Carlos A Zarate

Publications (99)573.04 Total impact

• Article: Neural Correlates of Rapid Antidepressant Response to Ketamine in Treatment-Resistant Unipolar Depression: A Preliminary Positron Emission Tomography Study.

  Paul J Carlson, Nancy Diazgranados, Allison C Nugent, Lobna Ibrahim, David A Luckenbaugh, Nancy Brutsche, Peter Herscovitch, Husseini K Manji, Carlos A Zarate, Wayne C Drevets
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  ABSTRACT: BACKGROUND: Multiple lines of evidence support a role for the glutamatergic system in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate antagonist, rapidly improves depressive symptoms in individuals with treatment-resistant depression. The neural mechanisms underlying this effect remain unknown. METHODS: In this preliminary study, 20 unmedicated participants with treatment-resistant MDD underwent positron emission tomography to measure regional cerebral glucose metabolism at baseline and following ketamine infusion (single dose of .5mg/kg intravenous over 40minutes). Metabolic data were compared between conditions using a combination of region-of-interest and voxelwise analyses, and differences were correlated with the associated antidepressant response. RESULTS: Whole-brain metabolism did not change significantly following ketamine. Regional metabolism decreased significantly under ketamine in the habenula, insula, and ventrolateral and dorsolateral prefrontal cortices of the right hemisphere. Metabolism increased postketamine in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices. Improvement in depression ratings correlated directly with change in metabolism in right superior and middle temporal gyri. Conversely, clinical improvement correlated inversely with metabolic changes in right parahippocampal gyrus and temporoparietal cortex. CONCLUSIONS: Although preliminary, these results indicate that treatment-resistant MDD subjects showed decreased metabolism in the right habenula and the extended medial and orbital prefrontal networks in association with rapid antidepressant response to ketamine. Conversely, metabolism increased in sensory association cortices, conceivably related to the illusory phenomena sometimes experienced with ketamine. Further studies are needed to elucidate how these functional anatomical changes relate to the molecular mechanisms underlying ketamine's rapid antidepressant effects.
  Biological psychiatry 03/2013; · 8.93 Impact Factor
• Article: Combining a dopamine agonist and selective serotonin reuptake inhibitor for the treatment of depression: A double-blind, randomized pilot study.

  Jose A Franco-Chaves, Camilo F Mateus, David A Luckenbaugh, Pedro E Martinez, Alan G Mallinger, Carlos A Zarate
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  ABSTRACT: BACKGROUND: Antidepressants that act on two or more amine neurotransmitters may confer higher remission rates when first-line agents affecting a single neurotransmitter have failed. Pramipexole, a dopamine agonist, has antidepressant effects in patients with major depressive disorder (MDD). This pilot study examined the efficacy and safety of combination therapy with pramipexole and the selective serotonin reuptake inhibitor (SSRI) escitalopram in MDD. METHODS: In this double-blind, controlled, pilot study, 39 patients with DSM-IV MDD who had failed to respond to a standard antidepressant treatment trial were randomized to receive pramipexole (n=13), escitalopram (n=13), or their combination (n=13) for six weeks. Pramipexole was started at 0.375mg/day and titrated weekly up to 2.25mg/day; escitalopram dosage remained at 10mg/day. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Subjects receiving pramipexole monotherapy had significantly lower MADRS scores than the combination group (p=0.01); no other primary drug comparisons were significant. The combination group had a substantially higher dropout rate than the escitalopram and pramipexole groups (69%, 15%, 15%, respectively). Only 15% of patients in the combination group tolerated regularly scheduled increases of pramipexole throughout the study, compared with 46% of patients in the pramipexole group. LIMITATIONS: Group size was small and the treatment phase lasted for only six weeks. CONCLUSIONS: The combination of an SSRI and a dopamine agonist was not more effective than either agent alone, nor did it produce a more rapid onset of antidepressant action. Combination therapy with escitalopram and pramipexole may not be well-tolerated.
  Journal of affective disorders 03/2013; · 3.76 Impact Factor
• Article: Defining anxious depression: a review of the literature.

