Dost Ongür

Harvard Medical School, Boston, Massachusetts, United States

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Publications (63)336.38 Total impact

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    ABSTRACT: Multiple lines of evidence indicate that mood disorders are associated with abnormalities in the brain's cellular composition, especially in glial cells. Considered inert support cells in the past, glial cells are now known to be important for brain function. Treatments for mood disorders enhance glial cell proliferation, and experimental stimulation of cell growth has antidepressant effects in animal models of mood disorders. These findings suggest that the proliferation and survival of glial cells may be important in the pathogenesis of mood disorders and may be possible targets for the development of new treatments. In this article we review the evidence for glial abnormalities in mood disorders, and we discuss glial cell biology and evidence from postmortem studies of mood disorders. The goal is not to carry out a comprehensive review but to selectively discuss existing evidence in support of an argument for the role of glial cells in mood disorders.
    Harvard Review of Psychiatry 11/2014; 22(6):334-7. · 3.50 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) as disease associated variants for schizophrenia (SCZ), bipolar disorder (BPD), or both. Although these results are statistically robust, the functional effects of these variants and their role in the pathophysiology of SCZ or BPD remain unclear. Dissecting the effects of risk genes on distinct domains of brain function can provide important biological insights into the mechanisms by which these genes may confer illness risk. This study used quantitative event related potentials to characterize the neurophysiological effects of well-documented GWAS-derived SCZ/BPD susceptibility variants in order to map gene effects onto important domains of brain function. We genotyped 199 patients with DSM-IV diagnoses of SCZ or BPD and 74 healthy control subjects for 19 risk SNPs derived from previous GWAS findings and tested their association with five neurophysiologic traits (P3 amplitude, P3 latency, N1 amplitude, P2 amplitude, and P50 sensory gating responses) known to be abnormal in psychosis. The TCF4 SNP rs17512836 risk allele showed a significant association with reduced auditory P3 amplitude (P = 0.00016) after correction for multiple testing. The same allele was also associated with delayed P3 latency (P = 0.005). Our results suggest that a SCZ risk variant in TCF4 is associated with neurophysiologic traits thought to index attention and working memory abnormalities in psychotic disorders. These findings suggest a mechanism by which TCF4 may contribute to the neurobiological basis of psychotic illness. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2014; 165(1):9-18. · 3.23 Impact Factor
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    ABSTRACT: The quest to understand the neurobiology of schizophrenia and bipolar disorder is ongoing with multiple lines of evidence indicating abnormalities of glia, mitochondria, and glutamate in both disorders. Despite high heritability estimates of 81% for schizophrenia and 75% for bipolar disorder, compelling links between findings from neurobiological studies, and findings from large-scale genetic analyses, are only beginning to emerge. Ten publically available gene sets (pathways) related to glia, mitochondria, and glutamate were tested for association to schizophrenia and bipolar disorder using MAGENTA as the primary analysis method. To determine the robustness of associations, secondary analyses were performed with: ALIGATOR, INRICH, and Set Screen. Data from the Psychiatric Genomics Consortium (PGC) were used for all analyses. There were 1,068,286 SNP-level p-values for schizophrenia (9,394 cases/12,462 controls), and 2,088,878 SNP-level p-values for bipolar disorder (7,481 cases/9,250 controls). The Glia-Oligodendrocyte pathway was associated with schizophrenia, after correction for multiple tests, according to primary analysis (MAGENTA p = 0.0005, 75% requirement for individual gene significance) and also achieved nominal levels of significance with INRICH (p = 0.0057) and ALIGATOR (p = 0.022). For bipolar disorder, Set Screen yielded nominally and method-wide significant associations to all three glial pathways, with strongest association to the Glia-Astrocyte pathway (p = 0.002). Consistent with findings of white matter abnormalities in schizophrenia by other methods of study, the Glia-Oligodendrocyte pathway was associated with schizophrenia in our genomic study. These findings suggest that the abnormalities of myelination observed in schizophrenia are at least in part due to inherited factors, contrasted with the alternative of purely environmental causes (e.g. medication effects or lifestyle). While not the primary purpose of our study, our results also highlight the consequential nature of alternative choices regarding pathway analysis, in that results varied somewhat across methods, despite application to identical datasets and pathways.
