Research Team: Douglas Kondo MD, Kristen Fiedler BS, Elliott Bueler
Based on the results of prior clinical trials, the research team is conducting a study to learn if the nutritional supplement CREATINE is an effective adjunctive (i.e. add-on) treatment for SSRI-resistant Major Depression.
Agarawal, N., Port, J. D., Bazzocchi, M., & Renshaw, P. F. (2010). Update on the use of MR for assessment and diagnosis of psychiatric diseases. Radiology, 255(1), 23-41.
The lack of quantitative objective measures of psychiatric diseases such as anxiety and depression is one reason that the causative factors of psychiatric diseases remain obscure. The fact that human behavior is complex and cannot be easily tested in laboratories or reproduced in animal models further complicates our understanding of psychiatric diseases. During the past 3 decades, several magnetic resonance (MR)-based tools such as MR morphometry, diffusion-tensor imaging, functional MR imaging, and MR spectroscopy have yielded findings that provide tangible evidence of the neurobiologic manifestations of psychiatric diseases. In this article, we summarize major MR findings of schizophrenia, bipolar disorder, anxiety disorders, and attention deficit-hyperactivity disorder as examples to illustrate the promise that MR techniques hold for not only revealing the neurobiological underpinnings of psychiatric disorders but also enhancing our understanding of healthy human behavior. However, many radiologists remain skeptical about the diagnostic value of MR in psychiatric disease. Many inconsistent, noncomparable reports in the literature contribute to this skepticism. The aims of this article are to (a) illustrate the most reported MR findings of major psychiatric disorders such as schizophrenia, mood disorders, anxiety disorders, and attention deficit-hyperactivity disorder; (b) inform radiologists of the potential roles of MR imaging in psychiatric imaging research; and (c) discuss several confounding factors in the design and interpretation of MR imaging findings in psychiatry.
Allen MH, Daniel DG, Revicki DA, Canuso CM, Turkoz I, Fu DJ, Alphs L, Ishak KJ, Bartko JJ, Lindemayer JP. (2011).Development and Psychometric Evaluation of a Clinical Global Impression for Schizoaffective Disorder Scale. Innov Clin Neurosci. 2012;9(1):15–24
ABSTRACT: Objective: The Clinical Global Impression for Schizoaffective Disorder scale is a new rating scale adapted from the Clinical Global Impression scale for use in patients with schizoaffective disorder. The psychometric characteristics of the Clinical Global Impression for Schizoaffective Disorder are described. Design: Content validity was assessed using an investigator questionnaire. Inter-rater reliability was determined with 12 sets of videotaped interviews rated independently by two trained individuals. Test-retest reliability was assessed using 30 randomly selected raters from clinical trials who evaluated the same videos on separate occasions two weeks apart. Convergent and divergent validity and effect size were evaluated by comparing scores between the Clinical Global Impression for Schizoaffective Disorder and the Positive and Negative Syndrome Scale, 21-item Hamilton Rating Scale for Depression, and Young Mania Rating Scale scales using pooled patient data from two clinical trials. Clinical Global Impression for Schizoaffective Disorder scores were then linked to corresponding Positive and Negative Syndrome Scale scores. Results: Content validity was strong. Inter-rater agreement was good to excellent for most scales and subscales (intra-class correlation coefficient ³0.50). Test-retest showed good reproducibility, with intraclass correlation coefficients ranging from 0.444 to 0.898. Spearman correlations between Clinical Global Impression for Schizoaffective Disorder domains and corresponding symptom scales were 0.60 or greater, and effect sizes for Clinical Global Impression for Schizoaffective Disorder overall and domain scores were similar to Positive and Negative Syndrome Scale, Young Mania Rating Scale, and 21-item Hamilton Rating Scale for Depression scores. Raters anticipated that the scale might be less effective in distinguishing negative from depressive symptoms, and, in fact, the results here may reflect that clinical reality. Conclusion: Multiple lines of evidence support the reliability and validity of the Clinical Global Impression for Schizoaffective Disorder for studies in schizoaffective disorder.
