Resilience is the ability to adapt successfully in the face of stress and adversity. Stressful life events, trauma, and chronic adversity can have a substantial impact on brain function and structure, and can result in the development of posttraumatic stress disorder (PTSD), depression and other psychiatric disorders. However, most individuals do not develop such illnesses after experiencing stressful life events, and are thus thought to be resilient. Resilience as successful adaptation relies on effective responses to environmental challenges and ultimate resistance to the deleterious effects of stress, therefore a greater understanding of the factors that promote such effects is of great relevance. This review focuses on recent findings regarding genetic, epigenetic, developmental, psychosocial, and neurochemical factors that are considered essential contributors to the development of resilience. Neural circuits and pathways involved in mediating resilience are also discussed. The growing understanding of resilience factors will hopefully lead to the development of new pharmacological and psychological interventions for enhancing resilience and mitigating the untoward consequences.

The substance P-neurokinin-1 receptor (SP-NK1R) system has been extensively studied in experimental models of stress, fear, and reward. Elevated cerebrospinal fluid (CSF) SP levels were reported previously in combat-related PTSD. No medication specifically targeting this system has been tested in PTSD. This proof-of-concept randomized, double-blind, placebo-controlled trial evaluated the selective NK1R antagonist GR205171 in predominately civilian PTSD. Following a 2-week placebo lead-in, 39 outpatients with chronic PTSD and a Clinician-Administered PTSD Scale (CAPS) score ≥ 50 were randomized to a fixed dose of GR205171 (N=20) or placebo (N=19) for 8 weeks. The primary endpoint was mean change from baseline to endpoint in total CAPS score. Response rate (≥ 50% reduction in baseline CAPS) and safety/tolerability were secondary endpoints. CSF SP concentrations were measured in a subgroup of patients prior to randomization. There was significant improvement in the mean CAPS total score across all patients over time, but no significant difference was found between GR205171 and placebo. Likewise, there was no significant effect of drug on the proportion of responders [40% GR205171 vs. 21% placebo (p=0.30)]. An exploratory analysis showed that GR205171 treatment was associated with significant improvement compared to placebo on the CAPS hyperarousal symptom cluster. GR205171 was well-tolerated, with no discontinuations due to adverse events. CSF SP concentrations were positively correlated with baseline CAPS severity. The selective NK1R antagonist GR205171 had fewer adverse effects but was not significantly superior to placebo in the short-term treatment of chronic PTSD. (ClinicalTrials.gov Identifier: NCT 00211861, NCT 00383786)

Background

Increased activity of the habenula has been implicated in the etiology of major depressive disorder (MDD), in which reductions in habenula volume are present at postmortem. We conducted the first MRI analysis of habenula volume in MDD and bipolar disorder (BD).

Methods

High-resolution images (resolution≈0.4mm3) were acquired using a 3T scanner, and a pulse sequence optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. Seventy-four healthy controls (HC) were compared to both medicated (lithium/divalproex, n=15) and unmedicated, depressed BD (n=22) patients, unmedicated, depressed MDD patients (n=28), and unmedicated MDD patients in remission (RD, n=32).

Results

The unmedicated BD patients displayed significantly smaller absolute (p<0.01) and normalized (p<0.05) habenula volumes than the HC subjects. In post hoc assessments analyzing males and females separately, the currently-depressed females with MDD had smaller absolute (p<0.05) habenula volumes than the healthy control females. None of the other psychiatric groups differed significantly from the HC group.

Conclusions

We provide further evidence for the involvement of the habenula in affective illness, but suggest that a reduction in volume may be more pronounced in unmedicated, depressed BD subjects and female, currently depressed MDD subjects. The habenula plays major roles in the long-term modification of monoamine transmission and behavioral responses to stress, and in the suppression of dopamine cell activity following the absence of an expected reward. A reduction in habenula volume may thus have functional consequences which contribute to the risk for developing affective disease.