    PLoS ONE 01/2014; 9(2):e89441. · 3.53 Impact Factor
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    ABSTRACT: Neuroimaging techniques have begun to elucidate the neurophysiology of bipolar disorder (BPD). Several features of BPD have hindered understanding of how mood-state changes are reflected in changes in brain physiology. Longitudinal studies have advantages in isolating state-related changes and in studying the instability, inherent in these disorders, that gives rise to pathological mood states. To assess the state of the art in longitudinal neuroimaging studies in BPD, we conducted a literature review, searching MEDLINE for articles that included the key words bipolar disorder and magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), or emission tomography. The search was limited to studies with multiple subjects at two distinct and defined mood states. This search yielded eight MRS studies, four functional MRI studies, and three positron emission tomography studies. Although longitudinally designed studies allow for the isolation of biomarkers of mood state (including euthymia), the current literature is hampered by a lack of replication between studies. The current body of longitudinal BPD imaging studies is heterogeneous and incomplete, and does not lend itself to the construction of an explanatory model of mood-state transitions. Drawing on extant studies, we propose a hypothetical framework for future experiments combining multimodal imaging with a longitudinal study design.
    Harvard Review of Psychiatry 12/2013; · 3.50 Impact Factor
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    ABSTRACT: IMPORTANCE Psychotic disorders (including schizophrenia, schizoaffective disorder, and psychotic bipolar disorder) are devastating illnesses characterized by breakdown in the integration of information processing. Recent advances in neuroimaging allow for the estimation of brain networks on the basis of intrinsic functional connectivity, but the specific network abnormalities in psychotic disorders are poorly understood. OBJECTIVE To compare intrinsic functional connectivity across the cerebral cortex in patients with schizophrenia spectrum disorders or psychotic bipolar disorder and healthy controls. DESIGN, SETTING, AND PARTICIPANTS We studied 100 patients from an academic psychiatric hospital (28 patients with schizophrenia, 32 patients with schizoaffective disorder, and 40 patients with bipolar disorder with psychosis) and 100 healthy controls matched for age, sex, race, handedness, and scan quality from December 2009 to October 2011. MAIN OUTCOMES AND MEASURES Functional connectivity profiles across 122 regions that covered the entire cerebral cortex. RESULTS Relative to the healthy controls, individuals with a psychotic illness had disruption across several brain networks, with preferential reductions in functional connectivity within the frontoparietal control network (P < .05, corrected for family-wise error rate). This functionally defined network includes portions of the dorsolateral prefrontal cortex, posteromedial prefrontal cortex, lateral parietal cortex, and posterior temporal cortex. This effect was seen across diagnoses and persisted after matching patients and controls on the basis of scan quality. CONCLUSIONS AND RELEVANCE Our study results support the view that cortical information processing is disrupted in psychosis and provides new evidence that disruptions within the frontoparietal control network may be a shared feature across both schizophrenia and affective psychosis.
    JAMA Psychiatry 12/2013; · 12.01 Impact Factor
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    ABSTRACT: Criteria for psychiatric hospitalization have undergone marked changes. Efforts to limit length-of-hospitalization risk greater morbidity at discharge and increased needs for appropriate aftercare. Accordingly, we evaluated factors associated with length of psychiatric hospitalization and aftercare-types. We reviewed medical records of 589 patients with major psychiatric disorders hospitalized in a university-affiliated, not-for-profit psychiatric hospital to identify characteristics associated with length of hospitalization, types of aftercare and insurance coverage, using standard bivariate and multivariate analytical methods. Notable factors associated with longer hospitalization included: more highly supervised aftercare, diagnosis of schizophrenia or schizoaffective>affective disorders, longer illnesses, higher antipsychotic doses and more complex drug-treatments at discharge, lower GAF functional status, unemployment, being unmarried, as well as public vs. private insurance. Multivariate modeling sustained association of longer hospitalization with higher antipsychotic doses, more structured aftercare, public insurance, lower GAF scores, and diagnoses of chronic psychotic disorders. Structured aftercare was associated with younger age, fewer years ill, and private insurance, but varied little by diagnosis and was unrelated to ethnicity. Public insurance was associated notably with being unemployed, unmarried, less functional, having a chronic psychotic disorder for more years, and lack of structured aftercare. Illness severity and functional impairment may modulate efforts to limit psychiatric hospitalization. Higher-level aftercare was associated with illness and disability factors as well as with private insurance; public insurance was associated with dysfunction, unemployment and chronic illness, as well as longer hospitalization.