Bracken, B. K., Jensen, J. E., Prescot, A. P., Cohen, B. M., Renshaw, P. F., & Ongur, D. (2011). Brain metabolite concentrations across cortical regions in healthy adults. Brain Research, 1369, 89-94.
Magnetic resonance spectroscopy (MRS) can provide in vivo information about metabolite levels across multiple brain regions. This study used MRS to examine concentrations of N-acetylaspartate (NAA), a marker of neuronal integrity and function, and choline (Cho), which is related to the amount of cell membrane per unit volume, in anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) in healthy individuals. Data were drawn from two experiments which examined glutamatergic and GABAergic signaling in schizophrenia and bipolar disorder. After controlling for gray matter percentages, NAA/creatine (Cr) was 18% higher in POC than in ACC (p<0.001); Cho/Cr was 46% lower in POC than in ACC (p<0.001). There was an effect of study (p<0.001 for both metabolites), but no region by study interaction (NAA p=0.101, Cho p=0.850). Since NAA is localized to the intracellular space, these data suggest that ACC neuronal compartment is reduced as compared with POC, or that there is a lower concentration of NAA per cell in the ACC than POC, or both. Since elevated Cho suggests more cell membrane per unit volume, reduced NAA in ACC appears to be coupled with increases in overall cell membrane compartment. These findings are consistent with a number of previous studies using proton MRS which found increasing NAA and decreasing Cho moving caudally, and with postmortem anatomical studies which found neurons in more widely spaced bundles in ACC when compared to parietal and occipital cortices. MRS may be a useful tool for studying physical properties of the living human brain.
DelMastro, K., Hellem, T., Kim, N., Kondo, D., Sung, Y. H., & Renshaw, P. F. (2011). Incidence of major depressive episode correlates with elevation of substate region of residence. Journal of Affective Disorders, 129(1-3), 376-379.
BACKGROUND: Major depressive disorder (MDD) is a common disorder that is often associated with suicide. We have recently suggested that elevation may play a role in regional variations in rates of suicide. We hypothesize that there is also a significant correlation between incidence of MDD and elevation of residence. METHODS: The substate estimates from the 2004 to 2006 National Surveys on Drug Use and Health (NSDUH) report from SAMHSA was used to extract substate level data related to percentages of people 18 years or older who experienced serious psychological distress or a major depressive episode in the past year. Mean elevation of each substate region was calculated by averaging the weighted elevations of its relevant counties. Average elevation for United States counties was calculated using the Shuttle Radar Topography Mission (SRTM) elevation dataset. Pearson correlation coefficients were computed to investigate the association between average substate elevation and rate of serious psychological distress or major depressive episode. RESULTS: There was a significant correlation between percentage of people experiencing serious psychological distress in the past year in a substate region and that substate region's mean elevation (r=0.18; p=0.0005), as well as between the percentage of people having at least one major depressive episode in the past year in a substate region and that substate region's mean elevation (r=0.27; p0.0001). CONCLUSIONS: Elevation appears to be a significant risk factor for MDD. Further studies are indicated to determine whether the increased incidence of depression with increased elevation may be due to the hypoxic effects on subjects with MDD.
Dennehy, E. B., Marangell, L. B., Allen, M. H., Chessick, C., Wisniewski, S. R., & Thase, M. E. (2011). Suicide and suicide attempts in the Systematic Treatment Enhancement Program for bipolar disorder (STEP-BD). 133, 423-427.
BACKGROUND: The current report describes individuals with bipolar disorder who attempted or completed suicide while participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. METHODS: Baseline and course features of individuals with suicide events are described. RESULTS: Among the 4360 people with bipolar disorder enrolled, 182 individuals made 270 prospectively observed suicidal acts, including 8 completed suicides. This represents a suicide rate of .014 per 100 person years in STEP-BD, which included frequent clinical visits, evidence based care, and standardized assessment at each patient contact. Approximately 1/3 of those who attempted suicide had more than one attempt during study participation. Those who completed suicide tended to do so early in study participation, and half of them did so on their first attempt. LIMITATIONS: While this study is limited to description of individuals and precipitants of completed suicides and attempts in STEP-BD, further analyses are planned to explore risk factors and potential interventions for prevention of suicidal acts in persons with bipolar disorder. CONCLUSIONS: Persons with bipolar disorder are at high risk for suicide. Overall rates of suicide events in STEP-BD were lower than expected, suggesting that the combination of frequent clinical visits (i.e., access to care), standardized assessment, and evidence-based treatment were helpful in this population.
