Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression.

The mechanisms of action of the rapid antidepressant effects of ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, have not been fully elucidated. This study examined the effects of ketamine on ligand binding to a metabotropic glutamatergic receptor (mGluR5) in individuals with major depressive disorder (MDD) and healthy controls. Thirteen healthy and 13 MDD nonsmokers participated in two [11C]ABP688 positron emission tomography (PET) scans on the same day-before and during intravenous ketamine administration-and a third scan 1 day later. At baseline, significantly lower [11C]ABP688 binding was detected in the MDD as compared with the control group. We observed a significant ketamine-induced reduction in mGluR5 availability (that is, [11C]ABP688 binding) in both MDD and control subjects (average of 14±9% and 19±22%, respectively; P<0.01 for both), which persisted 24 h later. There were no differences in ketamine-induced changes between MDD and control groups at either time point (P=0.8). A significant reduction in depressive symptoms was observed following ketamine administration in the MDD group (P<0.001), which was associated with the change in binding (P<0.04) immediately after ketamine. We hypothesize that glutamate released after ketamine administration moderates mGluR5 availability; this change appears to be related to antidepressant efficacy. The sustained decrease in binding may reflect prolonged mGluR5 internalization in response to the glutamate surge.

Anterior hippocampal dysconnectivity in posttraumatic stress disorder: a dimensional and multimodal approach.

The anterior hippocampus (aHPC) has a central role in the regulation of anxiety-related behavior, stress response, emotional memory and fear. However, little is known about the presence and extent of aHPC abnormalities in posttraumatic stress disorder (PTSD). In this study, we used a multimodal approach, along with graph-based measures of global brain connectivity (GBC) termed functional GBC with global signal regression (f-GBCr) and diffusion GBC (d-GBC), in combat-exposed US Veterans with and without PTSD. Seed-based aHPC anatomical connectivity analyses were also performed. A whole-brain voxel-wise data-driven investigation revealed a significant association between elevated PTSD symptoms and reduced medial temporal f-GBCr, particularly in the aHPC. Similarly, aHPC d-GBC negatively correlated with PTSD severity. Both functional and anatomical aHPC dysconnectivity measures remained significant after controlling for hippocampal volume, age, gender, intelligence, education, combat severity, depression, anxiety, medication status, traumatic brain injury and alcohol/substance comorbidities. Depression-like PTSD dimensions were associated with reduced connectivity in the ventromedial and dorsolateral prefrontal cortex. In contrast, hyperarousal symptoms were positively correlated with ventromedial and dorsolateral prefrontal connectivity. We believe the findings provide first evidence of functional and anatomical dysconnectivity in the aHPC of veterans with high PTSD symptomatology. The data support the putative utility of aHPC connectivity as a measure of overall PTSD severity. Moreover, prefrontal global connectivity may be of clinical value as a brain biomarker to potentially distinguish between PTSD subgroups.

Genome-wide significant loci for addiction and anxiety.

BACKGROUND: Psychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology. METHODS: Here we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits. RESULTS: Addiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2-q21.2, LOD=3.322) and a broad anxiety phenotype (12q24.32-q24.33, LOD=2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg=0.550-0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1-q33.2, LOD=3.054) and drug dependence-anxiety (18p11.23-p11.22, LOD=3.425). CONCLUSIONS: This study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics.

Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans.

N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter the brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of 22 subjects and to an additional, partially overlapping, sample of 12 subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Syndrome Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 min of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints, and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia.

Memantine, an NMDA receptor antagonist, differentially influences Go/No-Go performance and fMRI activity in individuals with and without a family history of alcoholism.

RATIONALE: Individuals with a family history of alcoholism (family history positive [FHP]) show higher alcoholism rates and are more impulsive than those without such a family history (family history negative [FHN]), possibly due to altered N-methyl-D-aspartate (NMDA) receptor function. OBJECTIVES: We investigated whether memantine, an NMDA receptor antagonist, differentially influences impulsivity measures and Go/No-Go behavior and fMRI activity in matched FHP and FHN individuals. METHODS: On separate days, participants received a single dose of 40 mg memantine or identical-appearing placebo. RESULTS: No group performance differences were observed on placebo for Go correct hit or No-Go false alarm reaction time on the Go/No-Go task. During fMRI, right cingulate activation differed for FHP vs. FHN subjects during No-Go correct rejects. Memantine had attenuated effects in FHP vs. FHN subjects: For No-Go false alarms, memantine was associated with limited reduction in subcortical, cingulate, and temporal regions in FHP subjects and reduced activity in fronto-striatal-parietal networks in FHN subjects. For No-Go correct rejects, memantine (relative to placebo) reduced activity in left cingulate and caudate in FHP but not FHN subjects. CONCLUSIONS: Lower sensitivity to the effects of memantine in FHP subjects is consistent with greater NMDA receptor function in this group.