    Comprehensive psychiatry 11/2013; · 2.08 Impact Factor
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    ABSTRACT: IMPORTANCE Abnormalities in neural activity and cerebral bioenergetics have been observed in schizophrenia (SZ). Further defining energy metabolism anomalies would provide crucial information about molecular mechanisms underlying SZ and may be valuable for developing novel treatment strategies. OBJECTIVE To investigate cerebral bioenergetics in SZ via measurement of creatine kinase activity using in vivo 31P magnetization transfer spectroscopy. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional case-control study in the setting of clinical services and a brain imaging center of an academic psychiatric hospital. Twenty-six participants with chronic SZ (including a subgroup diagnosed as having schizoaffective disorder) and 26 age-matched and sex-matched healthy control subjects (25 usable magnetic resonance spectroscopy data sets from the latter). INTERVENTION 31P magnetization transfer spectroscopy. MAIN OUTCOMES AND MEASURES The primary outcome measure was the forward rate constant (kf) of the creatine kinase enzyme in the frontal lobe. We also collected independent measures of brain intracellular pH and steady-state metabolite ratios of high-energy phosphate-containing compounds (phosphocreatine and adenosine triphosphate [ATP]), inorganic phosphate, and the 2 membrane phospholipids phosphodiester and phosphomonoester. RESULTS A substantial (22%) and statistically significant (P = .003) reduction in creatine kinase kf was observed in SZ. In addition, intracellular pH was significantly reduced (7.00 in the SZ group vs 7.03 in the control group, P = .007) in this condition. The phosphocreatine to ATP ratio, inorganic phosphate to ATP ratio, and phosphomonoester to ATP ratio were not substantially altered in SZ, but a significant (P = .02) reduction was found in the phosphodiester to ATP ratio. The abnormalities were similar between SZ and schizoaffective disorder. CONCLUSIONS AND RELEVANCE Using a novel 31P magnetization transfer magnetic resonance spectroscopy approach, we provide direct and compelling evidence for a specific bioenergetic abnormality in SZ. Reduced kf of the creatine kinase enzyme is consistent with an abnormality in storage and use of brain energy. The intracellular pH reduction suggests a relative increase in the contribution of glycolysis to ATP synthesis, providing convergent evidence for bioenergetic abnormalities in SZ. The similar phosphocreatine to ATP ratios in SZ and healthy controls suggest that the underlying bioenergetics abnormality is not associated with change in this metabolite ratio.
    JAMA Psychiatry 11/2013; · 12.01 Impact Factor
  • Dost Ongür
    JAMA Psychiatry 10/2013; · 12.01 Impact Factor
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    ABSTRACT: Neurocognitive dysfunction is a major symptom feature of schizophrenia and bipolar disorder. A prognostic relationship between cognition and community outcomes is well-documented in schizophrenia and increasingly recognized in bipolar disorder. However, specific associations among neurocognition, diagnosis, state symptomatology, and community functioning are unclear, and few studies have compared these relationships among patients with affective and non-affective psychoses in the same study. We examined neurocognitive, clinical, and community functioning in a cross-diagnostic sample of patients with psychotic disorders over a 6-month follow-up interval. Neurocognitive, clinical and community functioning were assessed in participants with schizophrenia (n=13), schizoaffective disorder (n=17), or bipolar disorder with psychosis (n=18), and healthy controls (n=18) at baseline and 6months later. Neurocognitive functioning was impaired in all diagnostic groups and, despite reductions in primary symptoms, did not recover on most measures over the follow-up period. Neurocognitive impairment was not associated with diagnosis or clinical improvement. Several neurocognitive scores at baseline (but not diagnosis or clinical baseline or follow-up scores) predicted community functioning at follow-up. In one of the few studies to longitudinally examine neurocognition in association with clinical and outcomes variables in a cross diagnostic sample of psychotic disorders patients, neurocognitive deficits were pronounced across diagnoses and did not recover on most measures despite significant reductions in clinical symptoms. Baseline neurocognitive functioning was the only significant predictor of patients' community functioning six months later. Efforts to recognize and address cognitive deficits, an approach that has shown promise in schizophrenia, should be extended to all patients with psychosis.