Background

Multiple studies have documented deficits in verbal declarative memory function in depression that improve with resolution of symptoms; imaging studies show deficits in anterior cingulate function in depression, a brain area that mediates memory. No studies to date have examined neural correlates of emotionally valenced declarative memory using affectively negative (sad) verbal material that is clinically relevant to understanding depression. Also no studies have examined the effects of treatment on neural correlates of verbal declarative memory. The purpose of this study was to examine the effects of treatment with antidepressants on verbal declarative memory in patients with depression.

Methods

Subjects with (N =18) and without (N=9) mid-life major depression underwent positron emission tomography (PET) imaging during verbal declarative memory tasks with both neutral paragraph encoding compared to a control condition, and emotional (sad) word pair retrieval compared to a control condition. Imaging was repeated in 13 subjects with depression after treatment with antidepressants.

Results

Patients with untreated depression had a failure of anterior cingulate activation relative to controls during retrieval of emotional word pairs. Antidepressant treatment resulted in increased anterior cingulate function compared to the untreated baseline for both neutral and emotional declarative memory.

Limitations

Limitations include a small sample size and variety of antidepressants used.

Conclusions

These results are consistent with alterations in anterior cingulate function that are reversible with treatment in patients with depression. These findings may have implications for understanding the mechanism of action of antidepressants in the treatment of depression.

Objective

Corticotropin-releasing factor (CRF) and somatostatin both play important roles in mediating responses to acute and chronic stress. The purpose of this study was to measure CSF concentrations of CRF and somatostatin in patients with chronic combat-related post-traumatic stress disorder (PTSD) and comparison subjects.

Method

Lumbar punctures for collection of CSF were performed in Vietnam combat veterans with PTSD (N=11) and comparison subjects (N=17). CSF concentrations of CRF and somatostatin were compared between the two groups.

Results

CSF concentrations of CRF were higher in the PTSD patients than in the comparison subjects (mean=29.0 pg/ml, SD=7.8, versus mean=21.9 pg/ml, SD=6.0). This group difference remained significant after covariance for age. CSF somatostatin concentrations in PTSD patients were higher than those of the comparison subjects (mean=19.9 pg/ml, SD=5.4, versus mean=13.7 pg/ml, SD=8.0). However, covarying for age reduced the level of significance.

Conclusions

Higher CSF CRF concentrations in patients with PTSD may reflect alterations in stress-related neurotransmitter systems. The higher CSF CRF concentrations may play a role in disturbances of arousal in patients with PTSD.

Background

In the conditioned fear paradigm, repeated pairing of an aversive unconditioned stimulus (US) (e.g. electric shock) with a neutral conditioned stimulus (CS) (e.g. bright light) results in a conditioned fear response to the light alone. Animal studies have shown that the amygdala plays a critical role in acquisition of conditioned fear responses, while the medial prefrontal cortex (including anterior cingulate), through inhibition of amygdala responsiveness, has been hypothesized to play a role in extinction of fear responses. No studies have examined neural correlates of fear conditioning and extinction in patients with post-traumatic stress disorder (PTSD).

Method

Women with early childhood sexual-abuse-related PTSD (n=8) and women without abuse or PTSD (n=11) underwent measurement of psychophysiological (skin conductance) responding as well as positron emission tomographic (PET) measurement of cerebral blood flow during habituation, acquisition and extinction conditions. During habituation subjects were repeatedly exposed to a blue square on a screen. During acquisition, exposure to the blue square (CS) was paired with an electric shock to the forearm (US). With extinction, subjects were again exposed to the blue squares without shock. On a different day subjects went through the same procedure with electric shocks administered randomly in the absence of the blue square.

Results

Skin conductance responding to the CS was consistent with the development of conditioned responses with this paradigm. PTSD patients had increased left amygdala activation with fear acquisition, and decreased anterior cingulate function during extinction, relative to controls.

Conclusions

These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.

Background

Patients with posttraumatic stress disorder (PTSD) show a reliable increase in PTSD symptoms and physiological reactivity following exposure to traumatic pictures and sounds. In this study neural correlates of exposure to traumatic pictures and sounds were measured in PTSD.

