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1.  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.
Objective
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.
Method
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).
Results
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.
Conclusions
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.
doi:10.1176/appi.ajp.2013.13030392
PMCID: PMC3992936  PMID: 23982301
2.  Tryptophan Depletion and Emotional Processing in Healthy Volunteers at High Risk for Depression 
Biological psychiatry  2011;69(8):804-807.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2010.12.033
PMCID: PMC3941748  PMID: 21377656
Affective go/no-go; emotional processing; family history; high risk; major depression; tryptophan depletion
3.  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.
doi:10.1017/S1461145709000169
PMCID: PMC3883127  PMID: 19288975
Ketamine; lamotrigine; major depression; riluzole; treatment resistance
4.  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.
doi:10.1007/s11920-012-0321-8
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
5.  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.
doi:10.1038/nn.3234
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
6.  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 PubMed.gov and ClinicalTrials.gov 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.
doi:10.1016/j.biopsych.2012.05.003
PMCID: PMC3438349  PMID: 22705040
Antidepressant; bipolar disorder; glutamate; ketamine; major depressive disorder; treatment-resistant depression
7.  Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression 
Biological psychiatry  2012;74(4):250-256.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2012.06.022
PMCID: PMC3725185  PMID: 22840761
major depressive disorder; treatment-resistant depression; ketamine; antidepressant; glutamate; experimental therapeutics
8.  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.
doi:10.3389/fnbeh.2013.00010
PMCID: PMC3573269  PMID: 23422934
resilience; stress; neurobiology; depression; PTSD
9.  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. (ClinicalTrials.gov Identifier: NCT 00211861, NCT 00383786)
doi:10.1016/j.euroneuro.2010.11.012
PMCID: PMC3478767  PMID: 21194898
NK1; substance P; PTSD; clinical trial; randomized
10.  Habenula Volume in Bipolar Disorder and Major Depressive Disorder: A High Resolution MRI Study 
Biological psychiatry  2010;69(4):336-343.
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.
doi:10.1016/j.biopsych.2010.09.027
PMCID: PMC3030670  PMID: 21094939
major depressive disorder; bipolar disorder; habenula; magnetic resonance imaging; high resolution; lithium
11.  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.
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.
doi:10.1016/j.jad.2006.10.028
PMCID: PMC3233752  PMID: 17182108
PET; Memory; Depression; Cingulate; Frontal cortex
12.  Elevated CSF Corticotropin-Releasing Factor Concentrations in Posttraumatic Stress Disorder 
The American journal of psychiatry  1997;154(5):624-629.
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.
PMCID: PMC3233756  PMID: 9137116
13.  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.
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.
PMCID: PMC3233760  PMID: 15997600
14.  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.
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.
PMCID: PMC3233761  PMID: 10202567
Positron emission tomography; memory; postttraumatic stress disorder; frontal cortex; cingulate; function
15.  Long-Term Treatment with Paroxetine Increases Verbal Declarative Memory and Hippocampal Volume in Posttraumatic Stress Disorder 
Biological psychiatry  2003;54(7):693-702.
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.
PMCID: PMC3233762  PMID: 14512209
Posttraumatic stress disorder; memory; hippocampus; stress; paroxetine; selective serotonin reuptake inhibitors
16.  Regional Brain Metabolic Correlates of α-Methylparatyrosine–Induced Depressive Symptoms 
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.
doi:10.1001/jama.289.23.3125
PMCID: PMC3233764  PMID: 12813118
17.  MRI-Based Measurement of Hippocampal Volume in Patients With Combat-Related Posttraumatic Stress Disorder 
The American journal of psychiatry  1995;152(7):973-981.
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.
PMCID: PMC3233767  PMID: 7793467
18.  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.
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.
PMCID: PMC3233772  PMID: 10553744
19.  Childhood Trauma Associated With Smaller Hippocampal Volume in Women With Major Depression 
The American journal of psychiatry  2002;159(12):2072-2080.
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.
PMCID: PMC3230324  PMID: 12450959
20.  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.
doi:10.1196/annals.1364.014
PMCID: PMC3230329  PMID: 16891570
cortisol; PTSD; stress; paroxetine; SSRI; challenge; HPA axis
21.  Magnetic Resonance Imaging-Based Measurement of Hippocampal Volume in Posttraumatic Stress Disorder Related to Childhood Physical and Sexual Abuse—A Preliminary Report 
Biological psychiatry  1997;41(1):23-32.
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.
PMCID: PMC3229101  PMID: 8988792
Hippocampus; stress; posttraumatic stress disorder; cortisol; childhood abuse
22.  Habenula volume in post-traumatic stress disorder measured with high-resolution MRI 
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.
doi:10.1186/2045-5380-1-7
PMCID: PMC3384261  PMID: 22738208
23.  Plasma NPY concentrations during tryptophan and sham depletion in medication-free patients with remitted depression 
Journal of affective disorders  2008;110(3):277-281.
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.
doi:10.1016/j.jad.2008.01.014
PMCID: PMC3102760  PMID: 18281099
Major depressive disorder; Serotonin; Neuropeptide Y; Tryptophan depletion; Neurobiology
24.  Reward Processing After Catecholamine Depletion in Unmedicated, Remitted Subjects with Major Depressive Disorder 
Biological psychiatry  2009;66(3):201-205.
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.
doi:10.1016/j.biopsych.2009.02.029
PMCID: PMC3073352  PMID: 19393989
Anhedonia; dopamine; major depressive disorder; monetary incentive delay task; norepinephrine; reward
25.  AMYGDALA VOLUME IN DEPRESSED PATIENTS WITH BIPOLAR DISORDER ASSESSED USING HIGH RESOLUTION 3T MRI: THE IMPACT OF MEDICATION 
NeuroImage  2009;49(4):2966.
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.
doi:10.1016/j.neuroimage.2009.11.025
PMCID: PMC2818548  PMID: 19931399

Results 1-25 (51)