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1.  Glutamate Receptor Antagonists as Fast-Acting Therapeutic Alternatives for the Treatment of Depression: Ketamine and Other Compounds 
The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine’s antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine’s antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine’s antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine’s adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine’s antidepressant effects.
PMCID: PMC4089991  PMID: 24392693
NMDA receptor antagonist; rapid-acting antidepressants; major depressive disorder; bipolar depression; preclinical models of depression; mammalian target of rapamycin; mTOR
2.  Psychosocial facets of resilience: implications for preventing posttrauma psychopathology, treating trauma survivors, and enhancing community resilience 
European Journal of Psychotraumatology  2014;5:10.3402/ejpt.v5.23970.
There is a range of potential responses to stress and trauma. Whereas, on one extreme, some respond to stress and trauma by developing psychiatric disorders (e.g., posttraumatic stress disorder, PTSD), on the other extreme are the ones who exhibit resilience. Resilience is broadly defined as adaptive characteristics of an individual to cope with and recover from adversity.
Understanding of the factors that promote resilience is warranted and can be obtained by interviewing and learning from particularly resilient individuals as well as empirical research. In this paper, we discuss a constellation of factors comprising cognitive, behavioral, and existential elements that have been identified as contributing to resilience in response to stress or trauma.
The psychosocial factors associated with resilience include optimism, cognitive flexibility, active coping skills, maintaining a supportive social network, attending to one's physical well-being, and embracing a personal moral compass.
These factors can be cultivated even before exposure to traumatic events, or they can be targeted in interventions for individuals recovering from trauma exposure. Currently available interventions for PTSD could be expanded to further address these psychosocial factors in an effort to promote resilience. The cognitive, behavioral, and existential components of psychosocial factors that promote individual resilience can also inform efforts to promote resilience to disaster at the community level.
PMCID: PMC4185137  PMID: 25317258
Resilience; trauma; psychosocial; factors
3.  The genetic interacting landscape of 63 candidate genes in Major Depressive Disorder: an explorative study 
BioData Mining  2014;7:19.
Genetic contributions to major depressive disorder (MDD) are thought to result from multiple genes interacting with each other. Different procedures have been proposed to detect such interactions. Which approach is best for explaining the risk of developing disease is unclear.
This study sought to elucidate the genetic interaction landscape in candidate genes for MDD by conducting a SNP-SNP interaction analysis using an exhaustive search through 3,704 SNP-markers in 1,732 cases and 1,783 controls provided from the GAIN MDD study. We used three different methods to detect interactions, two logistic regressions models (multiplicative and additive) and one data mining and machine learning (MDR) approach.
Although none of the interaction survived correction for multiple comparisons, the results provide important information for future genetic interaction studies in complex disorders. Among the 0.5% most significant observations, none had been reported previously for risk to MDD. Within this group of interactions, less than 0.03% would have been detectable based on main effect approach or an a priori algorithm. We evaluated correlations among the three different models and conclude that all three algorithms detected the same interactions to a low degree. Although the top interactions had a surprisingly large effect size for MDD (e.g. additive dominant model Puncorrected = 9.10E-9 with attributable proportion (AP) value = 0.58 and multiplicative recessive model with Puncorrected = 6.95E-5 with odds ratio (OR estimated from β3) value = 4.99) the area under the curve (AUC) estimates were low (< 0.54). Moreover, the population attributable fraction (PAF) estimates were also low (< 0.15).
We conclude that the top interactions on their own did not explain much of the genetic variance of MDD. The different statistical interaction methods we used in the present study did not identify the same pairs of interacting markers. Genetic interaction studies may uncover previously unsuspected effects that could provide novel insights into MDD risk, but much larger sample sizes are needed before this strategy can be powerfully applied.
