Dost Ongur

McLean Hospital, Cambridge, Massachusetts, United States

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Publications (31)185.26 Total impact

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    ABSTRACT: The study was designed to validate use of electronic health records (EHRs) for diagnosing bipolar disorder and classifying control subjects. EHR data were obtained from a health care system of more than 4.6 million patients spanning more than 20 years. Experienced clinicians reviewed charts to identify text features and coded data consistent or inconsistent with a diagnosis of bipolar disorder. Natural language processing was used to train a diagnostic algorithm with 95% specificity for classifying bipolar disorder. Filtered coded data were used to derive three additional classification rules for case subjects and one for control subjects. The positive predictive value (PPV) of EHR-based bipolar disorder and subphenotype diagnoses was calculated against diagnoses from direct semistructured interviews of 190 patients by trained clinicians blind to EHR diagnosis. The PPV of bipolar disorder defined by natural language processing was 0.85. Coded classification based on strict filtering achieved a value of 0.79, but classifications based on less stringent criteria performed less well. No EHR-classified control subject received a diagnosis of bipolar disorder on the basis of direct interview (PPV=1.0). For most subphenotypes, values exceeded 0.80. The EHR-based classifications were used to accrue 4,500 bipolar disorder cases and 5,000 controls for genetic analyses. Semiautomated mining of EHRs can be used to ascertain bipolar disorder patients and control subjects with high specificity and predictive value compared with diagnostic interviews. EHRs provide a powerful resource for high-throughput phenotyping for genetic and clinical research.
    American Journal of Psychiatry 04/2015; 172(4):363-72. DOI:10.1176/appi.ajp.2014.14030423 · 13.56 Impact Factor
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    ABSTRACT: Converging evidence suggests bioenergetic abnormalities in bipolar disorder (BD). In the brain, phosphocreatine (PCr) acts a reservoir of high-energy phosphate (HEP) bonds, and creatine kinases (CK) catalyze the transfer of HEP from adenosine triphosphate (ATP) to PCr and from PCr back to ATP, at times of increased need. This study examined the activity of this mechanism in BD by measuring the levels of HEP molecules during a stimulus paradigm that increased local energy demand. Twenty-three patients diagnosed with BD-I and 22 healthy controls (HC) were included. Levels of phosphorus metabolites were measured at baseline and during visual stimulation in the occipital lobe using (31)P magnetic resonance spectroscopy at 4T. Changes in metabolite levels showed different patterns between the groups. During stimulation, HC had significant reductions in PCr but not in ATP, as expected. In contrast, BD patients had significant reductions in ATP but not in PCr. In addition, PCr/ATP ratio was lower at baseline in patients, and there was a higher change in this measure during stimulation. This pattern suggests a disease-related failure to replenish ATP from PCr through CK enzyme catalysis during tissue activation. Further studies measuring the CK flux in BD are required to confirm and extend this finding.Molecular Psychiatry advance online publication, 10 March 2015; doi:10.1038/mp.2015.13.
    Molecular Psychiatry 03/2015; DOI:10.1038/mp.2015.13 · 15.15 Impact Factor
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    ABSTRACT: Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2), an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct) within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2), which has been previously shown to produce antidepressant- and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress-related disorders.
    PLoS ONE 01/2015; 10(3):e0120693. DOI:10.1371/journal.pone.0120693 · 3.53 Impact Factor
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    ABSTRACT: Background Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide (CO2), possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that CO2-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function. Methods We conducted a case-control analysis (N=414 PD cases, 846 healthy controls) of ACCN2single nucleotide polymorphisms (SNPs) and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n=1,048) and/or task-evoked reactivity to emotional stimuli (n=103) in healthy individuals. Results Two SNPs at the ACCN2 locus showed evidence of association with PD: rs685012 (OR=1.32, gene-wise corrected p=0.011) and rs10875995 (OR=1.26, gene-wise corrected p=0.046). The association appeared to be stronger when early-onset (age ≤ 20) PD cases and when cases with prominent respiratory symptoms were compared to controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p=0.035), as well as task-evoked amygdala reactivity to fearful and angry faces (p=0.0048). Conclusions Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to anxiety proneness. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD.
    Biological psychiatry 12/2014; DOI:10.1016/j.biopsych.2013.12.018 · 9.47 Impact Factor
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    Dataset: Jordan
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    Matcheri S Keshavan, Dost Ongur
    World psychiatry: official journal of the World Psychiatric Association (WPA) 02/2014; 13(1):44-6. DOI:10.1002/wps.20105 · 12.85 Impact Factor