Methods

Positron emission tomography and H2[15O] were used to measure cerebral blood flow during exposure to combat-related and neutral pictures and sounds in Vietnam combat veterans with and without PTSD.

Results

Exposure to traumatic material in PTSD (but not non-PTSD) subjects resulted in a decrease in blood flow in medial prefrontal cortex (area 25), an area postulated to play a role in emotion through inhibition of amygdala responsiveness. Non-PTSD subjects activated anterior cingulate (area 24) to a greater degree than PTSD patients. There were also differences in cerebral blood flow response in areas involved in memory and visuospatial processing (and by extension response to threat), including posterior cingulate (area 23), precentral (motor) and inferior parietal cortex, and lingual gyrus. There was a pattern of increases in PTSD and decreases in non-PTSD subjects in these areas.

Conclusions

The findings suggest that functional alterations in specific cortical and subcortical brain areas involved in memory, visuospatial processing, and emotion underlie the symptoms of patients with PTSD.

Background

Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD.

Methods

Declarative memory was assessed with the Wechsler Memory Scale–Revised and Selective Reminding Test before and after 9–12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging.

Results

Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume.

Conclusions

These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD.

Context

We previously used positron emission tomography (PET) measurement of brain metabolism with 18fluorodeoxyglucose to show that patients receiving selective serotonin reuptake inhibitors (SSRIs) who have a tryptophan depletion–induced return of depressive symptoms have an acute decrease in metabolism in orbitofrontal cortex, dorsolateral prefrontal cortex, and thalamus. Many patients with depression in remission while taking norepinephrine reuptake inhibitors (NRIs) (but not SSRIs) experience a return of depressive symptoms with depletion of norepinephrine and dopamine using α-methylparatyrosine (AMPT).

Objective

To assess brain metabolic correlates of AMPT administration in patients with depression in remission while receiving NRIs.

Design, Setting, and Participants

Randomized, controlled, double-blind trial in which 18 patients recruited in 1997–2000 from the general community who had depression in remission while taking NRIs had PET imaging in a psychiatric research unit following AMPT and placebo administration.

Interventions

After initial medication with desipramine and follow-up until response, patients underwent active AMPT (five 1-g doses administered orally over 28 hours) and placebo (diphenhydramine hydrochloride, five 50- mg doses administered similarly) catecholamine depletion challenges in randomized order of assignment, after which PET imaging was performed on day 3 of each condition. Both study conditions were performed 1 week apart.

Main Outcome Measures

Regional brain metabolism rates in patients with and without AMPT-induced return of depressive symptoms.

Results

AMPT-induced return of depressive symptoms was experienced by 11 of the 18 patients and led to decreased brain metabolism in a number of cortical areas, with the greatest magnitude of effects in orbitofrontal (P=.002) and dorsolateral prefrontal (P=.03) cortex and thalamus (P=.006). Increased resting metabolism in prefrontal and limbic areas predicted vulnerability to return of depressive symptoms.

Conclusions

Different neurochemical systems that mediate depression may have effects on a common brain circuitry. Baseline metabolism in successfully treated depressed patients may predict vulnerability to future episodes of depression.

Objective

Studies in nonhuman primates suggest that high levels of cortisol associated with stress have neurotoxic effects on the hippocampus, a brain structure involved in memory. The authors previously showed that patients with combat-related posttraumatic stress disorder (PTSD) had deficits in short-term memory. The purpose of this study was to compare the hippocampal volume of patients with PTSD to that of subjects without psychiatric disorder.

Method

Magnetic resonance imaging was used to measure the volume of the hippocampus in 26 Vietnam combat veterans with PTSD and 22 comparison subjects selected to be similar to the patients in age, sex, race, years of education, socioeconomic status, body size, and years of alcohol abuse.

