Biological Psychiatry

A brief summary of the articles appearing in this issue of Biological Psychiatry

2012-06-01

In this double-blind, randomized, crossover study, Zarate et al. (pages 939–946) sought to replicate prior findings of a rapid antidepressant response to ketamine in bipolar depression. They administered a single intravenous infusion of ketamine or placebo to individuals with bipolar depression who were also receiving either lithium or valproate. Within 40 minutes, depressive symptoms and suicidal ideation significantly improved in subjects receiving ketamine compared to placebo; this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial.

Enhancing Prolonged Exposure Therapy for Posttraumatic Stress Disorder with D-Cycloserine: Further Support for Treatments That Promote Experience-Dependent Neuroplasticity

John H. Krystal — 2012-06-01

Posttraumatic stress disorder (PTSD) is a common, distressing, and debilitating consequence of the experience of extremely stressful life events, exemplified by combat, sexual assault, torture, or natural disasters. Although the majority of people exposed to these extreme events recover within days to months, long-term follow-up of Vietnam Veterans and survivors of the Nazi Death Camps indicate that for many traumatized people, symptoms persist for decades, perhaps for the rest of their lives (). The very persistence of the impact of what can be a single life experience suggests that traumatization profoundly engages neuroplasticity mechanisms. In addition, compromised neuroplasticity may be a factor preventing individuals with PTSD from benefiting from available social supports and from psychotherapies and pharmacotherapies for PTSD.

Translating the Rosetta Stone of N-Acetylcysteine

Olivia M. Dean, Ashley I. Bush, Michael Berk — 2012-06-01

The history of the field of biological psychiatry can be cynically encapsulated by the quest to reverse engineer serendipitous clinical findings. The role of monoamines in depression, dopamine in schizophrenia, and second messengers in bipolar disorder have all been reversed engineered from understanding the effects of tricyclics, antipsychotics, and lithium, respectively. In this context, the emergence of N-acetylcysteine (NAC) as a potential therapeutic modality provides a dual opportunity: a novel therapy and a key to unlocking the pathophysiology of the targeted disorders. One of the perplexing and curious things about NAC is that it appears to be of potential value for a multitude of phenomena in a diversity of seemingly disparate disorders. Mirroring what we have seen with atypical antipsychotics and even antidepressants, efficacy patterns of NAC show little respect for the chapter structure of the DSM-IV system. Positive trials are reported for negative and extrapyramidal symptoms in schizophrenia, depression in bipolar disorder, cocaine craving, smoking cessation, trichotillomania, and gambling (). Given the frequency of negative studies for established agents, the paucity of negative published studies is noteworthy.

N-Acetylcysteine for the Treatment of Glutathione Deficiency and Oxidative Stress in Schizophrenia

Dikoma C. Shungu — 2012-06-01

Despite decades of intense research and development, current treatments for schizophrenia (SZ) have not only met with limited efficacy but are also often associated with serious side effects, justifying the heightened interest in the development of alternate therapies (). With mounting experimental evidence implicating glutathione (GSH) deficiency and increased oxidative stress in the pathophysiology of most major psychiatric disorders (), novel neuroprotective strategies that aim to limit oxidative stress-mediated cellular damage in such disorders, including SZ, are being increasingly scrutinized ().

Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial

2012-02-02

Background: Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. Methods: In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion. Results: Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d = .89, 95% confidence interval = .61–1.16, and .98, 95% confidence interval = .64–1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point. Conclusions: This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.

D-Cycloserine Effects on Extinction of Conditioned Responses to Drug-Related Cues

Karyn M. Myers, William A. Carlezon — 2012-06-01

D-cycloserine (DCS) is an N-methyl-D-aspartate (NMDA) receptor partial agonist that facilitates extinction of conditioned fear in animals and cue exposure therapy (CET) for fear and anxiety disorders in people. Recent preclinical and clinical studies have examined the effect of DCS on extinction of conditioned responses elicited by cues paired with administration of or withdrawal from drugs of abuse, including physiological responses, craving, withdrawal, and drug-seeking behavior. DCS facilitates extinction and blunts postextinction recovery of these responses in animal models, including place conditioning and drug self-administration, but DCS effects on CET in substance users/abusers are less robust. Some of the null effects in the clinical literature might be attributable to issues related to sample size, data characteristics, DCS administration, and participant characteristics, among others. In this review we describe the preclinical and clinical literatures on DCS modulation of extinction of addiction-related conditioned responses, consider possible limitations of the clinical studies that have been published to date, and propose ways of designing future clinical studies so as to maximize the probability of detecting a DCS effect. We also discuss concerns with regard to potential harmful effects of DCS-coupled CET in addicts and describe how these concerns might be mitigated. We conclude that it is as yet unclear whether DCS-coupled CET might be a useful approach in the treatment of addiction.