  Dawn F Ionescu, Mark J Niciu, Ioline D Henter, Carlos A Zarate
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  ABSTRACT: The diagnosis of anxious depression is presently inconsistent. The many different definitions of anxious depression have complicated its diagnosis, leading to clinical confusion and inconsistencies in the literature. This article reviewed the extant literature in order to identify the varying definitions of anxious depression, which were then compared using Feighner's diagnostic criteria. Notably, these suggest a different clinical picture of patients with anxious depression. For instance, relying on The International Classification of Diseases (ICD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses yields a clinical picture of a comparatively mild or transient disorder; in contrast, using dimensional criteria such as DSM criteria combined with additional rating scales-most commonly the anxiety somatization factor score from the Hamilton Depression Rating Scale (HAM-D)-yields a more serious clinical picture. The evidence reviewed here suggests that defining anxious depression in a dimensional manner may be the most useful and clinically relevant way of differentiating it from other types of mood and anxiety disorders, and of highlighting the most clinically significant differences between patients with anxious depression versus depression or anxiety alone.
  CNS spectrums 03/2013; · 2.20 Impact Factor
• Article: NEUROBIOLOGY OF ANXIOUS DEPRESSION: A REVIEW.

  Dawn F Ionescu, Mark J Niciu, Daniel C Mathews, Erica M Richards, Carlos A Zarate
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  ABSTRACT: Anxious depression is a common, distinct clinical subtype of major depressive disorder (MDD). This review summarizes current neurobiological knowledge regarding anxious depression. Peer-reviewed articles, published January 1970 through September 2012, were identified via PUBMED, EMBASE, and Cochrane Library, using the following key words: anxious depression electroencephalography (EEG), anxious depression functional magnetic resonance imaging (fMRI), anxious depression genetics, anxious depression neurobiology, and anxious melancholia neurobiology. Despite a general dearth of neurobiological research, the results suggest that anxious depression-when defined either syndromally or dimensionally-has distinct neurobiological findings that separate it from nonanxious depression. Structural neuroimaging, EEG, genetics, and neuropsychiatric studies revealed differences in subjects with anxious depression compared to other groups. Endocrine differences between individuals with anxious depression and those with nonanxious depression have also been noted, as evidenced by abnormal responses elicited by exogenous stimulation of the system. Despite these findings, heterogeneity in the definition of anxious depression complicates the results. Because exploring the neurobiology of this depressive subtype is important for improving diagnosis, prognosis, and treatment, enrichment strategies to decrease heterogeneity within the field should be employed for future research.
  Depression and Anxiety 03/2013; · 4.18 Impact Factor
• Article: Second messenger/signal transduction pathways in major mood disorders: moving from membrane to mechanism of action, part I: major depressive disorder.

  Mark J Niciu, Dawn F Ionescu, Daniel C Mathews, Erica M Richards, Carlos A Zarate
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  ABSTRACT: The etiopathogenesis and treatment of major mood disorders have historically focused on modulation of monoaminergic (serotonin, norepinephrine, dopamine) and amino acid [γ-aminobutyric acid (GABA), glutamate] receptors at the plasma membrane. Although the activation and inhibition of these receptors acutely alter local neurotransmitter levels, their neuropsychiatric effects are not immediately observed. This time lag implicates intracellular neuroplasticity as primary in the mechanism of action of antidepressants and mood stabilizers. The modulation of intracellular second messenger/signal transduction cascades affects neurotrophic pathways that are both necessary and sufficient for monoaminergic and amino acid-based treatments. In this review, we will discuss the evidence in support of intracellular mediators in the pathophysiology and treatment of preclinical models of despair and major depressive disorder (MDD). More specifically, we will focus on the following pathways: cAMP/PKA/CREB, neurotrophin-mediated (MAPK and others), p11, Wnt/Fz/Dvl/GSK3β, and NFκB/ΔFosB. We will also discuss recent discoveries with rapidly acting antidepressants, which activate the mammalian target of rapamycin (mTOR) and release of inhibition on local translation via elongation factor stimulation. Throughout this discourse, we will highlight potential intracellular targets for therapeutic intervention. Finally, future clinical implications are discussed.
  CNS spectrums 03/2013; · 2.20 Impact Factor
• Article: Reduced post-synaptic serotonin type 1A receptor binding in bipolar depression.