Freedman, R., & Goldowitz, D. (2010). Studies on the hippocampal formation: From basic development to clinical applications: Studies on schizophrenia. Progress in Neurobiology, 90(2), 263-275.
The hippocampal formation plays a critical role in cognitive function. The developmental events that shape the hippocampal formation are continuing to be elucidated and their implications for brain function are emerging as well as applying those advances to interventions that have important possibilities for the treatment of brain dysfunction. The story told in this chapter is about the use of the in oculo transplant method to illuminate intrinsic and extrinsic features that underlie the development of the dentate gyrus and adjacent hippocampus and the role of one molecule in the hippocampus and schizophrenia. Schizophrenia, originally conceptualized as a dysfunction in dopaminergic neurotransmission, is now known to involve multiple neuronal systems. Dysfunction of hippocampal neurons is emerging as one of its signature pathological features. Basic insights into the development and function of hippocampal interneurons form the basis of a new treatment initiative for this illness. Evidence for the role of the alpha 7-nicotinic acetylcholine receptor in the development and function of these neurons in rodents has led to human trials of nicotinic agonists for cognitive dysfunction in schizophrenia and the possibility of improving hippocampal development in children at risk for schizophrenia by perinatal supplementation with choline, which can act as an alpha 7-nicotinic acetylcholine receptor agonist.
Hallahan, B., Newell, J., Soares, J. C., Brambilla, P. Strakowski, S. M., Fleck, D. E., Kieseppa, T., Altshuler, L. L., Fornito, A., Malhi, G. S., McIntosh, A. M., Yurgelun-Todd, D. A., Labar, K. S., Sharma, V., MacQueen, G. M., Murray, R. M., & McDonald, C. (2011). Structural magnetic resonance imaging in bipolar disorder: An international collaborative mega-analysis of individual adult patient data. Biological Psychiatry, 69(4), 326-335.
BACKGROUND: There is substantial inconsistency in results of brain structural magnetic resonance imaging studies in adult bipolar disorder. This is likely consequent upon limited statistical power of studies together with their clinical and methodological heterogeneity. The current study was undertaken to perform an international collaborative mega-analysis of regional volumetric measurements of individual patient and healthy subject data, to optimize statistical power, detect case-control differences, assess the association of psychotropic medication usage with brain structural variation, and detect other possible sources of heterogeneity. METHODS: Eleven international research groups contributed published and unpublished data on 321 individuals with bipolar disorder I and 442 healthy subjects. We used linear mixed effects regression models to evaluate differences in brain structure between patient groups. RESULTS: Individuals with bipolar disorder had increased right lateral ventricular, left temporal lobe, and right putamen volumes. Bipolar patients taking lithium displayed significantly increased hippocampal and amygdala volume compared with patients not treated with lithium and healthy comparison subjects. Cerebral volume reduction was significantly associated with illness duration in bipolar individuals. CONCLUSIONS: The application of mega-analysis to bipolar disorder imaging identified lithium use and illness duration as substantial and consistent sources of heterogeneity, with lithium use associated with regionally specific increased brain volume.