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    ABSTRACT: Background / Purpose: Insight is a measure of understanding one’s illness and symptoms. Insight is often impaired in people with psychosis and can be correlated with treatment adherence, social outcomes, and suicidality. This cross-sectional analysis investigates the association between clinical and demographic features of patients with psychotic disorders and degree of insight. Main conclusion: Our findings suggest an association between insight and clinical variables – in particular, increased severity of delusions, disorganization, and mania seem to be associated with lower insight. Demographic factors, such as age, sex, and education are not associated with level of insight.
    Society for Research in Psychopathology meeting 2013; 11/2013
  • Joseph T Coyle, Dost Ongur
    JAMA Psychiatry 11/2013; 70(11):1248. DOI:10.1001/jamapsychiatry.2013.2879 · 12.01 Impact Factor
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    ABSTRACT: Background / Purpose: The aim of this poster was to assess the factors associated with the number of lifetime hospitalizations in individuals with psychotic disorders. We analyzed the association between both clinical and demographic variables and number of previous hospitalizations. Main conclusion: Our findings indicate that number of lifetime hospitalizations is most strongly associated with demographic factors and less with specific clinical factors.
    Society for Research in Psychopathology meeting 2013; 10/2013
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    ABSTRACT: Background / Purpose: In schizophrenia (SZ), disturbances in integration of activity among brain regions appear to be as important as abnormal activity of any single region. Brain regions are connected through white matter (WM) tracts, and diffusion tensor imaging (DTI) has provided compelling evidence for WM abnormalities in SZ, though DTI alone cannot currently pinpoint the biological basis of these abnormalities. In this study, we combined two MR-based approaches to probe specific WM abnormalities in SZ: magnetization transfer ratio (MTR), which is myelin-specific, and diffusion tensor spectroscopy (DTS), which is axon-specific. Main conclusion: MTR was significantly reduced in SZ, suggesting reduced myelin content. By contrast, the apparent diffusion coefficient of N-aceytlaspartate (NAA ADC) was significantly elevated, suggesting intra-axonal abnormalities.
    Society for Research in Psychopathology meeting 2013; 10/2013
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    ABSTRACT: Background / Purpose: Cognitive dysfunction is persistent, associated with functional outcomes and a necessary target for remediation in bipolar disorder. This study investigated the utility of the MATRICS Consensus Cognitive Battery (MCCB) for use in bipolar disorder in order to encourage cross-diagnostic trials for improving cognition. Main conclusion: Bipolar disorder patients performed significantly worse than healthy controls and normative means on most domains of cognition and the composite. The measure of social cognition included in this battery may not be sufficient for detecting social cognitive deficits in bipolar disorder.
    Society for Research in Psychopathology meeting 2013; 09/2013
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    ABSTRACT: Background: Schizophrenia patients exhibit deficient processing of perceptual and cognitive information. However, it is not well-understood how basic perceptual deficits contribute to higher level cognitive problems in this mental disorder. Perception of biological motion, a motion-based cognitive recognition task, relies on both basic visual motion processing and social cognitive processing, thus providing a useful paradigm to evaluate the potentially hierarchical relationship between these two levels of information processing. Methods: In this study, we designed a biological motion paradigm in which basic visual motion signals were manipulated systematically by incorporating different levels of motion noise. We measured the performances of schizophrenia patients (n = 21) and healthy controls (n = 22) in this biological motion perception task, as well as in coherent motion detection, theory of mind, and a widely used biological motion recognition task. Results: Schizophrenia patients performed the biological motion perception task with significantly lower accuracy than healthy controls when perceptual signals were moderately degraded by noise. A more substantial degradation of perceptual signals, through using additional noise, impaired biological motion perception in both groups. Performance levels on biological motion recognition, coherent motion detection and theory of mind tasks were also reduced in patients. Conclusion: The results from the motion-noise biological motion paradigm indicate that in the presence of visual motion noise, the processing of biological motion information in schizophrenia is deficient. Combined with the results of poor basic visual motion perception (coherent motion task) and biological motion recognition, the association between basic motion signals and biological motion perception suggests a need to incorporate the improvement of visual motion perception in social cognitive remediation.
    Frontiers in Psychology 07/2013; 4:391. DOI:10.3389/fpsyg.2013.00391 · 2.80 Impact Factor