  Allison C Nugent, Earle E Bain, Paul J Carlson, Alexander Neumeister, Omer Bonne, Richard E Carson, William Eckelman, Peter Herscovitch, Carlos A Zarate, Dennis S Charney, Wayne C Drevets
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  ABSTRACT: Multiple lines of evidence suggest that serotonin type 1A (5-HT(1A)) receptor dysfunction is involved in the pathophysiology of mood disorders, and that alterations in 5-HT(1A) receptor function play a role in the mechanisms of antidepressant and mood stabilizer treatment. The literature is in disagreement, however, as to whether 5-HT(1A) receptor binding abnormalities exist in bipolar disorder (BD). We acquired PET images of 5-HT(1A) receptor binding in 26 unmedicated BD subjects and 37 healthy controls using [(18)F]FCWAY, a highly selective 5-HT(1A) receptor radio-ligand. The mean 5-HT(1A) receptor binding potential (BP(P)) was significantly lower in BD subjects compared to controls in cortical regions where 5-HT(1A) receptors are expressed post-synaptically, most prominently in the mesiotemporal cortex. Post-hoc assessments involving other receptor specific binding parameters suggested that this difference particularly affected the females with BD. The mean BP(P) did not differ between groups in the raphe nucleus, however, where 5-HT(1A) receptors are predominantly expressed pre-synaptically. Across subjects the BP(P) in the mesiotemporal cortex was inversely correlated with trough plasma cortisol levels, consistent with preclinical literature indicating that hippocampal 5-HT(1A) receptor expression is inhibited by glucocorticoid receptor stimulation. These findings suggest that 5-HT(1A) receptor binding is abnormally reduced in BD, and this abnormality may particularly involve the postsynaptic 5-HT(1A) receptor system of individuals with a tendency toward cortisol hypersecretion.
  European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 02/2013; · 3.68 Impact Factor
• Source

  Available from: Giacomo Salvadore

  Dataset: JCP,2010b

  Jorge A Quiroz, Rodrigo Machado-Vieira, Husseini K Manji, Giacomo Salvadore, Carlos A Zarate, Ioline D Henter
• Article: Potential of Pretreatment Neural Activity in the Visual Cortex During Emotional Processing to Predict Treatment Response to Scopolamine in Major Depressive Disorder.

  Maura L Furey, Wayne C Drevets, Elana M Hoffman, Erica Frankel, Andrew M Speer, Carlos A Zarate
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  ABSTRACT: CONTEXT The need for improved treatment options for patients with major depressive disorder (MDD) is critical. Faster-acting antidepressants and biomarkers that predict clinical response will facilitate treatment. Scopolamine produces rapid antidepressant effects and thus offers the opportunity to characterize potential biomarkers of treatment response within short periods. OBJECTIVE To determine if baseline brain activity when processing emotional information can predict treatment response to scopolamine in MDD. DESIGN A double-blind, placebo-controlled, crossover study together with repeated functional magnetic resonance imaging, acquired as participants performed face-identity and face-emotion working memory tasks. SETTING National Institute of Mental Health Division of Intramural Research Programs. PARTICIPANTS Fifteen currently depressed outpatients meeting DSM-IV criteria for recurrent MDD and 21 healthy participants, between 18 and 55 years of age. MAIN OUTCOME MEASURE The magnitude of treatment response to scopolamine (percentage of change in the Montgomery-Asberg Depression Rating Scale score between study end and baseline) was correlated with blood oxygen level-dependent (BOLD) signal associated with each working memory component (encode, maintenance, and test) for both identity and emotion tasks. Treatment response also was correlated with change in BOLD response (scopolamine vs baseline). Baseline activity was compared between healthy and MDD groups. RESULTS Baseline BOLD response in the bilateral middle occipital cortex, selectively during the stimulus-processing components of the emotion working memory task (no correlation during the identity task), correlated with treatment response magnitude. Change in BOLD response following scopolamine administration in overlapping areas in the middle occipital cortex while performing the same task conditions also correlated with clinical response. Healthy controls showed higher activity in the same visual regions than patients with MDD during baseline. CONCLUSION These results implicate cholinergic and visual processing dysfunction in the pathophysiology of MDD and suggest that neural response in the visual cortex, selectively to emotional stimuli, may provide a useful biomarker for identifying patients who will respond favorably to scopolamine. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT00055575.
  JAMA psychiatry (Chicago, Ill.). 01/2013;
• Article: Human Biomarkers of Rapid Antidepressant Effects.