A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism

2012-02-20

Background: An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism. Methods: This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale. Results: Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2–10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96). Conclusions: Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted.

A Randomized Placebo-Controlled Trial of d-Cycloserine to Enhance Exposure Therapy for Posttraumatic Stress Disorder

2012-04-05

Background: Posttraumatic stress disorder (PTSD) is a complex and debilitating anxiety disorder, and, although prolonged exposure therapy has been proven effective, many patients remain symptomatic after treatment. In other anxiety disorders, the supplementary use of d-cycloserine (DCS), a partial agonist at the glutamatergic N-methyl-D-aspartate receptor, showed promise in enhancing treatment effects. We examined whether augmentation of prolonged exposure therapy for PTSD with DCS enhances treatment efficacy. Methods: In a randomized, double-blind, placebo-controlled trial we administered 50 mg DCS or placebo 1 hour before each exposure session to 67 mixed trauma patients, recruited from regular referrals, with a primary PTSD diagnosis satisfying DSM-IV criteria. Results: Although DCS did not enhance overall treatment effects, the participants having received DCS did show a stronger treatment response. Exploratory session-by-session analyses revealed that DCS yielded higher symptom reduction in those participants that had more severe pretreatment PTSD and needed longer treatment. Conclusions: The present study found preliminary support for the augmentation of exposure therapy with DCS, specifically for patients with more severe PTSD needing longer treatment.

Glutamatergic Modulation of Auditory Information Processing in the Human Brain

2011-10-31

Background: Auditory mismatch negativity (MMN) and P300 event-related potentials (ERPs) are reduced in schizophrenia patients and healthy volunteers administered the N-methyl-D-aspartate glutamate receptor antagonist, ketamine. In rodents, N-acetylcysteine (NAC), a stimulator of the cystine-glutamate exchanger, attenuates the cognitive and behavioral effects of N-methyl-D-aspartate receptor antagonists. On the basis of these findings, we tested whether NAC would reduce ketamine effects on behavior, MMN, and P300 in healthy humans. Methods: This randomized, double-blind, placebo-controlled study consisted of 2 test days during which subjects (n = 16) were administered oral NAC (3000 mg in divided doses) or matching placebo 165 min before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Behavioral and ERP data including auditory MMN and P300 were collected during each test day. Results: Ketamine produced psychotic-like positive symptoms, reductions in working memory and sustained attention performance, and amplitude reductions for the frequency- and intensity-deviant MMNs and P300. NAC pretreatment did not reduce the behavioral or ERP effects of ketamine. In addition, NAC reduced frequency-deviant MMN amplitude and increased target and novelty P3 amplitudes. The decrements in frequency-deviant MMN amplitude produced by ketamine and NAC were not additive. Conclusions: NAC did not attenuate the effects of ketamine in humans, in contrast to previous studies in animals. NAC merits further investigation as a cognitive enhancing agent due to its ability to increase the P300 amplitude.

The Effect of N-Acetylcysteine in the Nucleus Accumbens on Neurotransmission and Relapse to Cocaine