Results

The PTSD patients had a statistically significant 8% smaller right hippocampal volume relative to that of the comparison subjects, but there was no difference in the volume of other brain regions (caudate and temporal lobe). Deficits in short-term verbal memory as measured with the Wechsler Memory Scale were associated with smaller right hippocampal volume in the PTSD patients only.

Conclusions

These findings are consistent with a smaller right hippocampal volume in PTSD that is associated with functional deficits in verbal memory.

Objective

Childhood sexual abuse is very common in our society, but little is known about the long-term effects of abuse on brain function. The purpose of this study was to measure neural correlates of memories of childhood abuse in sexually abused women with and without the diagnosis of posttraumatic stress disorder (PTSD).

Method

Twenty-two women with a history of childhood sexual abuse underwent injection of [15O]H2O, followed by positron emission tomography imaging of the brain while they listened to neutral and traumatic (personalized childhood sexual abuse events) scripts. Brain blood flow during exposure to traumatic and neutral scripts was compared for sexually abused women with and without PTSD.

Results

Memories of childhood sexual abuse were associated with greater increases in blood flow in portions of anterior prefrontal cortex (superior and middle frontal gyri—areas 6 and 9), posterior cingulate (area 31), and motor cortex in sexually abused women with PTSD than in sexually abused women without PTSD. Abuse memories were associated with alterations in blood flow in medial prefrontal cortex, with decreased blood flow in subcallosal gyrus (area 25), and a failure of activation in anterior cingulate (area 32). There was also decreased blood flow in right hippocampus, fusiform/inferior temporal gyrus, supramarginal gyrus, and visual association cortex in women with PTSD relative to women without PTSD.

Conclusions

These findings implicate dysfunction of medial prefrontal cortex (subcallosal gyrus and anterior cingulate), hippocampus, and visual association cortex in pathological memories of childhood abuse in women with PTSD. Increased activation in posterior cingulate and motor cortex was seen in women with PTSD. Dysfunction in these brain areas may underlie PTSD symptoms provoked by traumatic reminders in subjects with PTSD.

Objective

Smaller hippocampal volume has been reported only in some but not all studies of unipolar major depressive disorder. Severe stress early in life has also been associated with smaller hippocampal volume and with persistent changes in the hypothalamic-pituitary-adrenal axis. However, prior hippocampal morphometric studies in depressed patients have neither reported nor controlled for a history of early childhood trauma. In this study, the volumes of the hippocampus and of control brain regions were measured in depressed women with and without childhood abuse and in healthy nonabused comparison subjects.

Method

Study participants were 32 women with current unipolar major depressive disorder—21 with a history of prepubertal physical and/or sexual abuse and 11 without a history of prepubertal abuse—and 14 healthy nonabused female volunteers. The volumes of the whole hippocampus, temporal lobe, and whole brain were measured on coronal MRI scans by a single rater who was blind to the subjects’ diagnoses.

Results

The depressed subjects with childhood abuse had an 18% smaller mean left hippocampal volume than the nonabused depressed subjects and a 15% smaller mean left hippocampal volume than the healthy subjects. Right hippocampal volume was similar across the three groups. The right and left hippocampal volumes in the depressed women without abuse were similar to those in the healthy subjects.

Conclusions

A smaller hippocampal volume in adult women with major depressive disorder was observed exclusively in those who had a history of severe and prolonged physical and/or sexual abuse in childhood. An unreported history of childhood abuse in depressed subjects could in part explain the inconsistencies in hippocampal volume findings in prior studies in major depressive disorder.

Posttraumatic stress disorder (PTSD) is typically accompanied by both acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but studies have also used a challenge model to assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. The purpose of this article was to assess the effect of long-term treatment with the selective reuptake inhibitor (SSRI), paroxetine, on stress reactivity in patients with PTSD. We assessed diurnal salivary cortisol and urinary cortisol as well as cortisol, heart rate, and behavioral responses to a standardized cognitive stress challenge, in 13 female patients with chronic PTSD before and after 12 months of paroxetine treatment. Treatment resulted in a significant decrease in PTSD symptoms. Twenty-four-hour urinary cortisol was lower compared to base line after successful treatment. Treatment resulted in a decrease of salivary cortisol levels on all time points on a diurnal curve. Despite similar stress perception, cortisol response to the cognitive stress challenge resulted in a 26.5% relative decrease in stress-induced salivary cortisol with treatment. These results suggest that successful treatment with SSRI in chronic PTSD is associated with a trend for a decrease in baseline diurnal cortisol and with reduced cortisol reactivity to stress.