Han DH, Renshaw PF. Bupropion in the treatment of problematic online game play in patients with major depressive disorder. J Psychopharmacol. 2011 Mar 29. [Epub ahead of print]
As one of the problematic behaviors in patients with major depressive disorder (MDD), excessive online game play (EOP) has been reported in a number of recent studies. Bupropion has been evaluated as a potential treatment for MDD and substance dependence. We hypothesized that bupropion treatment would reduce the severity of EOP as well as depressive symptoms. Fifty male subjects with comorbid EOP and MDD were randomly assigned to bupropion + education for internet use (EDU) or placebo + EDU groups. The current study consisted in a 12-week, prospective, randomized, double-blind clinical trial, including an eight-week active treatment phase and a four-week post treatment follow-up period. During the active treatment period, Young Internet Addiction Scale (YIAS) scores and the mean time of online game playing in the bupropion group were greatly reduced compared with those of the placebo group. The Beck Depression Inventory (BDI) scores in the bupropion group were also greatly reduced compared with those of the placebo group. During the four-week post-treatment follow-up period, bupropion-associated reductions in online game play persisted, while depressive symptoms recurred. Conclusively, bupropion may improve depressive mood as well as reduce the severity of EOP in patients with comorbid MDD and online game addiction.
Hart T, Hoffman JM, Pretz C, Kennedy R, Clark AN, Brenner LA. (2012). A Longitudinal Study of Major and Minor Depression Following Traumatic Brain Injury. Archives of Physical Medicine, 93, 1343-9.
OBJECTIVE: To examine patterns of change and factors associated with change in depression, both major (major depressive disorder [MDD]) and minor, between 1 and 2 years after traumatic brain injury (TBI). DESIGN: Observational prospective longitudinal study. SETTING: Inpatient rehabilitation centers, with 1- and 2-year follow-up conducted primarily by telephone. PARTICIPANTS: Persons with TBI (N=1089) enrolled in the Traumatic Brain Injury Model Systems database, followed at 1 and 2 years postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Patient Health Questionnaire-9. RESULTS: Among participants not depressed at 1 year, close to three fourths remained so at 2-year follow-up. However, 26% developed MDD or minor depression between the first and second years postinjury. Over half of participants with MDD at year 1 also reported MDD the following year, with another 22% reporting minor depression; thus three fourths of those with MDD at year 1 experienced clinically significant symptoms at year 2. Almost one third of those with minor depression at year 1 traversed to MDD at year 2. Polytomous logistic regression confirmed that worse depression at year 1 was associated with higher odds of depression a year later. For those without depression at year 1, symptom worsening over time was related to year 2 problematic substance use and lower FIM motor and cognitive scores. For those with depression at year 1, worsening was associated with lower cognitive FIM, poor social support, and preinjury mental health issues including substance abuse. CONCLUSIONS: Major and minor depression exist on a continuum along which individuals with TBI may traverse over time. Predictors of change differ according to symptom onset. Results highlight importance of long-term monitoring for depression, treating minor as well as major depression, and developing interventions for comorbid depression and substance abuse.
Hart, T., Brenner, L. A., Clark, A. N., Bogner, J. A., Novack, T. A., Chervoneva, I. et al. (2011). Major and minor depression following traumatic brain injury. Archives of Physical Medicine, 92, 1211-1219.
OBJECTIVE: To examine minor as well as major depression at 1 year posttraumatic brain injury (TBI), with particular attention to the contribution of depression severity to levels of societal participation. DESIGN: Observational prospective study with a 2-wave longitudinal component. SETTING: Inpatient rehabilitation centers, with 1-year follow up conducted primarily by telephone. PARTICIPANTS: Persons with TBI (N=1570) enrolled in the TBI Model System database and followed up at 1-year postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FIM, Patient Health Questionnaire-9, Participation Assessment with Recombined Tools-Objective, Glasgow Outcome Scale-Extended, and the Satisfaction With Life Scale. RESULTS: Twenty-two percent of the sample reported minor depression, and 26% reported major depression at 1-year post-TBI. Both levels of depression were associated with sex (women), age (younger), preinjury mental health treatment and substance abuse, and cause of injury (intentional). There was a monotonic dose-response relationship between severity of depression and all 1-year outcomes studied, including level of cognitive and physical disability, global outcome, and satisfaction with life. With other predictors controlled, depression severity remained significantly associated with the level of societal participation at 1-year post-TBI. CONCLUSIONS: Minor depression may be as common as major depression after TBI and should be taken seriously for its association to negative outcomes related to participation and quality of life. Findings suggest that, as in other populations, minor and major depression are not separate entities, but exist on a continuum. Further research should determine whether people with TBI traverse between the 2 diagnoses as in other patient groups.
