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1.  EFFECTS OF KETAMINE ON EXPLICIT AND IMPLICIT SUICIDAL COGNITION: A RANDOMIZED CONTROLLED TRIAL IN TREATMENT-RESISTANT DEPRESSION 
Depression and anxiety  2014;31(4):335-343.
Background
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.
Method
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.
Results
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.
Conclusions
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.
doi:10.1002/da.22253
PMCID: PMC4112410  PMID: 24668760
suicide/self-harm; depression; clinical trials; biological markers; mood disorders; antidepressants
2.  Ketamine for Treatment-Resistant Unipolar Depression 
CNS drugs  2012;26(3):189-204.
Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD.
doi:10.2165/11599770-000000000-00000
PMCID: PMC3677048  PMID: 22303887
Antidepressants; Depressive-disorders; Glutamate-receptor-agonists; Ketamine; Major-depressive-disorder; NMDA-receptor-agonists
3.  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
4.  Treatment-resistant depression: recent developments and future directions 
Depression and anxiety  2008;25(12):989-992.
doi:10.1002/da.20540
PMCID: PMC2933841  PMID: 19058261
5.  Hippocampal N-Acetylaspartate Concentration and Response to Riluzole in Generalized Anxiety Disorder 
Biological psychiatry  2007;63(9):891-898.
Background:
Previous research has suggested the therapeutic potential of glutamate-modulating agents for severe mood and anxiety disorders, potentially due to enhancement of neuroplasticity. We used proton magnetic resonance spectroscopic imaging (1H MRSI) to examine the acute and chronic effects of the glutamate-release inhibitor riluzole on hippocampal N-acetylaspartate (NAA), a neuronal marker, in patients with generalized anxiety disorder (GAD), and examined the relationship between changes in NAA and clinical outcome.
Methods:
Fourteen medication-free GAD patients were administered open-label riluzole and then evaluated by 1H MRSI before drug administration, and 24 hours and 8 weeks following treatment. Patients were identified as responders (n = 9) or non-responders (n = 5). Seven untreated, medically healthy volunteers, comparable in age, sex, IQ, and body mass index to the patients, received scans at the same time intervals. Molar NAA concentrations in bilateral hippocampus and change in anxiety ratings were the primary outcome measures.
Results:
A group-by-time interaction was found, with riluzole responders showing mean increases in hippocampal NAA across the three time points, while non-responders had decreases over time. In GAD patients at Week 8, hippocampal NAA concentration and proportional increase in NAA from baseline both were positively associated with improvements in worry and clinician-rated anxiety.
Conclusions:
These preliminary data support a specific association between hippocampal NAA and symptom alleviation following riluzole treatment in GAD. Placebo-controlled investigations that examine hippocampal NAA as a viable surrogate endpoint for clinical trials of neuroprotective and plasticity-enhancing agents are warranted.
doi:10.1016/j.biopsych.2007.09.012
PMCID: PMC2385784  PMID: 18028881
6.  Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates 
Psychiatry research  2011;192(1):37-44.
Male bonnet monkeys (Macaca radiata) were subjected to the Variable Foraging Demand (VFD) early stress paradigm as infants, MRI scans were completed an average of four years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of Interest (ROI) hippocampus and whole brain voxel- based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. Animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.
doi:10.1016/j.pscychresns.2010.11.006
PMCID: PMC4090111  PMID: 21377844
stress; monkeys; corpus callosum; hippocampus; brain abnormalities; 5-HTTLPR
7.  Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial 
Trials  2014;15:240.
Background
Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD.
Methods/design
Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months’ duration, are being enrolled in a parallel-group, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks’ exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one-month follow-up period to monitor for sustained response and resolution of any adverse effects.
Discussion
Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD.
Trial registration
Clinicaltrials.gov Identifier: NCT01018992.
Registered 6 November 2009. First patient randomized 14 January 2010.
doi:10.1186/1745-6215-15-240
PMCID: PMC4082482  PMID: 24950747
Clinical Research Protocol; Drugs; Investigational; HPA Axis; Anxiety disorders; Fear-potentiated startle; Fear conditioning; Neuropsychological tests; Placebo; Psychophysiology; CRH
8.  The Emerging Use of Ketamine for Anesthesia and Sedation in Traumatic Brain Injuries 
CNS neuroscience & therapeutics  2013;19(6):390-395.