PMCID: PMC4181757  PMID: 25279001
Additive interaction; Multiplicative interaction; Logistic regression; Data mining and machine learning; Major depressive disorder
4.  Reduced post-synaptic serotonin type 1A receptor binding in bipolar depression 
Multiple lines of evidence suggest that serotonin type 1A (5-HT1A) receptor dysfunction is involved in the pathophysiology of mood disorders, and that alterations in 5-HT1A receptor function play a role in the mechanisms of antidepressant and mood stabilizer treatment. The literature is in disagreement, however, as to whether 5-HT1A receptor binding abnormalities exist in bipolar disorder (BD). We acquired PET images of 5-HT1A receptor binding in 26 unmedicated BD subjects and 37 healthy controls using [18F]FCWAY, a highly selective 5-HT1A receptor radio-ligand. The mean 5-HT1A receptor binding potential (BPP) was significantly lower in BD subjects compared to controls in cortical regions where 5-HT1A receptors are expressed post-synaptically, most prominently in the mesiotemporal cortex. Post-hoc assessments involving other receptor specific binding parameters suggested that this difference particularly affected the females with BD. The mean BPP did not differ between groups in the raphe nucleus, however, where 5-HT1A receptors are predominantly expressed pre-synaptically. Across subjects the BPP in the mesiotemporal cortex was inversely correlated with trough plasma cortisol levels, consistent with preclinical literature indicating that hippocampal 5-HT1A receptor expression is inhibited by glucocorticoid receptor stimulation. These findings suggest that 5-HT1A receptor binding is abnormally reduced in BD, and this abnormality may particularly involve the postsynaptic 5-HT1A receptor system of individuals with a tendency toward cortisol hypersecretion.
PMCID: PMC3748207  PMID: 23434290
5-HT1A receptor; Positron-emission tomography; Bipolar disorder; (18F)FCWAY
Depression and anxiety  2014;31(4):335-343.
Preliminary evidence suggests intravenous ketamine has rapid effects on suicidal cognition, making it an attractive candidate for depressed patients at imminent risk of suicide. In the first randomized controlled trial of ketamine using an anesthetic control condition, we tested ketamine’s acute effects on explicit suicidal cognition and a performance-based index of implicit suicidal cognition (Implicit Association Test; IAT) previously linked to suicidal behavior.
Symptomatic patients with treatment-resistant unipolar major depression (inadequate response to ≥3 antidepressants) were assessed using a composite index of explicit suicidal ideation (Beck Scale for Suicidal Ideation, Montgomery-Asberg Rating Scale suicide item, Quick Inventory of Depressive Symptoms suicide item) and the IAT to assess suicidality implicitly. Measures were taken at baseline and 24 hr following a single subanesthetic dose of ketamine (n = 36) or midazolam (n = 21), a psychoactive placebo agent selected for its similar, rapid anesthetic effects. Twenty four hours postinfusion, explicit suicidal cognition was significantly reduced in the ketamine but not the midazolam group.
Fifty three percent of ketamine-treated patients scored zero on all three explicit suicide measures at 24 hr, compared with 24% of the midazolam group (χ2 = 4.6; P = .03). Implicit associations between self- and escape-related words were reduced following ketamine (P = .01; d = .58) but not midazolam (P = .68; d = .09). Ketamine-specific decreases in explicit suicidal cognition were largest in patients with elevated suicidal cognition at baseline, and were mediated by decreases in nonsuicide-related depressive symptoms.
Intravenous ketamine produces rapid reductions in suicidal cognition over and above active placebo. Further study is warranted to test ketamine’s antisuicidal effects in higher-risk samples.
PMCID: PMC4112410  PMID: 24668760
suicide/self-harm; depression; clinical trials; biological markers; mood disorders; antidepressants
6.  Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial 
The American journal of psychiatry  2013;170(10):1134-1142.
Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression.
This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).
The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively.
Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.
PMCID: PMC3992936  PMID: 23982301
7.  Tryptophan Depletion and Emotional Processing in Healthy Volunteers at High Risk for Depression 
Biological psychiatry  2011;69(8):804-807.
Studies in depressed patients have demonstrated the presence of emotional bias toward negative stimuli, as well as dysregulated brain serotonin function. The present study compared the effects of acute tryptophan depletion (ATD) on both an emotional processing and a planning task in never-depressed healthy volunteers at high and low familial risk for depression.
Young adults with no personal psychiatric history were stratified into two groups based on family history (n = 25). Participants were enrolled in a randomized, double-blind, placebo-controlled crossover ATD study and completed the affective go/no-go and Tower of London tasks once during each condition.
There was a significant treatment by valence by group interaction on the affective go/no-go, driven primarily by a greater frequency of inappropriate responses to sad than to happy distracters in the high-risk group during ATD. No group differences were observed on the Tower of London.
Asymptomatic individuals at high familial risk for depression showed abnormalities in emotional processing while undergoing experimentally induced tryptophan depletion. These findings support emotional processing disturbances as potential trait-level abnormalities associated with the risk of mood disorder.