  Carlos A Zarate, Daniel C Mathews, Maura L Furey
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  ABSTRACT: Mood disorders such as major depressive disorder and bipolar disorder-and their consequent effects on the individual and society-are among the most disabling and costly of all medical illnesses. Although a number of antidepressant treatments are available in clinical practice, many patients still undergo multiple and lengthy medication trials before experiencing relief of symptoms. Therefore a tremendous need exists to improve current treatment options and to facilitate more rapid, successful treatment in patients suffering from the deleterious neurobiological effects of ongoing depression. Toward that end, ongoing research is exploring the identification of biomarkers that might be involved in prevention, diagnosis, treatment response, severity, or prognosis of depression. Biomarkers evaluating treatment response will be the focus of this review, given the importance of providing relief to patients in a more expedient and systematic manner. A novel approach to developing such biomarkers of response would incorporate interventions with a rapid onset of action-such as sleep deprivation or intravenous drugs (e.g., ketamine or scopolamine). This alternative translational model for new treatments in psychiatry would facilitate shorter studies, improve feasibility, and increase higher compound throughput testing for these devastating disorders.
  Biological psychiatry 01/2013; · 8.93 Impact Factor
• Article: Acute Stress Symptoms Do Not Worsen in Posttraumatic Stress Disorder and Abuse with a Single Subanesthetic Dose of Ketamine.

  Mary C Zeng, Mark J Niciu, David A Luckenbaugh, Dawn F Ionescu, Daniel C Mathews, Erica M Richards, Jose Franco-Chaves, Nancy E Brutsche, Carlos A Zarate
  Biological psychiatry 12/2012; · 8.93 Impact Factor
• Article: A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression.

  Carlos A Zarate, Daniel Mathews, Lobna Ibrahim, Jose Franco Chaves, Craig Marquardt, Immaculata Ukoh, Libby Jolkovsky, Nancy E Brutsche, Mark A Smith, David A Luckenbaugh
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  ABSTRACT: BACKGROUND: The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD). METHODS: In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on 2 test days 1 week apart. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on Days 1, 2, 3, and 7 postinfusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale. RESULTS: Within 80 min, Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d = .40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d = .49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects. CONCLUSIONS: In patients with treatment-resistant MDD, a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed.
  Biological psychiatry 11/2012; · 8.93 Impact Factor
• Article: Antidepressant Effects of the Muscarinic Cholinergic Receptor Antagonist Scopolamine: A Review.

  Wayne C Drevets, Carlos A Zarate, Maura L Furey
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  ABSTRACT: The muscarinic cholinergic receptor system has been implicated in the pathophysiology of depression, with physiological evidence indicating this system is overactive or hyperresponsive in depression and with genetic evidence showing that variation in genes coding for receptors within this system are associated with higher risk for depression. In studies aimed at assessing whether a reduction in muscarinic cholinergic receptor function would improve depressive symptoms, the muscarinic receptor antagonist scopolamine manifested antidepressant effects that were robust and rapid relative to conventional pharmacotherapies. Here, we review the data from a series of randomized, double-blind, placebo-controlled studies involving subjects with unipolar or bipolar depression treated with parenteral doses of scopolamine. The onset and duration of the antidepressant response are considered in light of scopolamine's pharmacokinetic properties and an emerging literature that characterizes scopolamine's effects on neurobiological systems beyond the cholinergic system that appear relevant to the neurobiology of mood disorders. Scopolamine infused at 4.0 μg/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion. Placebo-adjusted remission rates were 56% and 45% for the initial and subsequent replication studies, respectively. While effective in male and female subjects, the change in depression ratings was greater in female subjects. Clinical improvement persisted more than 2 weeks following the final infusion. The timing and persistence of the antidepressant response to scopolamine suggest a mechanism beyond that of direct muscarinic cholinergic antagonism. These temporal relationships suggest that scopolamine-induced changes in gene expression and synaptic plasticity may confer the therapeutic mechanism.
  Biological psychiatry 11/2012; · 8.93 Impact Factor
• Source