SUMMARY
Background
Traditionally, the use of ketamine for patients with traumatic brain injuries is contraindicated due to the concern of increasing intracranial pressure (ICP). These concerns, however, originated from early studies and case reports that were inadequately controlled and designed. Recently, the concern of using ketamine in these patients has been challenged by a number of published studies demonstrating that the use of ketamine was safe in these patients.
Aims
The purpose of this article was to review the current literature in regards to using ketamine in patients with traumatic brain injuries in different clinical settings associated with anesthesia, as well as review the potential mechanisms underlying the neuroprotective effects of ketamine.
Results
Studies examining the use of ketamine for induction, maintenance, and sedation in patients with TBI have had promising results. The use of ketamine in a controlled ventilation setting and in combination with other sedative agents has demonstrated no increase in ICP.
Conclusions
The role of ketamine as a neuroprotective agent in humans remains inconclusive and adequately powered; randomized controlled trials performed in patients undergoing surgery for traumatic brain injury are necessary.
doi:10.1111/cns.12077
PMCID: PMC3663879  PMID: 23480625
Behavioural neurology; Neuromuscular disease; Neuropsychopharmacology; Stroke
9.  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
10.  A Pilot Study of Hippocampal Volume and N-Acetylaspartate (NAA) as Response Biomarkers in Riluzole-Treated Patients with GAD 
Anxiolytic benefit following chronic treatment with the glutamate modulating agent riluzole in patients with generalized anxiety disorder (GAD) was previously associated with differential changes in hippocampal NAA concentrations. Here, we investigated the association between hippocampal volume and hippocampal NAA in the context of riluzole response in GAD. Eighteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. Participants underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. GAD patients who completed all interventions were classified as remitters (n = 7) or non-remitters (n = 6), based on final Hamilton Anxiety Rating Scale (HAM-A) scores ≤ 7. At baseline, GAD patients had a significant reduction in total hippocampal volume compared to healthy subjects (F(1,21) = 6.55, p = 0.02). This reduction was most pronounced in the remitters, compared to non-remitters and healthy subjects. Delta (final – baseline) hippocampal volume was positively correlated with delta NAA in GAD. This positive association was highly significant in the right hippocampus in GAD [r = 0.81, p = 0.002], with no significant association in healthy subjects [Fisher r-to-z p = 0.017]. Across all GAD patients, delta hippocampal volume was positively associated with improvement in HAM-A (rspearman = 0.62, p = 0.03). These preliminary findings support hippocampal NAA and volume as neural biomarkers substantially associated with therapeutic response to a glutamatergic drug.
doi:10.1016/j.euroneuro.2012.05.009
PMCID: PMC3473175  PMID: 22739126
Riluzole; generalized anxiety disorder; biomarkers; glutamate; N-Acetylaspartate; hippocampal volume; magnetic resonance spectroscopy
11.  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
12.  Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology 
NMR in biomedicine  2012;25(9):1073-1087.
Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using 1H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction. Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) 1H MRSI to measure CSF lactate; (ii) single-voxel 1H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) 31P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction. We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites. In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology.
doi:10.1002/nbm.2772
PMCID: PMC3896084  PMID: 22281935
MRS; lactate; cerebrospinal fluid; glutathione; arterial spin labeling; cerebral blood flow; chronic fatigue syndrome; major depressive disorder
13.  Reduced hippocampal N-acetyl-aspartate (NAA) as a biomarker for overweight☆ 
NeuroImage : Clinical  2014;4:326-335.
Objective
We previously demonstrated an inverse relationship between both dentate gyrus neurogenesis – a form of neuroplasticity – and expression of the antiapoptotic gene marker, BCL-2 and adult macaque body weight. We therefore explored whether a similar inverse correlation existed in humans between body mass index (BMI) and hippocampal N-acetyl-aspartate (NAA), a marker of neuronal integrity and putatively, neuroplasticity. We also studied the relationship of a potentially neurotoxic process, worry, to hippocampal NAA in patients with generalized anxiety disorder (GAD) and control subjects (CS).