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    ABSTRACT: Religious coping is very common among individuals with psychosis, however its relevance to symptoms and treatment outcomes remains unclear. We conducted a prospective study in a clinical sample of n=47 psychiatric patients with current/past psychosis receiving partial (day) treatment at McLean Hospital. Subjects completed measures of religious involvement, religious coping and suicidality prior to treatment, and we assessed for psychosis, depression, anxiety and psychological well-being over the course of treatment. Negative religious coping (spiritual struggle) was associated with substantially greater frequency and intensity of suicidal ideation, as well as greater depression, anxiety, and less well-being prior to treatment (accounting for 9.0-46.2% of the variance in these variables). Positive religious coping was associated with significantly greater reductions in depression and anxiety, and increases in well-being over the course of treatment (accounting for 13.7-36.0% of the variance in change scores). Effects remained significant after controlling for significant covariates. Negative religious coping appears to be a risk factor for suicidality and affective symptoms among psychotic patients. Positive religious coping is an important resource to this population, and its utilization appears to be associated with better treatment outcomes.
    05/2013; DOI:10.1016/j.psychres.2013.03.023
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    ABSTRACT: Although schizophrenia and schizoaffective disorders have both similar and differing clinical features, it is not well understood whether similar or differing pathophysiological processes mediate patients' cognitive functions. Using psychophysical methods, this study compared the performances of schizophrenia (SZ) patients, patients with schizoaffective disorder (SA), and a healthy control group in two face-related cognitive tasks: emotion discrimination, which tested perception of facial affect, and identity discrimination, which tested perception of non-affective facial features. Compared to healthy controls, SZ patients, but not SA patients, exhibited deficient performance in both fear and happiness discrimination, as well as identity discrimination. SZ patients, but not SA patients, also showed impaired performance in a theory-of-mind task for which emotional expressions are identified based upon the eye regions of face images. This pattern of results suggests distinct processing of face information in schizophrenia and schizoaffective disorders.
    Schizophrenia Research 08/2011; 134(1):95-100. DOI:10.1016/j.schres.2011.08.001 · 4.43 Impact Factor
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    ABSTRACT: Neurocognitive dysfunction in schizophrenia (SZ), bipolar (BD) and related disorders represents a core feature of these illnesses, possibly a marker of underlying pathophysiology. Substantial overlap in domains of neuropsychological deficits has been reported among these disorders after illness onset. However, it is unclear whether deficits follow the same longitudinal pre- and post-morbid course across diagnoses. We examine evidence for neurocognitive dysfunction as a core feature of all idiopathic psychotic illnesses, and trace its evolution from pre-morbid and prodromal states through the emergence of overt psychosis and into chronic illness in patients with SZ, BD and related disorders. Articles reporting on neuropsychological functioning in patients with SZ, BD and related disorders before and after illness onset were reviewed. Given the vast literature on these topics and the present focus on cross-diagnostic comparisons, priority was given to primary data papers that assessed cross-diagnostic samples and recent meta-analyses. Patients with SZ exhibit dysfunction preceding the onset of illness, which becomes more pronounced in the prodrome and early years following diagnosis, then settles into a stable pattern. Patients with BD generally exhibit typical cognitive development pre-morbidly, but demonstrate deficits by first episode that are amplified with worsening symptoms and exacerbations. Neuropsychological deficits represent a core feature of SZ and BD; however, their onset and progression differ between diagnostic groups. A lifetime perspective on the evolution of neurocognitive deficits in SZ and BD reveals distinct patterns, and may provide a useful guide to the examination of the pathophysiological processes underpinning these functions across disorders.
    Psychological Medicine 02/2011; 41(2):225-41. DOI:10.1017/S0033291710001042 · 5.43 Impact Factor
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    ABSTRACT: Early invasive electrical stimulation studies suggested that enhancement of cerebellar vermal activity might prove valuable in symptomatic treatment of refractory neuropsychiatric diseases via modulation of emotion and affect. This proof of principle study aimed to test this hypothesis using noninvasive brain stimulation, and to explore the safety of this protocol in schizophrenia. Eight treatment-refractory patients with schizophrenia underwent ten sessions of intermittent theta burst stimulation (TBS) to the cerebellar vermis using MRI-guided transcranial magnetic stimulation (TMS). Assessments included side effect questionnaires, cardiovascular monitoring, psychiatric evaluations and comprehensive neuropsychological testing before and after TBS and at one-week follow-up. Overall, TBS was tolerated well with mild side effects primarily comprising neck pain and headache. No serious adverse events occurred. Diastolic blood pressure (BP) showed mild decreases for five minutes post-TBS; no significant changes were detected for systolic BP or pulse. PANSS negative subscale showed significant improvements following TBS and during the follow-up. Calgary Depression Scale and self-report visual analog scales for Happiness and Sadness pointed to significant mood elevation. Neuropsychological testing revealed significantly fewer omissions in working memory and interference conditions of a Continuous Performance Test, a longer spatial span and better delay organization on the Rey-Osterrieth Complex Figure during follow-up. No significant worsening in psychiatric or neuropsychological measures was detected. Theta burst stimulation of the cerebellar vermis is safe and well-tolerated, while offering the potential to modulate affect, emotion and cognition in schizophrenia. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique.