  Available from: Rodrigo Machado-Vieira

  Article: Bcl-2 rs956572 Polymorphism is Associated with Increased Anterior Cingulate Cortical Glutamate in Euthymic Bipolar I Disorder.

  Márcio Gerhardt Soeiro-de-Souza, Giacomo Salvadore, Ricardo Alberto Moreno, Maria Concepción Garcia Otaduy, Kalil T Chaim, Wagner F Gattaz, Carlos A Zarate, Rodrigo Machado-Vieira
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  ABSTRACT: B-cell lymphoma 2 (Bcl-2) is an important regulator of cellular plasticity and resilience. In bipolar disorder (BD), studies have shown a key role for a Bcl-2 gene single-nucleotide polymorphism (SNP) rs956572 in the regulation of intracellular calcium (Ca(2+)) dynamics, Bcl-2 expression/levels, and vulnerability to cellular apoptosis. At the same time, Bcl-2 decreases glutamate (Glu) toxicity in neural cells. Abnormalities in Glu function have been implicated in BD. In magnetic resonance spectroscopy (MRS) studies, anterior cingulated cortex (ACC) Glu levels have been reported to be increased in bipolar depression and mania, but no study specifically evaluated ACC Glu levels in BD-euthymia. Here, we compared ACC Glu levels in BD-euthymia compared with healthy subjects using (1)H-MRS and also evaluated the selective role of the rs956572 Bcl-2 SNP in modulating ACC Glu and Glx (sum of Glu and glutamine) in euthymic-BD. Forty euthymic subjects with BD type I and forty healthy controls aged 18-40 were evaluated. All participants were genotyped for Bcl-2 rs956572 and underwent a 3-Tesla brain magnetic resonance imaging examination including the acquisition of an in vivo PRESS single voxel (2 cm(3)) (1)H-MRS sequence to obtain metabolite levels from the ACC. Euthymic-BD subjects had higher Glu/Cre (creatine) and Glx/Cre compared with healthy controls. The Bcl-2 SNP AA genotype was associated with elevated ACC Glu/Cre and Glx/Cre ratio in the BD group but not in controls. The present study reports for the first time an increase in ACC Glu/Cre and Glx/Cre ratios in BD-euthymia. Also, Bcl-2 AA genotype, previously associated with lower Bcl-2 expression and increase intracellular Ca(2+), showed to be associated with increased ACC Glu and Glx levels in euthymic-BD subjects. The present findings reinforce a key role for glutamatergic system dysfunction in the pathophysiology of BD, potentially involving modulatory effects by Bcl-2 in the ACC.Neuropsychopharmacology advance online publication, 17 October 2012; doi:10.1038/npp.2012.203.
  Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2012; · 6.99 Impact Factor
• Article: Family history of alcohol dependence and antidepressant response to an N-methyl-d-aspartate antagonist in bipolar depression.