We have previously reported smaller hippocampal volume and deficits in short-term memory in patients with combat-related posttraumatic stress disorder (PTSD) relative to comparison subjects. The purpose of this study was to compare hippocampal volume in adult survivors of childhood abuse to matched controls. Magnetic resonance imaging was used to measure volume of the hippocampus in adult survivors of childhood abuse (n = 17) and healthy subjects (n = 17) matched on a case-by-case basis for age, sex, race, handedness, years of education, body size, and years of alcohol abuse. All patients met criteria for PTSD secondary to childhood abuse. PTSD patients had a 12% smaller left hippocampal volume relative to the matched controls (p < .05), without smaller volumes of comparison regions (amygdala, caudate, and temporal lobe). The findings were significant after controlling for alcohol, age, and education, with multiple linear regression. These findings suggest that a decrease in left hippocampal volume is associated with abuse-related PTSD.

Background

The habenula plays an important role in regulating behavioral responses to stress and shows increased cerebral blood flow and decreased gray matter volume in patients with mood disorders. Here, we compare the volume of the habenula in unmedicated patients with post-traumatic stress disorder (PTSD) and healthy controls (HC) using MRI.

Findings

High-resolution images (resolution of approximately 0.4 mm3) were acquired using a 3T scanner and a pulse sequence optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. PTSD and HC participants did not differ significantly in absolute or normalized habenula volume. Post hoc analyses controlling for the effects of comorbid major depressive disorder (MDD) and type and age of trauma exposure were not significant. Further, there was no association between PTSD severity and habenula volume.

Conclusions

Our data suggest that PTSD is not associated with robust structural changes in the habenula. The modest size of the PTSD sample may have reduced statistical power thereby accounting for the negative results obtained.

Background

Neuropeptide Y (NPY) and serotonergic systems have been implicated in the pathophysiology of depression but have not yet been linked together.

Methods

In a randomized, double-blind crossover study, 28 medication-free patients with remitted depression and 26 healthy control subjects underwent tryptophan depletion (TD) and sham depletion. Plasma NPY concentrations were determined at baseline and at +5, +7, and +24 h during TD and sham depletion, respectively. Hamilton Depression Rating Scale (HDRS, 24-item) scores were assessed at baseline and at +7 and +24 h after TD and sham depletion, respectively.

Results

There was no difference between healthy subjects and patients with remitted depression in baseline plasma NPY concentrations and in plasma NPY concentrations during TD and sham depletion, respectively. Plasma NPY concentrations did not differ between TD and sham depletion. At no time point there was an association between HDRS scores and plasma NPY concentrations in patients with remitted depression.

Limitations

Plasma NPY concentrations in rMDD patients were not obtained during the symptomatic phase of the illness. Only peripheral measurements of NPY were used.

Conclusions

Decreased plasma NPY concentrations, as described previously during a spontaneous episode of major depression, appear as state but not as trait marker in depression. No evidence was found for an involvement of plasma NPY in relapse during TD. There appears no direct functional link between serotonergic neurotransmission and plasma NPY concentrations.

Background

We investigated whether performance on a reward processing task differs between fully remitted patients with major depressive disorder (MDD) and healthy control subjects after catecholamine depletion.

Methods

Seventeen unmedicated subjects with remitted MDD (RMDD) and 13 healthy control subjects underwent catecholamine depletion with oral α-methyl-para-tyrosine (AMPT) in a randomized, placebo-controlled, double-blind crossover study. The main outcome measure was the reaction time on the monetary incentive delay (MID) task.