Hooley, J.M., Gruber, S.A., Parker, H.A., Guillamot, J., Rogowska, J., & Yurgelun-Todd, D.A. (2010). Neural Processing of Emotional Overinvolvement in Borderline Personality Disorder. The Journal of Clinical Psychiatry.
OBJECTIVE: Patients with borderline personality disorder (BPD) fare better clinically if their families are rated as being high in emotional overinvolvement, which is characterized by marked emotionality, anxious concern, and protective behavior. This is not true of patients with disorders such as schizophrenia or major depression. We used functional magnetic resonance imaging methods to explore the link between emotional overinvolvement (EOI) and better clinical outcome in BPD. Specifically, we tested the hypothesis that, unlike healthy controls or people with other psychiatric problems, people with BPD process EOI as an approach-related stimulus. METHOD: Participants with BPD (n = 13) and dysthymia (n = 10) (DSM-IV criteria for both) and healthy controls (n = 11) were imaged using a high field strength (3T) scanner while they listened to a standardized auditory stimulus consisting of either 4 neutral or 4 EOI comments. Participants also rated their mood before and after exposure to the comments. RESULTS: All participants reported increased negative mood after hearing EOI and rated the EOI comments as negative stimuli. However, after subtracting activation to neutral comments, participants with BPD showed higher activation in left prefrontal regions during EOI compared to the other groups. Increased left prefrontal activation during EOI was also correlated with clinical measures indicative of borderline pathology. Participants with dysthymia showed increased amygdala activation during EOI. This was not true for the healthy controls or participants with BPD. CONCLUSIONS: For people with BPD, EOI may be activating neural circuitry implicated in the processing of approach-related stimuli. Increased left prefrontal activation to EOI may be a vulnerability marker for BPD. These findings may also help explain why BPD patients do better clinically in high EOI family environments.
Kondo, D. G., Hellem, T. L., Sung, Y. H., Kim, N., Jeong, E. K., Delmastro, K. K., Shi, X., & Renshaw, P.F. (2011). Review: Magnetic resonance spectroscopy studies of pediatric major depressive disorder. Depression Research & Treatment, Epub 2010 Oct 4.
Introduction. This paper focuses on the application of Magnetic Resonance Spectroscopy (MRS) to the study of Major Depressive Disorder (MDD) in children and adolescents. Method. A literature search using the National Institutes of Health's PubMed database was conducted to identify indexed peer-reviewed MRS studies in pediatric patients with MDD. Results. The literature search yielded 18 articles reporting original MRS data in pediatric MDD. Neurochemical alterations in Choline, Glutamate, and N-Acetyl Aspartate are associated with pediatric MDD, suggesting pathophysiologic continuity with adult MDD. Conclusions. The MRS literature in pediatric MDD is modest but growing. In studies that are methodologically comparable, the results have been consistent. Because it offers a noninvasive and repeatable measurement of relevant in vivo brain chemistry, MRS has the potential to provide insights into the pathophysiology of MDD as well as the mediators and moderators of treatment response.
Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, Spyker DA, Kehne JH, Cassella JV. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. 2012 Feb;14(1):31-40.
Lopez-Larson, M. P., Breeze, J. A., Kennedy, D. N., Hodge, S. M., Tang, L., Moore, C. et al. (2010). Age-related changes in the corpus callosum in early-onset bipolar disorder assessed using volumetric and cross-sectional measurements. Brain Imaging and Behavior, 4(3-4), 220-231.