Toward a neurobiology of delusions.

Delusions are the false and often incorrigible beliefs that can cause severe suffering in mental illness. We cannot yet explain them in terms of underlying neurobiological abnormalities. However, by drawing on recent advances in the biological, computational and psychological processes of reinforcement learning, memory, and perception it may be feasible to account for delusions in terms of cognition and brain function. The account focuses on a particular parameter, prediction error--the mismatch between expectation and experience--that provides a computational mechanism common to cortical hierarchies, fronto-striatal circuits and the amygdala as well as parietal cortices. We suggest that delusions result from aberrations in how brain circuits specify hierarchical predictions, and how they compute and respond to prediction errors. Defects in these fundamental brain mechanisms can vitiate perception, memory, bodily agency and social learning such that individuals with delusions experience an internal and external world that healthy individuals would find difficult to comprehend. The present model attempts to provide a framework through which we can build a mechanistic and translational understanding of these puzzling symptoms.

Ethanol-like effects of thiopental and ketamine in healthy humans.

The gamma-aminobutyric acid-A (GABA(A)) and N-methyl-D-aspartate (NMDA) receptors mediate aspects of the behavioural effects of alcohol. Prior studies reported drugs that block NMDA receptors or facilitate GABA(A) receptor function produce ethanol-like effects in humans. The purpose of this study was to compare the ethanol-related effects of two pharmacological agents with known NMDA and GABA(A) receptor activity. As part of an ongoing, larger study, 28 subjects (age, 21-30) with no personal or family histories of alcoholism were administered subanesthetic doses of the GABA(A) receptor agonist thiopental, the NMDA receptor antagonist, ketamine and placebo on three separate test days. Various ethanol-related measures were administered. At doses of thiopental and ketamine that produced similar levels of sedation and cognitive effects, both agents produced significant ethanol-like effects and subjective intoxication. However, the intensity of the ethanol-like effects of ketamine was greater than that of thiopental. In addition, ketamine produced alterations in perception that were not produced by thiopental. These data provide further support for a model where GABA(A) receptor facilitation may contribute significantly to ethanol effects associated with social drinking, whereas NMDA receptor antagonism may contribute to relatively greater extent to features of ethanol 'intoxication'.

Confirmation and fine mapping of the chromosome 1 alcohol dependence risk locus.

Two previous large genetic linkage studies in the US population have implicated an area in chromosome 1p to contain a susceptibility gene for alcohol dependence. The 1-LOD support interval of the linkage signal spans about 30 cM and contains >30000000 DNA base pairs (bp) and 700 predicted genes. In order to reduce the size of the candidate area and potentially identify novel candidate genes within this region, we fine-mapped this area using closely spaced short tandem repeat (STR) markers and the transmission disequilibrium test (TDT) in small nuclear families. The subjects were 87 European-American families including one or more alcohol-dependent offspring (93 children and 174 parents). The initial marker set consisted of 30 STR markers, spanning the Marshfield map interval between 101.48 and 130.73 cM. Using the TDTPHASE program, we identified three markers in the distal part of this region (125-126 cM), which showed evidence of transmission disequilibrium. On the basis of this result, an additional 12 STR markers were genotyped in this region; some of these markers provided additional evidence for linkage disequilibrium. The strongest evidence for transmission disequilibrium was obtained at the marker D1S406 (P=0.005, 126.16 cM), with supporting evidence from three neighboring STR markers D1S424 (126.16 cM, P=0.01), D1S2804 (126.16 cM, P=0.04), and D1S2776 (126.16 cM, P=0.02), which are all located within a <350000 bp interval. These findings suggest that a gene (or genes) causing susceptibility to alcohol dependence resides near location 126.16 cM on chromosome 1. In addition, these results provide independent confirmation of the linkage finding regarding the identification of at least one gene in this region increasing the risk for alcohol dependence.

Neurobiological correlates of the disposition and maintenance of alcoholism.