Results

A diagnosis × drug interaction was evident (p = .001), which was attributable to an increase in reaction time across all incentive levels after AMPT in RMDD subjects (p = .001) but no significant AMPT effect on reaction time in control subjects (p = .17). There was no drug × diagnosis interaction on control tasks involving working memory or attention. In the RMDD sample the AMPT-induced depressive symptoms correlated with AMPT-induced changes in reaction time at all incentive levels of the MID task (r values = .58 –.82, p < .002).

Conclusions

Under catecholamine depletion the RMDD subjects were robustly differentiated from control subjects by development of performance deficits on a reward processing task. These performance deficits correlated directly with the return of depressive symptoms after AMPT administration. The sensitivity of central reward processing systems to reductions in brain catecholamine levels thus seems to represent a trait-like marker in MDD.

MRI-based reports of both abnormally increased and decreased amygdala volume in bipolar disorder (BD) have surfaced in the literature. Two major methodological weaknesses characterizing extant studies are treatment with medication and inaccurate segmentation of the amygdala due to limitations in spatial and tissue contrast resolution. Here, we acquired high-resolution images (voxel size=0.55×0.55×0.60mm) using a GE 3T MRI scanner, and a pulse sequence optimized for tissue contrast resolution. The amygdala was manually segmented by one rater blind to diagnosis, using coronal images. Eighteen unmedicated (mean medication-free period 11±10 months) BD subjects were age and gender matched with 18 healthy controls, and 17 medicated (lithium or divalproex) subjects were matched to 17 different controls. The unmedicated BD patients displayed smaller left and right amygdala volumes than their matched control group (p<0.01). Conversely, the BD subjects undergoing medication treatment showed a trend towards greater amygdala volumes than their matched HC sample (p=0.051). Right and left amygdala volumes were larger (p<0.05) or trended larger, respectively, in the medicated BD sample compared with the unmedicated BD sample. The two control groups did not differ from each other in either left or right amygdala volume. BD patients treated with lithium have displayed increased gray matter volume of the cortex and hippocampus relative to untreated BD subjects in previous studies. Here we extend these results to the amygdala. We raise the possibility that neuroplastic changes in the amygdala associated with BD are moderated by some mood stabilizing medications.

Background

Straub et al. (2002b) located a susceptibility region for schizophrenia at the DTNBP1 locus. At least 40 studies (including one study in US populations) attempted to replicate this original finding, but the reported findings are highly diverse and at least five pathways by which dysbindin protein might be involved in schizophrenia have been proposed. The present study aimed to test the association in two common US populations by using powerful analytic methods.

Methods

Six markers at DTNBP1 were genotyped by mass spectroscopy (“MassARRAY” technique) in a sample of 663 subjects, including 346 healthy subjects [298 European-Americans (EAs) and 48 African-Americans (AAs)] and 317 subjects with schizophrenia (235 EAs and 82 AAs). Thirty-eight ancestry-informative markers (AIMs) were genotyped in this sample to infer the ancestry proportions. Diplotype, haplotype, genotype, and allele frequency distributions were compared between cases and controls, controlling for possible population stratification, admixture, and sex-specific effects, and taking interaction effects into account, using a logistic regression analysis (an extended structured association (SA) method).

Results

Conventional case-control comparisons showed that genotypes of the markers P1578 (rs1018381) and P1583 (rs909706) were nominally associated with schizophrenia in EAs and in AAs, respectively. These associations became less or non-significant after controlling for population stratification and admixture effects (using SA or regression analysis), and became non-significant after correction for multiple testing. However, regression analysis demonstrated that the common diplotypes (ACCCTT/GCCGCC or GCCGCC/GCCGCC) and the interaction effects of haplotypes GCCGCC × GCCGCC significantly affected risk for schizophrenia in EAs, effects that were modified by sex. Fine-mapping using δ or J statistics located the specific markers (δ: P1328; J: P1333) closest to the putative risk sites in EAs.