2011-12-05

Background: Relapse to cocaine seeking has been linked with low glutamate in the nucleus accumbens core (NAcore) causing potentiation of synaptic glutamate transmission from prefrontal cortex (PFC) afferents. Systemic N-acetylcysteine (NAC) has been shown to restore glutamate homeostasis, reduce relapse to cocaine seeking, and depotentiate PFC-NAcore synapses. Here, we examine the effects of NAC applied directly to the NAcore on relapse and neurotransmission in PFC-NAcore synapses, as well as the involvement of the metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5). Methods: Rats were trained to self-administer cocaine for 2 weeks and following extinction received either intra-accumbens NAC or systemic NAC 30 or 120 minutes, respectively, before inducing reinstatement with a conditioned cue or a combined cue and cocaine injection. We also recorded postsynaptic currents using in vitro whole cell recordings in acute slices and measured cystine and glutamate uptake in primary glial cultures. Results: NAC microinjection into the NAcore inhibited the reinstatement of cocaine seeking. In slices, a low concentration of NAC reduced the amplitude of evoked glutamatergic synaptic currents in the NAcore in an mGluR2/3-dependent manner, while high doses of NAC increased amplitude in an mGluR5-dependent manner. Both effects depended on NAC uptake through cysteine transporters and activity of the cysteine/glutamate exchanger. Finally, we showed that by blocking mGluR5 the inhibition of cocaine seeking by NAC was potentiated. Conclusions: The effect of NAC on relapse to cocaine seeking depends on the balance between stimulating mGluR2/3 and mGluR5 in the NAcore, and the efficacy of NAC can be improved by simultaneously inhibiting mGluR5.

Differential Role of NR2A and NR2B Subunits in N-Methyl-D-Aspartate Receptor Antagonist-Induced Aberrant Cortical Gamma Oscillations

Bernat Kocsis — 2011-11-07

Background: N-methyl-D-aspartate receptor (NMDA-R) hypofunction plays an important role in cognitive impairment in schizophrenia. NMDA-R antagonists elicit psychotic symptoms in humans and schizophrenia-relevant signs in rodents, including a strong increase in cortical gamma activity. NMDA-Rs are composed of different subunits, and accumulating evidence indicates that neuronal damage due to NMDA-R antagonists depends on their action on a specific type of the receptor containing the NR2A subunit. In human schizophrenics, NR2A is selectively reduced in fast-firing interneurons. These neurons are critical for gamma oscillations, indicating that pathological changes in gamma activity may depend on subunit-specific NMDA-R deficit. The present study tested this hypothesis. Methods: Cortical electroencephalograms were recorded in freely moving rats and the changes in gamma power were measured after administration of NMDA-R antagonists with different subunit selectivity, including NR2A-preferring (PEAQX, n = 5; NVP-AAM077, n = 18), NR2B-selective (ifenprodil, n = 6; threo-ifenprodil, n = 4; Ro25-6985, n = 13), and NR2C/D-selective (n = 8) antagonists, along with vehicle and nonselective NMDA-R antagonists (ketamine, n = 10; MK801, n = 12). Changes in prepulse inhibition of startle was tested after MK-801 (n = 6), NVP-AAM077, and Ro-6891 (n = 5) injection. Results: Strong increase in gamma power was induced by nonselective NMDA-R antagonists and by blockade of NMDA-Rs containing the NR2A subunit, with co-occurring gating deficits and diminished low-frequency modulation of gamma oscillations. In contrast, selective blockade of NR2B, C, or D subunit-containing receptors had minor effects. Conclusions: Major subtype-specific differences in the role of NMDA-Rs in cortical gamma oscillation may have implications for the pathomechanism and treatment of cognitive impairment in schizophrenia.

Brain-Derived Neurotrophic Factor Val66Met Allele Impairs Basal and Ketamine-Stimulated Synaptogenesis in Prefrontal Cortex

2011-10-31

Background: Knock-in mice with the common human brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have impaired trafficking of BDNF messenger RNA to dendrites. It was hypothesized, given evidence that local synapse formation is dependent on dendritic translation of BDNF messenger RNA, that loss-of-function Met allele mice would show synaptic deficits both at baseline and in response to ketamine, an N-methyl-D-aspartate antagonist that stimulates synaptogenesis in prefrontal cortex (PFC). Methods: Whole-cell recordings from layer V medial PFC pyramidal cells in brain slices were combined with two-photon laser scanning for analysis of wildtype, Val/Met, and Met/Met mice both at baseline and in response to a low dose of ketamine. Results: Val/Met and Met/Met mice were found to have constitutive atrophy of distal apical dendrites and decrements in apically targeted excitatory postsynaptic currents in layer V pyramidal cells of PFC. In addition, spine density and diameter were decreased, indicative of impaired synaptic formation/maturation (synaptogenesis). In Met/Met mice the synaptogenic effect of ketamine was markedly impaired, consistent with the idea that synaptogenesis is dependent on dendritic translation/release of BDNF. In parallel behavioral studies, we found that the antidepressant response to ketamine in the forced swim test was blocked in Met/Met mice. Conclusions: The results demonstrate that expression of the BDNF Met allele in mice results in basal synaptic deficits and blocks synaptogenic and antidepressant actions of ketamine in PFC, suggesting that the therapeutic response to this drug might be attenuated or blocked in depressed patients who carry the loss of function Met allele.