Methods
We combined two previously studied cohorts of GAD and control subjects. Using proton magnetic resonance spectroscopy imaging (1H MRSI) in medication-free patients with GAD (n = 29) and a matched healthy control group (n = 22), we determined hippocampal concentrations of (1) NAA (2) choline containing compounds (CHO), and (3) Creatine + phosphocreatine (CR). Data were combined from 1.5 T and 3 T scans by converting values from each cohort to z-scores. Overweight and GAD diagnosis were used as categorical variables while the Penn State Worry Questionnaire (PSWQ) and Anxiety Sensitivity Index (ASI) were used as dependent variables.
Results
Overweight subjects (BMI ≥ 25) exhibited lower NAA levels in the hippocampus than normal-weight subjects (BMI < 25) (partial Eta-squared = 0.14) controlling for age, sex and psychiatric diagnosis, and the effect was significant for the right hippocampus in both GAD patients and control subjects. An inverse linear correlation was noted in all subjects between right hippocampal NAA and BMI. High scores on the PSWQ predicted low hippocampal NAA and CR. Both BMI and worry were independent inverse predictors of hippocampal NAA.
Conclusion
Overweight was associated with reduced NAA concentrations in the hippocampus with a strong effect size. Future mechanistic studies are warranted.
Highlights
•Overweight people show reduced concentrations of hippocampal N-acetylaspartate (NAA).•Reduced NAA reflects reduced neuronal viability.•There is an inverse relationship between BMI and hippocampal NAA.•Worry scores are independently associated with lower NAA.•Generalized anxiety disorder did not show low hippocampal NAA.
doi:10.1016/j.nicl.2013.12.014
PMCID: PMC3913836  PMID: 24501701
Body mass index; Generalized anxiety disorder; Penn State Worry Questionnaire; Neuronal integrity; Creatine (CR); Obesity
14.  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
15.  Early life stress and macaque amygdala hypertrophy: preliminary evidence for a role for the serotonin transporter gene 
Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. The primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals.
Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years).
Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: “high” cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls.
Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.
doi:10.3389/fnbeh.2014.00342
PMCID: PMC4186477  PMID: 25339875
amygdala; early life stress; non-human primates; MRI; stress; serotonin transporter gene
16.  Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders 
Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).
Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].
Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.
Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.
doi:10.3389/fnbeh.2014.00440
PMCID: PMC4274982  PMID: 25566007
variable foraging demand; MRI; cisternal tap; serotonin metabolite; monoamine metabolites
17.  Riluzole Effect on Occipital Cortex: A Structural and Spectroscopy Pilot Study 
Neuroscience letters  2012;530(1):103-107.
Background
To investigate the mechanism underlying the anxiolytic properties of riluzole, a glutamate-modulating agent, we previously studied the effect of this drug on hippocampal N-Acetylaspartate (NAA) and volume in patients with Generalized Anxiety Disorder (GAD). In the same cohort, we now extend our investigation to the occipital cortex, a brain region that was recently implicated in the antidepressant effect of riluzole.
Methods
Fourteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. The healthy group did not receive riluzole treatment. Both groups underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. Hamilton Anxiety Rating Scale (HAM-A) and Penn State Worry Questionnaire (PSWQ) were used as the primary and secondary outcome measures, respectively.
Results
At baseline, we found clusters of increased cortical thickness in the occipital region in GAD compared to healthy subjects. In the right hemisphere, eight weeks of treatment reduced occipital cortical thickness in the GAD group (t = 3.67, p = 0.004). In addition, the improvement in HAM-A scores was negatively correlated with post-treatment right occipital NAA (r = − 0.68, p = 0.008), and with changes in NAA levels (r = − 0.53, p = 0.051). In the left hemisphere, we found positive associations between changes in occipital cortical thickness and improvement in HAM-A (r = 0.60, p = 0.04) and PSWQ (r = 0.62, p = 0.03).
Conclusion
These pilot findings implicate the occipital cortex as a brain region associated with pathology and clinical improvement in GAD. In addition, the region specific effect of riluzole implies a distinct pathophysiology in the occipital cortex – compared to other, previously studied, frontolimbic brain structures.
doi:10.1016/j.neulet.2012.09.054
PMCID: PMC3490039  PMID: 23043888
Riluzole; generalized anxiety disorder; biomarkers; glutamate; N-Acetylaspartate; occipital cortex; magnetic resonance spectroscopy; structural MRI
18.  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
19.  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
20.  METABOLIC SYNDROME AND NEUROMETABOLIC ASYMMETRY OF HIPPOCAMPUS IN ADULT BONNET MONKEYS 
Physiology & behavior  2011;103(5):535-539.