Corpus callosum (CC) area abnormalities have been reported in magnetic resonance imaging (MRI) studies of adults and youths with bipolar disorder (BPD), suggesting interhemispheric communication may be abnormal in BPD and may be present early in the course of illness and affect normal neuromaturation of this structure throughout the lifecycle. Neuroimaging scans from 44 youths with DSM-IV BPD and 22 healthy controls (HC) were analyzed using cross-sectional area measurements and a novel method of volumetric parcellation. Univariate analyses of variance were conducted on CC subregions using both volume and traditional area measurements. Youths with BPD had smaller middle and posterior callosal regions, and reduced typical age-related increases in CC size. The cross-sectional area and novel volumetric methodologies resulted in similar findings. Future longitudinal assessments of CC development would track the evolution of callosal abnormalities in youths with BPD and allow exploration of the functional significance of these findings.
Lyoo IK, Yoon S, Kim TS, Hwang J, Kim JE, Won W, Bae S, Renshaw PF. A Randomized, Double-Blind Placebo-Controlled Trial of Oral Creatine Monohydrate Augmentation for Enhanced Response to a Selective Serotonin Reuptake Inhibitor in Women With Major Depressive Disorder. Am J Psychiatry. 2012 Aug 1. doi: 10.1176/appi.ajp.2012.12010009. [Epub ahead of print]
OBJECTIVE Antidepressants targeting monoaminergic neurotransmitter systems, despite their immediate effects at the synaptic level, usually require several weeks of administration to achieve clinical efficacy. The authors propose a strategy of adding creatine monohydrate (creatine) to a selective serotonin reuptake inhibitor (SSRI) in the treatment of patients with major depressive disorder. Such augmentation may lead to a more rapid onset of antidepressant effects and a greater treatment response, potentially by restoring brain bioenergetics at the cellular level. METHOD Fifty-two women with major depressive disorder were enrolled in an 8-week double-blind placebo-controlled clinical trial and randomly assigned to receive escitalopram in addition to either creatine (5 g/day, N=25) or placebo (N=27). Efficacy was primarily assessed by changes in the Hamilton Depression Rating Scale (HAM-D) score. RESULTS In comparison to the placebo augmentation group, patients receiving creatine augmentation showed significantly greater improvements in HAM-D score, as early as week 2 of treatment. This differential improvement favoring creatine was maintained at weeks 4 and 8. There were no differences between treatment groups in the proportion of patients who discontinued treatment prematurely (creatine: N=8, 32.0%; placebo: N=5, 18.5%) or in the overall frequency of all reported adverse events (creatine: 36 events; placebo: 45 events). CONCLUSIONS The current study suggests that creatine augmentation of SSRI treatment may be a promising therapeutic approach that exhibits more rapid and efficacious responses in women with major depressive disorder.
Lyoo, I. K., Dager, S. R., Kim, J. E., Yoon, S. J., Friedman, S. D., Dunner, D. L., & Renshaw, P.F. (2010). Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: A longitudinal brain imaging study. Neuropsychopharmacology,35(8), 1743-1750.
Preclinical studies suggest that lithium may exert neurotrophic effects that counteract pathological processes in the brain of patients with bipolar disorder (BD). To describe and compare the course and magnitude of gray matter volume changes in patients with BD who are treated with lithium or valproic acid (VPA) compared to healthy comparison subjects, and to assess clinical relationships to gray matter volume changes induced by lithium in patients with BD, we conducted longitudinal brain imaging and clinical evaluations of treatment response in 22 mood-stabilizing and antipsychotic medications-naive patients with BD who were randomly assigned to either lithium or VPA treatment after baseline assessment. Fourteen healthy comparison subjects did not take any psychotropic medications during follow-up. Longitudinal data analyses of 93 serial magnetic resonance images revealed lithium-induced increases in gray matter volume, which peaked at week 10-12 and were maintained through 16 weeks of treatment. This increase was associated with positive clinical response. In contrast, VPA-treated patients with BD or healthy comparison subjects did not show gray matter volume changes over time. Results suggest that lithium induces sustained increases in cerebral gray matter volume in patients with BD and that these changes are related to the therapeutic efficacy of lithium.