    Schizophrenia Research 12/2010; 124(1-3):91-100. DOI:10.1016/j.schres.2010.08.015 · 4.43 Impact Factor
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    Y Chen, R McBain, D Norton, D Ongur
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    ABSTRACT: Previous research has identified several key processes of visual perception and visually guided action that are implicated in schizophrenia. Yet, it is not well understood whether similar or different brain mechanisms mediate the abnormalities in these two processes. To explore this issue, we examined visual and visuomotor processing in schizophrenia, utilizing an illusion known as the Roelofs effect. This illusion refers to the spatial mislocalization of an object within an off-centered frame, with the object appearing to be shifted towards the opposite direction of the frame offset. In this study, localization of the object was measured either by a direct visual response or by an immediate or delayed visuomotor (reaching-to-touch) response. Patients demonstrated significantly greater magnitudes of the Roelofs effect in all response modes, indicating the existence of excessive spatial contextual effects of the frame during the processing of visual and visuomotor information, and when the two types of information are integrated over a delayed visuomotor response condition. These results provide evidence for a hypothesis of improper inhibitory control as a common mechanism underpinning abnormal visual and visuomotor processes in this mental disorder.
    Neuroscience 10/2010; 172:419-26. DOI:10.1016/j.neuroscience.2010.10.039 · 3.33 Impact Factor
  • European Neuropsychopharmacology 09/2009; 19. DOI:10.1016/S0924-977X(09)70793-X · 5.40 Impact Factor
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    ABSTRACT: Oral high-dose glycine administration has been used as an adjuvant treatment for schizophrenia to enhance glutamate neurotransmission and mitigate glutamate system hypofunction thought to contribute to the disorder. Prior studies in schizophrenia subjects documented clinical improvements after 2 weeks of oral glycine administration, suggesting that brain glycine levels are sufficiently elevated to evoke a clinical response within that time frame. However, no human study has reported on brain glycine changes induced by its administration. We utilized a noninvasive proton magnetic resonance spectroscopy ((1)H-MRS) technique termed echo time-averaged (TEAV) (1)H-MRS, which permits noninvasive quantification of brain glycine in vivo, to determine whether 2 weeks of oral glycine administration (peak dose of 0.8 g/kg/day) increased brain glycine/creatine (Gly/Cr) ratios in 11 healthy adult men. In scans obtained 17 h after the last glycine dose, brain (Gly/Cr) ratios were significantly increased. The data indicate that it is possible to measure brain glycine changes with proton spectroscopy. Developing a more comprehensive understanding of human brain glycine dynamics may lead to optimized use of glycine site agonists and glycine transporter inhibitors to treat schizophrenia, and possibly to treat other disorders associated with glutamate system dysfunction.
    Psychiatry Research 07/2009; 173(2):143-9. DOI:10.1016/j.pscychresns.2009.03.004 · 2.68 Impact Factor
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    ABSTRACT: Impaired emotion recognition has been reported in schizophrenia, yet the nature of this impairment is not completely understood. Recognition of facial emotion depends on processing affective and nonaffective facial signals, as well as basic visual attributes. We examined whether and how poor facial emotion recognition in schizophrenia is related to basic visual processing and nonaffective face recognition. Schizophrenia patients (n = 32) and healthy control subjects (n = 29) performed emotion discrimination, identity discrimination, and visual contrast detection tasks, where the emotionality, distinctiveness of identity, or visual contrast was systematically manipulated. Subjects determined which of two presentations in a trial contained the target: the emotional face for emotion discrimination, a specific individual for identity discrimination, and a sinusoidal grating for contrast detection. Patients had significantly higher thresholds (worse performance) than control subjects for discriminating both fearful and happy faces. Furthermore, patients' poor performance in fear discrimination was predicted by performance in visual detection and face identity discrimination. Schizophrenia patients require greater emotional signal strength to discriminate fearful or happy face images from neutral ones. Deficient emotion recognition in schizophrenia does not appear to be determined solely by affective processing but is also linked to the processing of basic visual and facial information.
    Biological psychiatry 04/2009; 65(12):1094-8. DOI:10.1016/j.biopsych.2009.01.026 · 9.47 Impact Factor

Publication Stats

517 Citations
185.26 Total Impact Points

Institutions

  • 2008–2015
    • McLean Hospital
      • Mailman Research Center
      Cambridge, Massachusetts, United States
  • 2008–2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2006–2014
    • Harvard Medical School
      • Department of Psychiatry
      Boston, Massachusetts, United States