    Schizophrenia Research 06/2013; · 4.59 Impact Factor
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    ABSTRACT: OBJECTIVES: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in bipolar disorder. However, due to discrepant studies measuring postmortem, cerebrospinal fluid, plasma, and in vivo brain levels of GABA, the nature of these abnormalities is unclear. Using proton magnetic resonance spectroscopy, we investigated tissue levels of GABA in the anterior cingulate cortex and parieto-occipital cortex of participants with bipolar disorder and healthy controls. METHODS: Fourteen stably medicated euthymic outpatients with bipolar disorder type I (mean age 32.6 years, eight male) and 14 healthy control participants (mean age 36.9 years, 10 male) completed a proton magnetic resonance spectroscopy scan at 4-Tesla after providing informed consent. We collected data from two 16.7-mL voxels using MEGAPRESS, and they were analyzed using LCModel. RESULTS: GABA/creatine ratios were elevated in bipolar disorder participants compared to healthy controls [F(1,21) = 4.4, p = 0.048] in the anterior cingulate cortex (25.1% elevation) and the parieto-occipital cortex (14.6% elevation). Bipolar disorder participants not taking GABA-modulating medications demonstrated greater GABA/creatine elevations than patients taking GABA-modulating medications. CONCLUSIONS: We found higher GABA/creatine levels in euthymic bipolar disorder outpatients compared to healthy controls, and the extent of this elevation may be affected by the use of GABA-modulating medications. Our findings suggest that elevated brain GABA levels in bipolar disorder may be associated with GABAergic dysfunction and that GABA-modulating medications reduce GABA levels in this condition.
    Bipolar Disorders 05/2013; · 4.62 Impact Factor
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    ABSTRACT: BACKGROUND: In schizophrenia (SZ), disturbances in integration of activity among brain regions seem to be as important as abnormal activity of any single region. Brain regions are connected through white matter (WM) tracts, and diffusion tensor imaging has provided compelling evidence for WM abnormalities in SZ. However, diffusion tensor imaging alone cannot currently pinpoint the biological basis of these abnormalities. METHODS: In this study, we combined a myelin-specific and an axon-specific magnetic resonance imaging approach to examine potentially distinct abnormalities of WM components in SZ. Magnetization transfer ratio (MTR) provides information on myelin content, whereas diffusion tensor spectroscopy provides information on metabolite diffusion within axons. We collected data from a 1×3×3 cm voxel within the right prefrontal cortex WM at 4 Tesla and studied 23 patients with SZ and 22 age- and sex-matched healthy control participants. RESULTS: The MTR was significantly reduced in SZ, suggesting reduced myelin content. By contrast, the apparent diffusion coefficient of N-acetylaspartate (NAA) was significantly elevated, suggesting intra-axonal abnormalities. Greater abnormality of both MTR and the apparent diffusion coefficient of NAA correlated with more adverse outcomes in the patient group. CONCLUSIONS: The results suggest that WM abnormalities in SZ include both abnormal myelination and abnormal NAA diffusion within axons. These processes might be associated with abnormal signal transduction and abnormal information processing in SZ.