Objective
Obesity is associated with the insulin resistance metabolic syndrome, postulated to be mediated by stress-induced alterations within the hypothalamic-pituitary-adrenal (HPA) axis. In adult bonnet macaques we examined relationships between components of the metabolic syndrome, hippocampal neurometabolic asymmetry, an indicator of negative affect, and juvenile cerebrospinal fluid (csf) corticotropin-releasing factor (CRF) levels obtained after stress exposure associated with maternal food insecurity and in controls.
Methods
Eleven adult male monkeys (seven with early life stress) who had undergone csf-CRF analyses as juveniles had magnetic resonance spectroscopic imaging (MRSI) of bilateral hippocampus, morphometry (body mass index, BMI; sagittal abdominal diameter, SAD) and determination of fasting plasma glucose and insulin as adults. Neurometabolite ratios included N-acetyl-aspartate as numerator (NAA; a marker of neuronal integrity) and choline (Cho; cell turnover) and creatine (Cr; reference analyte) as denominators.
Results
Elevated juvenile csf-CRF levels positively predicted adult BMI and SAD and were associated with right > left shift of NAA ratio within the hippocampus. Adult visceral obesity and insulin level correlated with right > left shift in hippocampal NAA concentrations, controlling for age and denominator.
Conclusion
Juvenile csf-CRF levels, a neuropeptide associated with early life stress, predict adult visceral obesity and hippocampal asymmetry supporting the hypothesis that metabolic syndrome in adults may be related to early life stress. Furthermore, this study demonstrates asymmetrical hippocampal alterations related to obesity.
doi:10.1016/j.physbeh.2011.03.020
PMCID: PMC3107881  PMID: 21459102
Corticotropin releasing factor; hippocampus; stress; metabolic syndrome; food insecurity; obesity
21.  Early-Life Stress and Neurometabolites of the Hippocampus 
Brain research  2010;1358:191-199.
We tested the hypothesis that early life stress would persistently compromise neuronal viability of the hippocampus of the grown nonhuman primate. Neuronal viability was assessed through ascertainment of N-acetyl aspartate (NAA) – an amino acid considered reflective of neuronal density/functional integrity – using in vivo proton magnetic resonance spectroscopic imaging (MRSI). The subjects reported herein represent a re-analysis of a sample of nineteen adult male bonnet macaques that had been reared in infancy under induced stress by maternal variable foraging demand (VFD) (N = 10) or control rearing conditions (N = 9). The MRSI spectral readings were recorded using a GE 1.5 Tesla machine under anesthesia. Relative NAA values were derived using NAA as numerator and both choline (Cho) or creatine (Cr) as denominators. Left medial temporal lobe (MTL) NAA/Cho but not NAA/Cr was decreased in VFD subjects versus controls. An MTL NAA/Cho ratio deficit remained significant when controlling for multiple confounding variables. Regression analyses suggested that the NAA/Choline finding was due to independently low left NAA and high left choline. Right MTL showed no rearing effects for NAA, but right NAA was positively related to body mass, irrespective of denominator. The current data indicate that decreased left MTL NAA/Cho may reflect low neuronal viability of the hippocampus following early life stress in VFD-reared versus normally-reared subjects. Given the importance of the hippocampus in stress-mediated toxicity, validation of these data using absolute quantification is suggested and correlative neurohistological studies of hippocampus are warranted.
doi:10.1016/j.brainres.2010.08.021
PMCID: PMC2988576  PMID: 20713023
Early-Life Stress; Nonhuman Primate; Magnetic Resonance Spectroscopy; Hippocampus; N-Acetyl-Aspartate; Brain laterality
22.  The role of early life stress in development of the anterior limb of the internal capsule in non-human primates 
Neuroscience letters  2010;480(2):93-96.
Background
Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) may be effective in treating depression. Parental verbal abuse has been linked to decreased fractional anisotropy (FA) of white matter and reduced FA correlated with depression and anxiety scores. Utilizing a nonhuman primate model of mood and anxiety disorders following disrupted mother-infant attachment, we examined whether adverse rearing conditions lead to white matter impairment of the ALIC.
Methods
We examined white matter integrity using Diffusion Tensor Imaging (DTI) on a 3T-MRI. Twenty-one adult male Bonnet macaques participated in this study: 12 were reared under adverse [variable foraging demand (VFD)] conditions whereas 9 were reared under normative conditions. We examined ALIC, posterior limb of the internal capsule (PLIC) and occipital white matter.