Olincy, A., Braff, D. L., Adler, L. E., Cadenhead, K. S., Calkins, M. E., Dobie, D. J. et al. (Freedman, R.) (2010). Inhibition of the P50 cerebral evoked response to repeated auditory stimuli. Results from the Consortium on Genetics of Schizophrenia. Schizophrenia Research; June; 119(1-3), 175-1782.
Inhibition of the P50 evoked electroencephalographic response to the second of paired auditory stimuli has been frequently examined as a neurophysiological deficit in schizophrenia. The Consortium on the Genetics of Schizophrenia (COGS), a 7-site study funded by the National Institute of Mental Health, examined this endophenotype in recordings from 181 probands with schizophrenia, 429 of their first degree relatives, and 333 community comparison control subjects. Most probands were treated with second generation antipsychotic medications. Highly significant differences in P50 inhibition, measured as either the ratio of amplitudes or their difference in response to the two stimuli, were found between the probands and the community comparison sample. There were no differences between the COGS sites for these findings. For the ratio parameter, an admixture analysis found that nearly 40% of the relatives demonstrated deficiencies in P50 inhibition that are comparable to the deficit found in the probands. These results indicate that P50 auditory evoked potentials can be recorded across multiple sites and reliably demonstrate a physiological abnormality in schizophrenia. The appearance of the physiological abnormality in a substantial proportion of clinically unaffected first degree relatives is consistent with the hypothesis that deficits in cerebral inhibition are a familial neurobiological risk factor for the illness.
Ongür, D., Lundy, M., Greenhouse, I., Shinn, A. K., Menon, V., Cohen, B. M., & Renshaw, P.F. (2010). Default mode network abnormalities in bipolar disorder and schizophrenia. Psychiatry Research,183(1), 59-68.
The default-mode network (DMN) consists of a set of brain areas preferentially activated during internally focused tasks. We used functional magnetic resonance imaging (fMRI) to study the DMN in bipolar mania and acute schizophrenia. Participants comprised 17 patients with bipolar disorder (BD), 14 patients with schizophrenia (SZ) and 15 normal controls (NC), who underwent 10-min resting fMRI scans. The DMN was extracted using independent component analysis and template-matching; spatial extent and timecourse were examined. Both patient groups showed reduced DMN connectivity in the medial prefrontal cortex (mPFC) (BD: x=-2, y=54, z=-12; SZ: x=-2, y=22, z=18). BD subjects showed abnormal recruitment of parietal cortex (correlated with mania severity) while SZ subjects showed greater recruitment of the frontopolar cortex/basal ganglia. Both groups had significantly higher frequency fluctuations than controls. We found ventral mPFC abnormalities in BD and dorsal mPFC abnormalities in SZ. The higher frequency of BOLD signal oscillations observed in patients suggests abnormal functional organization of circuits in both disorders. Further studies are needed to determine how these abnormalities are related to specific symptoms of each condition.
Ongur, D., Prescot, A. P., McCarthy, J., Cohen, B. M., & Renshaw, P.F. (2010). Elevated gamma-aminobutyric acid levels in chronic schizophrenia. Biological Psychiatry, 68(7), 667-670.
BACKGROUND: Despite widely replicated abnormalities of gamma-aminobutyric acid (GABA) neurons in schizophrenia postmortem, few studies have measured tissue GABA levels in vivo. We used proton magnetic resonance spectroscopy to measure tissue GABA levels in participants with schizophrenia and healthy control subjects in the anterior cingulate cortex and parieto-occipital cortex. METHODS: Twenty-one schizophrenia participants effectively treated on a stable medication regimen (mean age 39.0, 14 male) and 19 healthy control subjects (mean age 36.3, 12 male) underwent a proton magnetic resonance spectroscopy scan using GABA-selective editing at 4 Tesla after providing informed consent. Data were collected from two 16.7-mL voxels and analyzed using LCModel. RESULTS: We found elevations in GABA/creatine in the schizophrenia group compared with control subjects [F(1,65) = 4.149, p = .046] in both brain areas (15.5% elevation in anterior cingulate cortex, 11.9% in parieto-occipital cortex). We also found a positive correlation between GABA/creatine and glutamate/creatine, which was not accounted for by % GM or brain region. CONCLUSIONS: We found elevated GABA/creatinine in participants with chronically treated schizophrenia. Postmortem studies report evidence for dysfunctional GABAergic neurotransmission in schizophrenia. Elevated GABA levels, whether primary to illness or compensatory to another process, may be associated with dysfunctional GABAergic neurotransmission in chronic schizophrenia.