    Biological psychiatry 04/2013; · 8.93 Impact Factor
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    ABSTRACT: The presence of a single first-rank auditory hallucination (FRAH) or bizarre delusion (BD) is sufficient to satisfy the symptom criterion for a DSM-IV-TR diagnosis of schizophrenia. We queried two independent databases to investigate how prevalent FRAH and BD are in schizophrenia spectrum disorders and whether the diagnosis depends on them. FRAH was common in both datasets (42.2% and 55.2%) and BD was present in the majority of patients (62.5% and 69.7%). However, FRAH and BD rarely determined the diagnosis. In the first database, we found only seven cases among 325 patients (2.1%) and in the second database we found only one case among 201 patients (0.5%) who were diagnosed based on FRAH or BD alone. Among patients with FRAH, 96% had delusions, 14-42% had negative symptoms, 15-21% had disorganized or catatonic behavior, and 20-23% had disorganized speech. Among patients with BD, 88-99% had hallucinations, 17-49% had negative symptoms, 20-27% had disorganized or catatonic behavior, and 21-25% had disorganized speech. We conclude that FRAH and BD are common features of schizophrenia spectrum disorders, typically occur in the context of other psychotic symptoms, and very rarely constitute the sole symptom criterion for a DSM-IV-TR diagnosis of schizophrenia.
    Schizophrenia Research 03/2013; · 4.59 Impact Factor
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    ABSTRACT: BACKGROUND: Suicide is a leading cause of death among patients with psychotic illnesses. Several researchers have suggested that specific illness symptoms may better predict suicide risk. An ability to identify high-risk patients would aid clinicians in instituting risk-reduction measures to decrease suicidal behavior in this population. METHODS: We examined the association between psychotic symptoms and suicidal behavior among 148 inpatients with psychosis using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the Scale for the Assessment of Positive Symptoms, and the Positive and Negative Syndrome Scale. Measures of suicidality were obtained from risk assessment clinical data routinely collected during intake. RESULTS: For individuals with a DSM-IV diagnosed psychotic spectrum disorder, 40% (n=57) endorsed suicidal ideation on admission and 23% (n=33) endorsed a recent suicide attempt. The presence of command auditory hallucinations was significantly associated with active suicidal ideation across diagnostic categories. Similarly, a greater percentage of patients endorsed a recent suicide attempt in the presence of command hallucinations. These correlations with CAH are noteworthy, as we found no significant difference in the prevalence of SI among those with and without general auditory hallucinations (42.5% and 37.7%). CONCLUSIONS: The presence of command auditory hallucinations, in particular, but not auditory hallucinations, in general, was associated with suicidal behavior. These results indicate that command auditory hallucinations may identify or even place psychotic individuals at greater risk for acute, suicidal behavior - these symptoms should be the target of immediate and aggressive characterization and treatment.
    Comprehensive psychiatry 01/2013; · 2.08 Impact Factor
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    Fei Du, Dost Ongür
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    ABSTRACT: In this manuscript we present novel MRI approaches to dissecting axon vs. myelin abnormalities in psychiatric disorders. Existing DTI approaches are not able to provide specific information on these subcellular elements but novel approaches are beginning to do so. We review two approaches (magnetization transfer ratio-MTR; and diffusion tensor spectroscopy-DTS) and the theoretical framework for interpreting data derived from these approaches. Work is ongoing to collect data that will answer some relevant questions using these techniques in schizophrenia and related conditions.
    Frontiers in Integrative Neuroscience 01/2013; 7:24.
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    ABSTRACT: BACKGROUND: Schizophrenia is a heterogeneous disorder that may consist of multiple etiologies and disease processes. Auditory hallucinations (AH), which are common and often disabling, represent a narrower and more basic dimension of psychosis than schizophrenia. Previous studies suggest that abnormal primary auditory cortex activity is associated with AH pathogenesis. We thus investigated functional connectivity, using a seed in primary auditory cortex, in schizophrenia patients with and without AH and healthy controls, to examine neural circuit abnormalities associated more specifically with AH than the myriad other symptoms that comprise schizophrenia. METHODS: Using resting-state fMRI (rsfMRI), we investigated functional connectivity of the primary auditory cortex, located on Heschl's gyrus, in schizophrenia spectrum patients with AH. Participants were patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder with lifetime AH (n=27); patients with the same diagnoses but no lifetime AH (n=14); and healthy controls (n=28). RESULTS: Patients with AH vulnerability showed increased left Heschl's gyrus functional connectivity with left frontoparietal regions and decreased functional connectivity with right hippocampal formation and mediodorsal thalamus compared to patients without lifetime AH. Furthermore, among AH patients, left Heschl's gyrus functional connectivity covaried positively with AH severity in left inferior frontal gyrus (Broca's area), left lateral STG, right pre- and postcentral gyri, cingulate cortex, and orbitofrontal cortex. There were no differences between patients with and without lifetime AH in right Heschl's gyrus seeded functional connectivity. CONCLUSIONS: Abnormal interactions between left Heschl's gyrus and regions involved in speech/language, memory, and the monitoring of self-generated events may contribute to AH vulnerability.