  David A Luckenbaugh, Lobna Ibrahim, Nancy Brutsche, Jose Franco-Chaves, Daniel Mathews, Craig A Marquardt, Christy Cassarly, Carlos A Zarate
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  ABSTRACT: Luckenbaugh DA, Ibrahim L, Brutsche N, Franco-Chaves J, Mathews D, Marquardt CA, Cassarly C, Zarate CA Jr. Family history of alcohol dependence and antidepressant response to an N-methyl-d-aspartate antagonist in bipolar depression. Bipolar Disord 2012: 00: 000-000. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. Objectives:  Both ketamine and ethanol are N-methyl-d-aspartate (NMDA) receptor antagonists. Ketamine has rapid antidepressant properties in major depressive disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive family history of alcohol dependence (FHP) was associated with greater improvement in depressive symptoms after ketamine administration compared to individuals whose family history of alcohol dependence was negative (FHN). This study investigated whether FHP influences ketamine's antidepressant and perceptual effects in individuals with bipolar depression. Methods:  A post hoc analysis was conducted on 33 subjects with DSM-IV bipolar disorder (BD) type I or II depression pooled from two previously published studies. All subjects had undergone a double-blind, randomized, crossover trial of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min; and at days 1, 2, 3, 7, 10, and 14 post-infusion. The primary outcome measure was Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Patients were categorized as FHP when they reported at least one first-degree relative with alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also collected. Results:  After ketamine infusion, subjects with FHP showed significantly greater improvement on MADRS scores than FHN subjects. In addition, patients with FHP had attenuated psychotomimetic and dissociative scores compared to FHN patients. Conclusions:  FHP appears to predict a more sustained antidepressant response to ketamine in individuals with BD. Family history of alcoholism may be an important consideration in the development of glutamatergic-based therapies for depression.
  Bipolar Disorders 09/2012; · 5.29 Impact Factor
• Source

  Available from: Simone Sarasso

  Article: Baseline delta sleep ratio predicts acute ketamine mood response in major depressive disorder.

  Wallace C Duncan, Jessica Selter, Nancy Brutsche, Simone Sarasso, Carlos A Zarate
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  ABSTRACT: BACKGROUND: Electroencephalographic (EEG) sleep slow wave activity (SWA; EEG power between 0.6 and 4Hz) has been proposed as a marker of central synaptic plasticity. Decreased generation of sleep slow waves - a core feature of sleep in depression - indicates underlying plasticity changes in the disease. Various measures of SWA have previously been used to predict antidepressant treatment response. This study examined the relationship between baseline patterns of SWA in the first two NREM episodes and antidepressant response to an acute infusion of the N-methyl-d-aspartate (NMDA) antagonist ketamine. METHODS: Thirty patients (20M, 10F, 18-65) fulfilling DSM-IV criteria for treatment-resistant major depressive disorder (MDD) who had been drug-free for two weeks received a single open-label infusion of ketamine hydrochloride (.5mg/kg) over 40min. Depressive symptoms were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS) before and after ketamine infusion. Sleep recordings were obtained the night before the infusion and were visually scored. SWA was computed for individual artifact-free NREM sleep epochs, and averaged for each NREM episode. Delta sleep ratio (DSR) was calculated as SWA(NREM1)/SWA(NREM2). RESULTS: A significant positive correlation was observed between baseline DSR and reduced MADRS scores from baseline to Day 1 (r=.414, p=.02). LIMITATIONS: The sample size was relatively small (N=30) and all subjects had treatment-resistant MDD, which may limit the generalizability of the findings. Further studies are needed to replicate and extend this observation to other patient groups. CONCLUSIONS: DSR may be a useful baseline predictor of ketamine response in individuals with treatment-resistant MDD.
  Journal of affective disorders 08/2012; · 3.76 Impact Factor
• Article: Automated subcortical segmentation using FIRST: Test-retest reliability, interscanner reliability, and comparison to manual segmentation.

