthymic BPD. The clinical implications remain unknown.     

Fluoxetine in the acute treatment and relapse prevention of combat-related post-traumatic stress disorder: Analysis of the veteran group of a placebo-controlled, randomized clinical trial.

The efficacy and safety of fluoxetine (20-80 mg) was compared with placebo in 144 veterans [36.2 years], diagnosed with combat-related post-traumatic stress disorder (PTSD) selected from a 12-week acute and 24-week relapse prevention PTSD trial. In the acute phase, improvements were greater with fluoxetine than placebo in the disease-specific outcome measures: Treatment Outcome PTSD (TOP-8) total scores (SE):-9.05 (0.90) and -5.20 (1.23), p = 0.001; Clinician Administered PTSD Scale (CAPS) total scores:-31.12 (2.72) and -16.07 (4.24), p < 0.001; all CAPS subscores; Davidson Trauma Scale (DTS) total scores; and other general outcome measures. In the maintenance phase, fluoxetine was superior to placebo in sustaining improvement in TOP-8 [-1.01 (0.91) and 1.56 (0.95)] and CAPS [-4.93 (3.54) and 5.48 (3.66)]. The risk of relapse in the placebo arm was significantly greater than in the fluoxetine arm (log-rank test chi 2 = 4.090, df = 1, p = 0.048). Fluoxetine was well tolerated at a mean daily dose of 65 mg.