PMCID: PMC3941748  PMID: 21377656
Affective go/no-go; emotional processing; family history; high risk; major depression; tryptophan depletion
8.  Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial 
The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine may have rapid, albeit transient, antidepressant properties. This study in patients with treatment-resistant major depression (TRD) aimed to (1) replicate the acute efficacy of single-dose intravenous (i.v.) ketamine; (2) test the efficacy of the glutamate-modulating agent riluzole in preventing post-ketamine relapse ; and (3) examine whether pretreatment with lamotrigine would attenuate ketamine’s psychotomimetic effects and enhance its antidepressant activity. Twenty-six medication-free patients received open-label i.v. ketamine (0.5 mg/kg over 40 min). Two hours prior to infusion, patients were randomized to lamotrigine (300 mg) or placebo. Seventeen patients (65%) met response criterion (≥50% reduction from baseline on the Montgomery–Asberg Depression Rating Scale) 24 h following ketamine. Lamotrigine failed to attenuate the mild, transient side-effects associated with ketamine and did not enhance its antidepressant effects. Fourteen patients (54%) met response criterion 72 h following ketamine and proceeded to participate in a 32-d, randomized, double-blind, placebo-controlled, flexible-dose continuation trial of riluzole (100–200 mg/d). The main outcome measure was time-to-relapse. An interim analysis found no significant differences in time-to-relapse between riluzole and placebo groups [log-rank χ2 = 0.17, d.f. = 1, p = 0.68], with 80% of patients relapsing on riluzole vs. 50% on placebo. The trial was thus stopped for futility. This pilot study showed that a sub-anaesthetic dose of i.v. ketamine is well-tolerated in TRD, and may have rapid and sustained antidepressant properties. Riluzole did not prevent relapse in the first month following ketamine. Further investigation of relapse prevention strategies post-ketamine is necessary.
PMCID: PMC3883127  PMID: 19288975
Ketamine; lamotrigine; major depression; riluzole; treatment resistance
9.  Is There Anything Really Novel on the Antidepressant Horizon? 
Current psychiatry reports  2012;14(6):643-649.
Major depression represents one of the most disabling illnesses and current treatments are only partially effective. All antidepressant agents modulate the monoamine system, which likely accounts for the similar efficacy profile of available treatments. Herein we will summarize the current state of depression therapeutics and assess the antidepressant development pipeline. Antidepressant response rates in controlled trials are estimated at ~54% and real-world effectiveness data suggests a somewhat lower rate. Response rates are lower still in patients who have not responded to previous treatment attempts and meaningful advancements will likely come only from identification of mechanistically novel agents. Monoaminergic agents largely dominate the antidepressant development pipeline, however the glutamate neurotransmitter system represents a bright spot on the antidepressant horizon. We review in detail findings regarding the antidepressant effects of the glutamate N-methyl-d-aspartate receptor antagonist ketamine in order to highlight the promise of novel agents as future treatments for major depression.
PMCID: PMC3662536  PMID: 22996298
Major depressive disorder; MDD; Treatment-resistant depression; TRD; Antidepressant; Drug discovery; Psychopharmacology; Glutamate; Ketamine; N-methyl-d-aspartate receptor; NMDAR; Mood disorders; Psychiatry
10.  Neurobiology of Resilience 
Nature neuroscience  2012;15(11):1475-1484.
Humans exhibit a remarkable degree of resilience in the face of extreme stress, with most resisting the development of neuropsychiatric disorders. Over the past 5 years, there has been increasing interest in the active, adaptive coping mechanisms of resilience; however, in humans, the majority of published work focuses on correlative neuroendocrine markers that are associated with a resilient phenotype. In this review, we highlight a growing literature in rodents that is starting to complement the human work by identifying the active behavioral, neural, molecular, and hormonal basis of resilience. The therapeutic implications of these findings are important and can pave the way for an innovative new approach to drug development for a range of stress–related syndromes.
PMCID: PMC3580862  PMID: 23064380
depression; anxiety; major depressive disorder (MDD); post–traumatic stress disorder (PTSD); stress disorders; sex differences; stress inoculation; stress mastery; mesolimbic dopamine system; synaptic plasticity; structural plasticity; glutamatergic neurotransmission; hypothalamic–pituitary–adrenal (HPA) axis; hypothalamic–pituitary–gonadal (HPG) axis; cortisol; corticosterone; estrogen; testosterone; progesterone; social defeat stress; chronic unpredictable stress; learned helplessness; early intermittent stress; neuroendocrine; glucocorticoid
11.  Ketamine for Depression: Where Do We Go from Here? 
Biological psychiatry  2012;72(7):537-547.
Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used and to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk–benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting.