The last decade witnessed a rapid increase in the knowledge of the etiopathology and treatment of alcoholism. The current disease concept includes psychosocial and neurobiological foundations and consequences of alcoholism. Neurobiological research points to dispositional factors such as a low level of response to alcohol, which is partly heritable and seems to be associated with monoaminergic dysfunction and reduced GABAergic alcohol effects. Chronic alcohol intake stimulates counteradaptive neuroadaptation in central GABAergic and glutamatergic neurotransmission, which increases alcohol tolerance. Neuroadaptation to chronic alcohol effects is not immediately reversed during detoxification and can cause clinical withdrawal once alcohol intake is terminated. Sensitization of the dopaminergic and opioidergic reward system may contribute to alcohol craving and reduced control of alcohol intake. New treatment options include pharmacological approaches and indicate that behavior or motivational therapy and the attendance of patient groups may equally reduce the relapse risk.

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments.

Glutamate and gamma-amino butyric acid (GABA) systems are emerging as targets for development of medications for mood disorders. There is increasing preclinical and clinical evidence that antidepressant drugs directly or indirectly reduce N-methyl-D-aspartate glutamate receptor function. Drugs that reduce glutamatergic activity or glutamate receptor-related signal transduction may also have antimanic effects. Recent studies employing magnetic resonance spectroscopy also suggest that unipolar, but not bipolar, depression is associated with reductions in cortical GABA levels. Antidepressant and mood-stabilizing treatments also appear to raise cortical GABA levels and to ameliorate GABA deficits in patients with mood disorders. The preponderance of available evidence suggests that glutamatergic and GABAergic modulation may be an important property of available antidepressant and mood-stabilizing agents. Future research will be needed to develop and evaluate new agents with specific glutamate and GABA receptor targets in the treatment of mood disorders.

NMDA receptor regulation of memory and behavior in humans.

N-methyl-D-aspartate (NMDA) receptor hypofunction is associated with a range of effects on cognition and behavior in whole animal and human studies. NMDA receptor hypofunction within the brain, which can be induced experimentally in vivo using NMDA receptor antagonist drugs, produces adverse effects on memory function. The results suggest that NMDA receptor hypofunction can preferentially affect neural mechanisms regulating the efficiency of encoding and consolidation into longer-term storage. More pronounced NMDA receptor hypofunction can produce a clinical syndrome that includes core features of psychosis, as well as dissociation. Finally, sustained and severe underexcitation of NMDA receptors in the adult brain is associated with a neurotoxic process with well-characterized neuropathological features. Progressive increases in severity of NMDA receptor hypofunction within the brain can produce a range of effects on brain function, involving local and distributed circuitry, which may underlie the observed changes in behavior. As the brain ages, the NMDA receptor system becomes progressively hypofunctional, potentially contributing to further age-related decreases in memory and learning performance. Pharmacological and genomic methods for preventing NMDA receptor hypofunction, or for preventing the upstream or downstream consequences modeled by treatment with NMDA antagonists, may be applicable to the prevention and treatment of memory and behavioral dysfunction in a variety of neuropsychiatric disease conditions.

Naltrexone in the treatment of alcohol dependence.

BACKGROUND: Although naltrexone, an opiate-receptor antagonist, has been approved by the Food and Drug Administration for the treatment of alcohol dependence, its efficacy is uncertain. METHODS: We conducted a multicenter, double-blind, placebo-controlled evaluation of naltrexone as an adjunct to standardized psychosocial treatment. We randomly assigned 627 veterans (almost all men) with chronic, severe alcohol dependence to 12 months of naltrexone (50 mg once daily), 3 months of naltrexone followed by 9 months of placebo, or 12 months of placebo. All patients were offered individual counseling and programs to improve their compliance with study medication and were encouraged to attend Alcoholics Anonymous meetings. RESULTS: There were 209 patients in each group; all had been sober for at least five days before randomization. At 13 weeks, we found no significant difference in the number of days to relapse between patients in the two naltrexone groups (mean, 72.3 days) and the placebo group (mean, 62.4 days; 95 percent confidence interval for the difference between groups, -3.0 to 22.8). At 52 weeks, there were no significant differences among the three groups in the percentage of days on which drinking occurred and the number of drinks per drinking day. CONCLUSIONS: Our findings do not support the use of naltrexone for the treatment of men with chronic, severe alcohol dependence.

Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists.

Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/kg/hr) in 26 ethanol-dependent inpatients who were sober for at least one month prior to testing. This study found that nimodipine reduced the capacity of ketamine to induce psychosis, negative symptoms, altered perception, dysphoria, verbal fluency impairment, and learning deficits. Nimodipine improved memory function, but had no other intrinsic behavioral activity in this patient group. Nimodipine pretreatment attenuated the perceived similarity of ketamine effects to ethanol as well as ketamine-induced euphoria and sedation. However, nimodipine did not reduce the stimulant effects of ketamine. These data suggest that antagonism of L-type VSCCs attenuates the behavioral effects of NMDA antagonists in humans. They support the continued evaluation of nimodipine in the treatment of neuropsychiatric disorders. They also suggest that drugs, such as ethanol, that combine NMDA and L-type VSCC antagonism may have enhanced tolerability without attenuation of their stimulant effects.

Effect of tryptophan depletion on alcohol cue-induced craving in abstinent alcoholic patients.

BACKGROUND: The capacity of alcohol cues to precipitate the desire to drink may be an important determinant of relapse to alcohol use in recovering alcohol-dependent patients. This study evaluated whether attenuation of serotonin synthesis via depletion of its precursor tryptophan reduces the magnitude of cue-induced craving for alcohol in recently abstinent alcoholic individuals. METHODS: Alcohol-dependent patients (n = 16), 1 to 3 months after detoxification, who exhibited a 20% or greater increase in reported craving when presented with an alcoholic beverage, completed two additional alcohol cue-exposure test days, 1 week apart. Each cue exposure was preceded by administration of a concentrated amino acid drink that resulted in a rapid and significant decline in plasma free tryptophan (active depletion, no tryptophan supplementation) or a similar drink containing tryptophan (placebo depletion). Tests were conducted in a randomized, double-blind fashion. RESULTS: There were no significant changes in the magnitude of cue-induced craving with active tryptophan depletion compared with placebo. CONCLUSIONS: These data question the dependence of alcohol cue-induced craving in sober alcoholics on the ongoing synthesis of serotonin.

A neurobiological basis for substance abuse comorbidity in schizophrenia.

It is commonly held that substance use comorbidity in schizophrenia represents self-medication, an attempt by patients to alleviate adverse positive and negative symptoms, cognitive impairment, or medication side effects. However, recent advances suggest that increased vulnerability to addictive behavior may reflect the impact of the neuropathology of schizophrenia on the neural circuitry mediating drug reward and reinforcement. We hypothesize that abnormalities in the hippocampal formation and frontal cortex facilitate the positive reinforcing effects of drug reward and reduce inhibitory control over drug-seeking behavior. In this model, disturbances in drug reward are mediated, in part, by dysregulated neural integration of dopamine and glutamate signaling in the nucleus accumbens resulting form frontal cortical and hippocampal dysfunction. Altered integration of these signals would produce neural and motivational changes similar to long-term substance abuse but without the necessity of prior drug exposure. Thus, schizophrenic patients may have a predilection for addictive behavior as a primary disease symptom in parallel to, and in many, cases independent from, their other symptoms.

Reductions in occipital cortex GABA levels in panic disorder detected with 1h-magnetic resonance spectroscopy.

BACKGROUND: There is preclinical evidence and indirect clinical evidence implicating gamma-aminobutyric acid (GABA) in the pathophysiology and treatment of human panic disorder. Specifically, deficits in GABA neuronal function have been associated with anxiogenesis, whereas enhancement of GABA function tends to be anxiolytic. Although reported peripheral GABA levels (eg, in cerebrospinal fluid and plasma) have been within reference limits in panic disorder, thus far there has been no direct assessment of brain GABA levels in this disorder. The purpose of the present work was to determine whether cortical GABA levels are abnormally low in patients with panic disorder. METHODS: Total occipital cortical GABA levels (GABA plus homocarnosine) were assessed in 14 unmedicated patients with panic disorder who did not have major depression and 14 retrospectively age- and sex-matched control subjects using spatially localized (1)H-magnetic resonance spectroscopy. All patients met DSM-IV criteria for a principal current diagnosis of panic disorder with or without agoraphobia. RESULTS: Patients with panic disorder had a 22% reduction in total occipital cortex GABA concentration (GABA plus homocarnosine) compared with controls. This finding was present in 12 of 14 patient-control pairs and was not solely accounted for by medication history. There were no significant correlations between occipital cortex GABA levels and measures of illness or state anxiety. CONCLUSIONS: Panic disorder is associated with reductions in total occipital cortex GABA levels. This abnormality might contribute to the pathophysiology of panic disorder.