N-Acetylcysteine Normalizes Neurochemical Changes in the Glutathione-Deficient Schizophrenia Mouse Model During Development

2011-09-27

Background: Glutathione (GSH) is the major cellular redox-regulator and antioxidant. Redox-imbalance due to genetically impaired GSH synthesis is among the risk factors for schizophrenia. Here we used a mouse model with chronic GSH deficit induced by knockout (KO) of the key GSH-synthesizing enzyme, glutamate-cysteine ligase modulatory subunit (GCLM). Methods: With high-resolution magnetic resonance spectroscopy at 14.1 T, we determined the neurochemical profile of GCLM-KO, heterozygous, and wild-type mice in anterior cortex throughout development in a longitudinal study design. Results: Chronic GSH deficit was accompanied by an elevation of glutamine (Gln), glutamate (Glu), Gln/Glu, N-acetylaspartate, myo-Inositol, lactate, and alanine. Changes were predominantly present at prepubertal ages (postnatal days 20 and 30). Treatment with N-acetylcysteine from gestation on normalized most neurochemical alterations to wild-type level. Conclusions: Changes observed in GCLM-KO anterior cortex, notably the increase in Gln, Glu, and Gln/Glu, were similar to those reported in early schizophrenia, emphasizing the link between redox imbalance and the disease and validating the model. The data also highlight the prepubertal period as a sensitive time for redox-related neurochemical changes and demonstrate beneficial effects of early N-acetylcysteine treatment. Moreover, the data demonstrate the translational value of magnetic resonance spectroscopy to study brain disease in preclinical models.

Translational Magnetic Resonance Spectroscopy Reveals Excessive Central Glutamate Levels During Alcohol Withdrawal in Humans and Rats

2011-09-12

Background: In alcoholism, excessive glutamatergic neurotransmission has long been implicated in the acute withdrawal syndrome and as a key signal for dependence-related neuroplasticity. Our understanding of this pathophysiological mechanism originates largely from animal studies, but human data are needed for translation into successful medication development. Methods: We measured brain glutamate levels during detoxification in alcohol-dependent patients (n = 47) and in healthy control subjects (n = 57) as well as in a rat model of alcoholism by state-of-the-art 1H-magnetic magnetic resonance spectroscopy at 3 and 9.4 T, respectively. Results: We found significantly increased glutamate levels during acute alcohol withdrawal in corresponding prefrontocortical regions of treatment-seeking alcoholic patients and alcohol-dependent rats versus respective control subjects. The augmented spectroscopic glutamate signal is likely related to increased glutamatergic neurotransmission because, enabled by the high field strength of the animal scanner, we detected a profoundly elevated glutamate/glutamine ratio in alcohol-dependent rats during acute withdrawal. All dependence-induced metabolic alterations normalize within a few weeks of abstinence in both humans and rats. Conclusions: Our data provide first-time direct support from humans for the glutamate hypothesis of alcoholism, demonstrate the comparability of human and animal magnetic resonance spectroscopy responses, and identify the glutamate/glutamine ratio as potential biomarker for monitoring disease progression.

1H-[13C]-Nuclear Magnetic Resonance Spectroscopy Measures of Ketamine's Effect on Amino Acid Neurotransmitter Metabolism

2011-12-12

Ketamine has recently gained significant attention owing to its psychotomimetic and more recently discovered rapid antidepressant-like properties. 1H-[13C]-nuclear magnetic resonance studies were employed to explore potential physiological processes underlying these unique effects. [1-13C]glucose and [2-13C]acetate-nuclear magnetic resonance ex vivo studies were performed on the medial prefrontal cortex (mPFC) and hippocampus of rats acutely treated with 30 mg/kg or 80 mg/kg ketamine and compared with saline-treated animals to determine the effects of ketamine on amino acid neurotransmitter cycling and glial metabolism. A subanesthetic, but not anesthetic, dose of ketamine significantly increased the percentage of 13C-enrichments of glutamate, γ-aminobutyric acid, and glutamine in the mPFC of rats. Subanesthetic doses of ketamine increased mPFC amino acid neurotransmitter cycling, as well as neuronal and glial energy metabolism. These data add to previous reports suggesting increased mPFC levels of glutamate release, following the administration of subanesthetic doses of ketamine, are related to the drug's acute effects on cognition, perception, and mood.