PMCID: PMC3438349  PMID: 22705040
Antidepressant; bipolar disorder; glutamate; ketamine; major depressive disorder; treatment-resistant depression
12.  Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression 
Biological psychiatry  2012;74(4):250-256.
Ketamine is reported to have rapid antidepressant effects, however there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in larger sample, inclusive of the original.
Participants with TRD (n=24) underwent a washout of antidepressant medication followed by a series of up to six intravenous (IV) infusions of ketamine (0.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion.
The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery–Asberg Depression Rating Scale (MADRS) score at two hours following the first ketamine infusion (18.9±6.6, p<0.001) and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at four hours (94% sensitive, 71% specific). Among responders, median time to relapse following the last ketamine infusion was 18 days.
Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.
PMCID: PMC3725185  PMID: 22840761
major depressive disorder; treatment-resistant depression; ketamine; antidepressant; glutamate; experimental therapeutics
13.  Understanding resilience 
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.
PMCID: PMC3573269  PMID: 23422934
resilience; stress; neurobiology; depression; PTSD
14.  A Selective Neurokinin-1 Receptor Antagonist in Chronic PTSD: a Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial 
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. ( Identifier: NCT 00211861, NCT 00383786)
PMCID: PMC3478767  PMID: 21194898
NK1; substance P; PTSD; clinical trial; randomized
15.  Habenula Volume in Bipolar Disorder and Major Depressive Disorder: A High Resolution MRI Study 
Biological psychiatry  2010;69(4):336-343.
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).
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).
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.
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.
PMCID: PMC3030670  PMID: 21094939
major depressive disorder; bipolar disorder; habenula; magnetic resonance imaging; high resolution; lithium
16.  Effects of antidepressant treatment on neural correlates of emotional and neutral declarative verbal memory in depression 
Journal of affective disorders  2006;101(1-3):99-111.
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.
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.
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 include a small sample size and variety of antidepressants used.
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.
PMCID: PMC3233752  PMID: 17182108
PET; Memory; Depression; Cingulate; Frontal cortex
17.  Elevated CSF Corticotropin-Releasing Factor Concentrations in Posttraumatic Stress Disorder 
The American journal of psychiatry  1997;154(5):624-629.
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.
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.
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.
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.
PMCID: PMC3233756  PMID: 9137116
18.  Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder 
Psychological medicine  2005;35(6):791-806.
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).
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.
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.
These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.
PMCID: PMC3233760  PMID: 15997600
19.  Neural Correlates of Exposure to Traumatic Pictures and Sound in Vietnam Combat Veterans with and without Posttraumatic Stress Disorder: A Positron Emission Tomography Study 
Biological psychiatry  1999;45(7):806-816.
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.
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.
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.
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.
PMCID: PMC3233761  PMID: 10202567
Positron emission tomography; memory; postttraumatic stress disorder; frontal cortex; cingulate; function
20.  Long-Term Treatment with Paroxetine Increases Verbal Declarative Memory and Hippocampal Volume in Posttraumatic Stress Disorder 
Biological psychiatry  2003;54(7):693-702.
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.
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.
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.
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.
PMCID: PMC3233762  PMID: 14512209
Posttraumatic stress disorder; memory; hippocampus; stress; paroxetine; selective serotonin reuptake inhibitors
21.  Regional Brain Metabolic Correlates of α-Methylparatyrosine–Induced Depressive Symptoms 
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).
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.
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.
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.
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.
PMCID: PMC3233764  PMID: 12813118
22.  MRI-Based Measurement of Hippocampal Volume in Patients With Combat-Related Posttraumatic Stress Disorder 
The American journal of psychiatry  1995;152(7):973-981.
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.
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.
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.
These findings are consistent with a smaller right hippocampal volume in PTSD that is associated with functional deficits in verbal memory.
PMCID: PMC3233767  PMID: 7793467
23.  Neural Correlates of Memories of Childhood Sexual Abuse in Women With and Without Posttraumatic Stress Disorder 
The American journal of psychiatry  1999;156(11):1787-1795.
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).
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.
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.
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.
PMCID: PMC3233772  PMID: 10553744
24.  Childhood Trauma Associated With Smaller Hippocampal Volume in Women With Major Depression 
The American journal of psychiatry  2002;159(12):2072-2080.
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.
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.
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.
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.
PMCID: PMC3230324  PMID: 12450959
25.  Alterations in Stress Reactivity After Long-Term Treatment with Paroxetine in Women with Posttraumatic Stress 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.
PMCID: PMC3230329  PMID: 16891570
cortisol; PTSD; stress; paroxetine; SSRI; challenge; HPA axis

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