    Schizophrenia Research 12/2012; · 4.59 Impact Factor
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    ABSTRACT: We evaluated prevalence and risk factors for metabolic syndrome in inpatients treated with antipsychotics, with or without other psychotropic drugs. Although the literature on metabolic syndrome in psychiatry has expanded in recent years, we seek to elucidate some of the remaining gaps by examining a severely and chronically ill population heavily treated with pharmacological agents. With data from medical records of 589 adults hospitalized at McLean Hospital in 2010 and 2011, we used standard statistical analyses to characterize risks and covariates of metabolic syndrome. With prior antipsychotic treatment, prevalence of metabolic syndrome was 29.5%. The syndrome was strongly associated with being overweight (≥25 kg/m(2) in 60.1% of subjects), older age, longer treatment-exposure, schizoaffective diagnosis (39.8%), more illness-episodes or hospitalizations, polytherapy, and higher total daily chlorpromazine-equivalent doses, but not sex. Notably, metabolic syndrome risk was greater among young, antipsychotic treated patients (15.5-fold at age ≤25 years). The findings extend information on the association of metabolic syndrome with antipsychotic treatment. Metabolic syndrome was found in 30% of antipsychotic-exposed inpatients. Risk was surprisingly high in young persons and after brief treatment-exposure, and psychotropic polytherapy increased risk. Copyright © 2012 John Wiley & Sons, Ltd.
    Human Psychopharmacology Clinical and Experimental 09/2012; 27(5):521-6. · 2.10 Impact Factor
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    ABSTRACT: Background: Reported rates of comorbid anxiety disorders in psychotic and mood disorders vary widely among studies. Sampling and Methods: We used the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, to examine rates of comorbid anxiety disorders in patients with schizoaffective disorder (SZA; n = 153), bipolar I disorder (BP; n = 304) and schizophrenia (SZ; n = 174). Results: The rates of anxiety disorders in participants with SZA (30.1%), BP (22.4%) and SZ (16.7%) differed significantly [χ(2)(2) = 8.368, p = 0.015]. Among anxiety disorders, this effect was most pronounced for panic disorder (PD). PD rates were significantly higher in participants with SZA (15.7%) as compared to participants with BP (6.9%) and SZ [6.9%; χ(2)(2) = 10.879, p = 0.004]. Logistic regression models controlling for demographic and clinical characteristics confirmed that primary diagnosis (SZA, BP or SZ) was a significant predictor of PD comorbidity and approached significance in predicting the comorbidity of any anxiety disorder. Conclusions: Our findings suggest that patients with SZA have high rates of anxiety disorders. Clinicians treating patients with SZA should evaluate for anxiety disorder comorbidity, especially as anxiety symptoms may not be reported at first presentation.
    Psychopathology 08/2012; · 1.62 Impact Factor
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    ABSTRACT: The human frontal lobe is critical for cognitive function in the healthy brain. Many psychiatric disorders including schizophrenia and bipolar disorder are associated with apparent mitochondrial dysfunction and bioenergetic abnormalities in the frontal lobe. Therefore, measuring cerebral bioenergetics associated with creatine kinase and adenosine triphosphate (ATP) synthase reactions could provide crucial information regarding the underlying molecular mechanisms associated with psychiatric disorders. In this study, the unidirectional forward chemical exchange metabolic fluxes of creatine kinase and ATP synthase reactions as well as reverse chemical exchange metabolic flux associated with ATP hydrolysis were determined at 4T by (31)P magnetization transfer. The current experiments indicate that the kinetic network of PCr↔ATP↔Pi can be measured reliably in the human frontal lobe at 4T, which will enable detailed in vivo characterization of bioenergetic abnormalities in a variety of neuropsychiatric disorders.