Is Deep Brain Stimulation Able to Make Antidepressants Effective in Resistant Obsessive-Compulsive Disorder?

2011-11-24

Deep brain stimulation (DBS), a nonablative, reversible, and adjustable neurosurgical procedure, has recently been considered as a potential therapeutic alternative for the management of resistant obsessive-compulsive disorder (OCD). The ventral striatum (VS) has been proposed as a subcortical target of special interest for DBS (). It has been extensively demonstrated to play a major role in the pathophysiology of OCD regarding convergent functional neuroimaging data and electrophysiologic recordings (). Here, we report the long-term course of OC symptoms during DBS of the VS and following its discontinuation in two patients suffering from severe, chronic, and incapacitating OCD and showing unsatisfactory responses to 1) the serotonin reuptake inhibitor (SRI) antidepressants fluoxetine, sertraline, paroxetine, fluvoxamine, and clomipramine; 2) augmentation with buspirone or lithium; and 3) adjunctive cognitive-behavioral therapy (). The standard instrument Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to assess clinical severity (). Written informed consent was obtained after the study had been fully explained.

Editorial Board

2012-06-01

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2012-06-01

Biological Psychiatry (ISSN 0006-3223) is published semimonthly by Elsevier Inc., 360 Park Avenue South, New York, NY 10010-1710. Periodicals postage paid at New York, NY and additional mailing offices.

2012-06-01

Guide for Authors

2012-06-01

Biological Psychiatry is the official journal of the Society of Biological Psychiatry. The Journal rapidly publishes reports of novel results on a broad range of topics related to the pathophysiology and treatment of major neuropsychiatric disorders. Both basic and clinical neuroscience contributions are encouraged, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Except where explicitly stated otherwise, Biological Psychiatry conforms to the guidelines set forth by the International Committee of Medical Journal Editors (ICMJE) (see Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication (April 2010): Available from http://www.ICMJE.org).

Manuscript Submission Form

2012-06-01

This form should be completed by every author and accompany every new manuscript submission. It must be fully complete and accurate, with signatures from ALL authors, before a manuscript can be finalized. Please scan the completed form(s) and attach them electronically during the submission process. If you are unable to do so, fax the completed form(s) to the Editorial Office at (214) 645-9208.

Biological Psychiatry

A brief summary of the articles appearing in this issue of Biological Psychiatry

Enhancing Prolonged Exposure Therapy for Posttraumatic Stress Disorder with D-Cycloserine: Further Support for Treatments That Promote Experience-Dependent Neuroplasticity

Translating the Rosetta Stone of N-Acetylcysteine

N-Acetylcysteine for the Treatment of Glutathione Deficiency and Oxidative Stress in Schizophrenia

Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial

D-Cycloserine Effects on Extinction of Conditioned Responses to Drug-Related Cues

A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism

A Randomized Placebo-Controlled Trial of d-Cycloserine to Enhance Exposure Therapy for Posttraumatic Stress Disorder

Glutamatergic Modulation of Auditory Information Processing in the Human Brain

The Effect of N-Acetylcysteine in the Nucleus Accumbens on Neurotransmission and Relapse to Cocaine

Differential Role of NR2A and NR2B Subunits in N-Methyl-D-Aspartate Receptor Antagonist-Induced Aberrant Cortical Gamma Oscillations

Brain-Derived Neurotrophic Factor Val66Met Allele Impairs Basal and Ketamine-Stimulated Synaptogenesis in Prefrontal Cortex

N-Acetylcysteine Normalizes Neurochemical Changes in the Glutathione-Deficient Schizophrenia Mouse Model During Development

Translational Magnetic Resonance Spectroscopy Reveals Excessive Central Glutamate Levels During Alcohol Withdrawal in Humans and Rats

1H-[13C]-Nuclear Magnetic Resonance Spectroscopy Measures of Ketamine's Effect on Amino Acid Neurotransmitter Metabolism

Is Deep Brain Stimulation Able to Make Antidepressants Effective in Resistant Obsessive-Compulsive Disorder?

Editorial Board

Subscribers Page

Table of Contents

Guide for Authors

Manuscript Submission Form