Results
VFD rearing was associated with significant reductions in FA in the ALIC with no changes evident in the PLIC or occipital cortex white matter.
Conclusion
Adverse rearing in monkeys persistently impaired frontal white matter tract integrity, a novel substrate for understanding affective susceptibility.
doi:10.1016/j.neulet.2010.06.012
PMCID: PMC2951885  PMID: 20541590
Diffusion tensor imaging; fractional anisotropy; white matter integrity; variable foraging demand
23.  Diffusion tensor imaging in studying white matter complexity: A gap junction hypothesis 
Neuroscience letters  2010;475(3):161-164.
The role of the prefrontal cortex as an executive oversight of posterior brain regions raises the question of the extent to which the anterior regions of the brain interconnect with the posterior regions. The aim of this study is to test the complexity of rostral white matter tracts, which connect anterior and posterior brain regions, in comparison to caudal white matter tracts and the corpus callosum. Diffusion tensor imaging (DTI) is a modality that measures fractional anisotropy (FA). Higher white matter complexity could result in a decrease of FA, possibly through denser intersection of fiber tracts. DTI was used to determine regional FA in 9 healthy bonnet macaques (Macaca radiata). Four regions of interest were included: anterior and posterior limbs of the internal capsule, the occipital lobe white matter, and the corpus callosum. FA of the anterior limbs of the internal capsule was lowest compared to all other regions of interest (Newman-Keuls (N-K); p < 0.0001), whereas FA of the corpus callosum was highest (N-K; p < 0.0001). The posterior limbs of the internal capsule and the occipital white matter were not distinguishable but exhibited intermediate FA in comparison to the former (N-K; p < 0.0001) and the latter (N-K; p < 0.0001). The current study demonstrates that FA, a measure of white matter complexity, can vary markedly as a function of region of interest. Moreover, validation of these findings using neurohistological studies and replication in human samples appears warranted.
doi:10.1016/j.neulet.2010.03.070
PMCID: PMC2862850  PMID: 20371267
Diffusion tensor imaging; fractional anisotropy; white matter; gap junctions; nonhuman primates; neuroimaging; neurodevelopment
24.  The Relationship between Intelligence and Anxiety: An Association with Subcortical White Matter Metabolism 
We have demonstrated in a previous study that a high degree of worry in patients with generalized anxiety disorder (GAD) correlates positively with intelligence and that a low degree of worry in healthy subjects correlates positively with intelligence. We have also shown that both worry and intelligence exhibit an inverse correlation with certain metabolites in the subcortical white matter. Here we re-examine the relationships among generalized anxiety, worry, intelligence, and subcortical white matter metabolism in an extended sample. Results from the original study were combined with results from a second study to create a sample comprised of 26 patients with GAD and 18 healthy volunteers. Subjects were evaluated using the Penn State Worry Questionnaire, the Wechsler Brief intelligence quotient (IQ) assessment, and proton magnetic resonance spectroscopic imaging (1H-MRSI) to measure subcortical white matter metabolism of choline and related compounds (CHO). Patients with GAD exhibited higher IQ’s and lower metabolite concentrations of CHO in the subcortical white matter in comparison to healthy volunteers. When data from GAD patients and healthy controls were combined, relatively low CHO predicted both relatively higher IQ and worry scores. Relatively high anxiety in patients with GAD predicted high IQ whereas relatively low anxiety in controls also predicted high IQ. That is, the relationship between anxiety and intelligence was positive in GAD patients but inverse in healthy volunteers. The collective data suggest that both worry and intelligence are characterized by depletion of metabolic substrate in the subcortical white matter and that intelligence may have co-evolved with worry in humans.
doi:10.3389/fnevo.2011.00008
PMCID: PMC3269637  PMID: 22347183
intelligence; anxiety; white matter; choline; magnetic resonance spectroscopic imaging
25.  Amino Acid Neurotransmitters Assessed by 1H MRS: Relationship to Treatment-Resistance in Major Depressive Disorder 
Biological psychiatry  2009;65(9):792-800.
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.
doi:10.1016/j.biopsych.2008.10.025
PMCID: PMC2934870  PMID: 19058788
glutamate; GABA; magnetic resonance; spectroscopy; depression

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