    Magnetic Resonance Imaging 08/2012; · 2.06 Impact Factor
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    ABSTRACT: Major depression is associated with both dysregulated glutamatergic neurotransmission and fewer astrocytes in limbic areas including the prefrontal cortex (PFC). These deficits may be functionally related. Notably, astrocytes regulate glutamate levels by removing glutamate from the synapse via the glutamate transporter (GLT-1). Previously, we demonstrated that central blockade of GLT-1 induces anhedonia and c-Fos expression in the PFC. Given the role of the PFC in regulating mood, we hypothesized that GLT-1 blockade in the PFC alone would be sufficient to induce anhedonia in rats. We microinjected the GLT-1 inhibitor, dihydrokainic acid (DHK), into the PFC and examined the effects on mood using intracranial self-stimulation (ICSS). At lower doses, intra-PFC DHK produced modest increases in ICSS thresholds, reflecting a depressive-like effect. At higher doses, intra-PFC DHK resulted in cessation of responding. We conducted further tests to clarify whether this total cessation of responding was related to an anhedonic state (tested by sucrose intake), a nonspecific result of motor impairment (measured by the tape test), or seizure activity (measured with electroencephalogram (EEG)). The highest dose of DHK increased latency to begin drinking without altering total sucrose intake. Furthermore, neither motor impairment nor evidence of seizure activity was observed in the tape test or EEG recordings. A decrease in reward value followed by complete cessation of ICSS responding suggests an anhedonic-like effect of intra-PFC DHK; a conclusion that was substantiated by an increased latency to begin sucrose drinking. Overall, these results suggest that blockade of astrocytic glutamate uptake in the PFC is sufficient to produce anhedonia, a core symptom of depression.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2012; 37(11):2467-75. · 8.68 Impact Factor
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    ABSTRACT: OBJECTIVE: Both categorical and dimensional methods appear relevant to classifying psychotic disorders; however, there is no clear consensus on the most appropriate categories and dimensions or on the best approach for constructing nosologic criteria that integrate these 2 methods. This review examines the evidence on specific dimensions and categories that would best characterize psychoses. METHOD: Entries in the MEDLINE database between 1980 and 2011 were searched for studies of the dimensional and/or categorical structure of psychosis. Studies were included if samples represented a spectrum of psychotic disorders and dimensions/categories were empirically derived using principal components analysis, factor analysis, or latent class analysis. RESULTS: Most dimensional studies observed 4 or 5 dimensions within psychosis, with positive, negative, disorganization, and affective symptom domains most frequently reported. Substance abuse, anxiety, early onset/developmental, insight, cognition, hostility, and behavioral/social disturbance dimensions appeared in some studies. Categorical studies suggested 3 to 7 major classes within psychosis, including a class similar to Kraepelin's dementia praecox and one or more classes with significant mood components. Only 2 studies compared the relative fit of empirically derived dimensions and categories within the same data set, and each had significant limitations. CONCLUSION: There is relatively consistent evidence on appropriate categories and dimensions for characterizing psychoses. However, the lack of studies directly comparing or combining these approaches provides insufficient evidence for definitive conclusions about their relative merits and integration. The authors provide specific recommendations for designing future studies to identify valid dimensions and/or categories of the psychoses and investigate hybrid approaches to model the structure of the underlying illnesses.
    Comprehensive psychiatry 06/2012; · 2.08 Impact Factor

Publication Stats

4k Citations
336.38 Total Impact Points


  • 2005–2014
    • Harvard Medical School
      • Department of Psychiatry
      Boston, Massachusetts, United States
  • 2013
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 2005–2013
    • McLean Hospital
      • McLean Imaging Center
      Cambridge, Massachusetts, United States
  • 2011
    • Massachusetts Institute of Technology
      • Department of Brain and Cognitive Sciences
      Cambridge, MA, United States
  • 2008
    • Dokuz Eylul University
      • Department of Psychiatry
      İzmir, Izmir, Turkey
  • 2003
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1998–2002
    • Washington University in St. Louis
      • Department of Anatomy and Neurobiology
      Saint Louis, MO, United States