  Allison C Nugent, David A Luckenbaugh, Suzanne E Wood, Wendy Bogers, Carlos A Zarate, Wayne C Drevets
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  ABSTRACT: Multiple techniques exist for the automated segmentation of magnetic resonance images (MRIs). The validity of these techniques can be assessed by evaluating test-retest reliability, interscanner reliability, and consistency with manual segmentation. We evaluate these measures for the FSL/FIRST subcortical segmentation tool. We retrospectively analyzed 190 MRI scans from 87 subjects with mood or anxiety disorders and healthy volunteers scanned multiple times on different platforms (N = 56) and/or the same platform (N = 45, groups overlap), and 146 scans from subjects who underwent both high-resolution and whole brain imaging in a single session, for comparison with manual segmentation of the hippocampus. The thalamus, caudate, putamen, hippocampus, and pallidum were reliably segmented in different sessions on the same scanner (Intraclass correlation coefficient (ICC) > 0.83 scanners and diagnostic groups pooled). In these regions, the range of between platform reliabilities were lower (0.527 < ICC < 0.953), although values below 0.7 were due to systematic differences between platforms or low reliability in the hippocampus between eight- and single-channel coil platforms. Accumbens and amygdala segmentations were generally unreliable within and between scanning platforms. ICC values for hippocampal volumes between automated and manual segmentations were acceptable (ICC > 0.7, groups pooled), and both methods detected significant differences between genders. In addition, FIRST segmentations were consistent with manual segmentations (in a subset of images; N = 20) in the left caudate and bilateral putamen. This retrospective analysis assesses realistic performance of the algorithm in conditions like those found in multisite trials or meta-analyses. In addition, the inclusion of psychiatric patients establishes reliability in subjects exhibiting volumetric abnormalities, validating patient studies. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
  Human Brain Mapping 07/2012; · 5.88 Impact Factor
• Article: Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date.

  Daniel C Mathews, Ioline D Henter, Carlos A Zarate
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  ABSTRACT: Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the 'monoamine hypothesis' for rational design of compounds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment. In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clinical evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a 'proof-of-concept' agent. The review also highlights potential molecular and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine. Because existing pharmacological treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.
  Drugs 06/2012; 72(10):1313-33. · 4.23 Impact Factor
• Article: A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder.

  Lobna Ibrahim, Nancy Diaz Granados, Libby Jolkovsky, Nancy Brutsche, David A Luckenbaugh, W Joseph Herring, William Z Potter, Carlos A Zarate
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  ABSTRACT: Converging lines of evidence suggest that the glutamatergic system may play an increasingly important role in the development of novel therapeutics for major depressive disorder (MDD), particularly agents associated with rapid antidepressant effects. Diverse glutamatergic modulators targeting N-methyl-D-aspartate receptors have shown efficacy in MDD, but their associated psychotomimetic effects presently preclude their use in larger samples. This small, randomized, double-blind, placebo-controlled, crossover pilot study evaluated the potential antidepressant efficacy and tolerability of an oral formulation of the selective N-methyl-D-aspartate NR2B antagonist MK-0657 in patients with treatment-resistant MDD (TRD). The TRD subjects underwent a 1-week drug-free period and were subsequently randomized to receive either MK-0657 monotherapy (4-8 mg/d) or placebo for 12 days. Because of recruitment challenges and the discontinuation of the compound's development by the manufacturer, only 5 of the planned 21 patients completed both periods of the crossover administration of MK-0657 and placebo. Significant antidepressant effects were observed as early as day 5 in patients receiving MK-0657 compared with those receiving placebo, as assessed by the Hamilton Depression Rating Scale and Beck Depression Inventory; however, no improvement was noted when symptoms were assessed with the Montgomery-Asberg Depression Rating Scale, the primary efficacy measure. No serious or dissociative adverse effects were observed in patients receiving this oral formulation of MK-0657. Despite the small sample size, this pilot study suggests that an oral formulation of the NR2B antagonist MK-0657 may have antidepressant properties in TRD patients. Further studies with larger sample sizes are necessary to confirm these preliminary findings.
  Journal of clinical psychopharmacology 06/2012; 32(4):551-7. · 5.09 Impact Factor
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  Available from: Marije aan het Rot

  Article: Ketamine for depression: where do we go from here?

  Marije Aan Het Rot, Carlos A Zarate, Dennis S Charney, Sanjay J Mathew
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  ABSTRACT: 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.
  Biological psychiatry 06/2012; 72(7):537-47. · 8.93 Impact Factor
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  Available from: Simone Sarasso

  Article: Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder.

  Wallace C Duncan, Simone Sarasso, Fabio Ferrarelli, Jessica Selter, Brady A Riedner, Nadia S Hejazi, Peixiong Yuan, Nancy Brutsche, Husseini K Manji, Giulio Tononi, Carlos A Zarate
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  ABSTRACT: The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.
  The International Journal of Neuropsychopharmacology 06/2012; · 4.58 Impact Factor