Conclusions

The present study shows that DTNBP1 is a risk gene for schizophrenia in EAs. Variation at DTNBP1 may modify risk for schizophrenia in this population.

Background

Genetic polymorphisms that influence serotonin (5-hydroxytryptamine, 5HT) neurotransmission are candidates for contributing to susceptibility to posttraumatic stress disorder (PTSD). The objective of our study was to determine if a variable length polymorphism for the promoter regions of the 5HT transporter (5HTTLPR), and/or a substitution polymorphism in the promoter region for the 5HT2A receptor, would be associated with PTSD in a trauma exposed population of adult African-Americans.

Methods

Using a case control design, 118 participants recruited from the primary care clinics and the campus of a historically black university who met inclusion criteria including trauma exposure provided blood samples for genomic DNA. PTSD criteria were determined by the Clinician Assessment of PTSD Scale (CAPS) and criteria for other psychiatric disorders by the Structured Clinical Interview for DSM-IV (SCID). 5HTTLPR and 5HT2A-1438A/G were genotyped using established methods. Associations of genotypes with lifetime PTSD, and models testing associations of allele “dose”, were analyzed.

Results

Fifty-five (47%) participants met lifetime criteria for PTSD and 26 (22%) met criteria for (mostly comorbid) major depression. The 5HT2A (lower expressing) G allele was significantly associated with PTSD. We did not find significant associations with 5HTTLPR.

Conclusions

Our findings suggest a relationship between genetic variation in the 5HT2A promoter region and PTSD.†

Background

Intravenous ketamine has shown rapid antidepressant effects in early trials, making it a potentially attractive candidate for depressed patients at imminent risk of suicide. The Implicit Association Test (IAT), a performance-based measure of association between two concepts, may have utility in suicide assessment.

Methods

Twenty-six patients with treatment-resistant depression were assessed for suicidality 2 hours prior to, and 24 hours following, a single subanesthetic dose of intravenous ketamine using the suicidality item of the Montgomery-Asberg Depression Rating Scale (MADRS-SI). Ten patients also completed IATs assessing implicit suicidal associations at comparable time points. In a second study, 9 patients received thrice-weekly ketamine infusions over a 12-day period.

Results

24-hours after a single infusion, MADRS-SI scores were reduced by an average of 2.08 points on a 0–6 scale (p<.001; d=1.37), and 81% of patients received a rating of 0 or 1 post-infusion. Implicit associations between self- and escape-related words were also reduced following ketamine (p=.003; d=1.36), with reductions correlated across implicit and explicit measures. MADRS-SI reductions were sustained for 12 days by repeated-dose ketamine (2.9-point mean reduction; p<.001; d=2.42).

Conclusions

These preliminary findings support the premise that ketamine has rapid beneficial effects on suicidal cognition and warrants further study.

Background

Significant alterations in γ-aminobutyric acid (GABA) and glutamate levels have been previously reported in symptomatic and remitted major depressive disorder (MDD); however, no studies to date have investigated potential associations between these amino acid neurotransmitters and treatment-resistance.

Methods

The objective of this study was to compare occipital cortex (OCC) and anterior cingulate cortex (ACC) GABA and glutamate+glutamine (“Glx”) levels measured in vivo by proton magnetic resonance spectroscopy (1H MRS) in 15 medication-free treatment-resistant depression (TRD) patients with those in 18 non-treatment-resistant MDD (nTRD) patients and 24 healthy volunteers (HVs).

Results

Levels of OCC GABA relative to voxel tissue water (W) were decreased in TRD patients compared to both HV (20.2% mean reduction; p=.001; Cohen’s d=1.3) and nTRD subjects (16.4% mean reduction; p=.007; Cohen’s d=1.4). There was a similar main effect of diagnosis for ACC GABA/W levels (p=.047; Cohen’s d=0.76) with TRD patients exhibiting reduced GABA in comparison to the other two groups (22.4–24.5% mean reductions). Group differences in Glx/W were not significant in either brain region in primary ANOVA analyses. Only GABA results in OCC survived correction for multiple comparisons.

Conclusions

Our findings corroborate previous reports of decreased GABA in MDD and provide initial evidence for a distinct neuronal amino acid profile in patients who have failed to respond to several standard antidepressants, possibly indicative of abnormal glutamate/glutamine/GABA cycling. Given interest in novel antidepressant mechanisms in TRD that selectively target amino acid neurotransmitter function, the translational relevance of these findings awaits further study.

Enhanced brain reward function could contribute to resilience to trauma. Reward circuitry in active duty, resilient special forces (SF) soldiers was evaluated using fMRI during a monetary incentive delay task. Findings in this group of resilient individuals revealed unique patterns of activation during expectation of reward in the subgenual prefrontal cortex and nucleus accumbens area; regions pivotal to reward processes.

Objective

The prototypical atypical antipsychotic agent, clozapine, is more efficacious for refractory schizophrenia than the “typical” antipsychotics, but the mechanism underlying this enhanced efficacy is still under investigation. Since 2002, at least 22 association studies have demonstrated that the DTNBP1 can be associated with the risk for schizophrenia. We hypothesized that DTNBP1 might also influence the response to antipsychotic treatments. The present study aimed to investigate the relationship between the DTNBP1 and the effects of clozapine and haloperidol on refractory schizophrenia.

Methods

Patients with refractory schizophrenia were assigned to clozapine (n=85) or haloperidol (n=96) and followed for 3 months. Symptom improvement was evaluated by PANSS score. Six markers at DTNBP1 and 38 ancestry informative markers (AIMs) were genotyped in all subjects. The relationships between the effects of antipsychotics and the diplotypes, haplotypes, genotypes, and alleles of DTNBP1 were tested by ANCOVA, ANOVA, and t-test.

Results

Patients with diplotype ACCCTC/GTTGCC, genotypes T/T+T/C, or allele T of marker rs742105 (P1333) have better response to clozapine (0.005≤p≤0.049), and patients with diplotype ACCCTC/GCCGCC, genotype A/G, or allele A of marker rs909706 (P1583) have better response to haloperidol (0.007≤p≤0.080) in European-Americans (EAs), African-Americans (AAs), and/or the combined sample; EA patients with diplotype ACCCTC/GCCGCC have worse response to clozapine on positive symptoms (p=0.011).

Conclusions

The present study demonstrates that the DTNBP1 gene modulates the effects of both the atypical antipsychotic clozapine, and the typical antipsychotic haloperidol. Subjects with different DTNBP1 diplotypes, haplotypes, genotypes, or alleles might have different responses to these antipsychotics.

Objective

Generalized social phobia involves fear/avoidance, specifically of social situations, whereas generalized anxiety disorder involves intrusive worry about diverse circumstances. It remains unclear the degree to which these two, often comorbid, conditions represent distinct disorders or alternative presentations of a single, core underlying pathology. Functional magnetic resonance imaging assessed the neural response to facial expressions in generalized social phobia and generalized anxiety disorder.

Method

Individuals matched on age, IQ, and gender with generalized social phobia without generalized anxiety disorder (N=17), generalized anxiety disorder (N= 17), or no psychopathology (N=17) viewed neutral, fearful, and angry expressions while ostensibly making a simple gender judgment.

Results

The patients with generalized social phobia without generalized anxiety disorder showed increased activation to fearful relative to neutral expressions in several regions, including the amygdala, compared to healthy individuals. This increased amygdala response related to self-reported anxiety in patients with generalized social phobia without generalized anxiety disorder. In contrast, patients with generalized anxiety disorder showed significantly less activation to fearful relative to neutral faces compared to the healthy individuals. They did show significantly increased response to angry expressions relative to healthy individuals in a lateral region of the middle frontal gyrus. This increased lateral frontal response related to self-reported anxiety in patients with generalized anxiety disorder.

Conclusions

These results suggest that neural circuitry dysfunctions differ in generalized social phobia and generalized anxiety disorder.