Osman, A., Bagge, C. L., Freedenthal, S., Gutierrez, P.M., & Emmerich, A. (2011). Development and evaluation of the social anxiety and depression life interference-24 (SADLI-24) inventory. Journal of Clinical Psychology, 67(1), 82-98.
We describe the development of a new self-report instrument, the Social Anxiety and Depression Life Interference-24 (SADLI-24) inventory. We initially retained 30 content specific items for the instrument (Study 1). In Study 2 (N = 438), we established a 2-factor solution, Social Anxiety Life Interference-12 (SALI-12) and Depression Life Interference-12 (DLI-12). We also examined estimates of known-groups and concurrent validity. Confirmatory factor analysis in Study 3 (N = 430) provided support for the oblique two-factor structure. In Study 4 (N = 179), we provided additional support for estimates of known-groups validity. In Study 5 (N = 63), we evaluated estimates of test-retest reliability. Both SADLI-24 scale scores showed good estimates of internal consistency.
Osman, A., Freedenthal, S., Fang, Q., Willis, J., Norizuki, T., & Gutierrez, P.M. (2011). The UTSA Future Disposition Inventory: Further analyses of reliability, validity, and potential correlates in non-clinical samples. In A. M. Columbus (Ed.) Advances in psychology research. Hauppauge, NY: Nova Science Publishers, Inc.
Osman, A., Freedenthal, S., Gutierrez, P.M., Wong, J. L., Emmerich, A., & Lozano, G. (2011). The Anxiety Depression Distress Inventory-27 (ADDI-27): A short version of the Mood and Anxiety Symptom Questionnaire-90. Journal of Clinical Psychology, 67(6), 591-608.
The authors conducted three studies to construct and examine the psychometric properties of a 27-item version of the Mood and Anxiety Symptom Questionnaire-90 (MASQ-90; Watson & Clark, 1991a). The Anxiety Depression Distress Inventory-27 (ADDI-27) contains three empirically derived scales: Positive Affect, Somatic Anxiety, and General Distress, which are relevant dimensions of the tripartite model of affect. Each scale is composed of nine items, and the estimate of scale reliability for each scale score was ≥ .80 across the three studies. Results of exploratory and confirmatory factor analyses provided adequate support for a 3-factor model. Additional estimates of concurrent validity documented the ADDI-27 scales' convergent and discriminant validity. We also identified three construct relevant correlates for each scale score. Overall, the ADDI-27 appears to be a content valid, reliable, and multidimensional measure of the tripartite model of affect.
Osman, A., Gutierrez, P.M., Bagge, C. L., Fang, Q., & Emmerich, A. (2010). Reynolds adolescent depression scale-second edition: A reliable and useful instrument. Journal of Clinical Psychology, 66(12), 1324-1345.
The authors conducted two studies to address issues of the dimensionality, scale reliability, and psychometric properties of scores on the Reynolds Adolescent Depression Scale-Second Edition (RADS-2; Reynolds, 2002) in samples of adolescent psychiatric inpatients. In Study 1 (N=262), they used bifactor analysis to further evaluate the general and specific components of the RADS-2. In Study 2 (N=196), they used confirmatory factor analysis to evaluate the fit of a 1-factor model, the original 4-factor model, a second-order model, and a bifactor model to a new sample data. In both studies, the total RADS-2 and content-specific subscale scores showed acceptable estimates of reliability (i.e., scale reliability estimates >.80). Estimates of concurrent validity were also examined. Scores of the RADS-2 total and content-specific subscale scores were useful in differentiating between the responses of youth with mood disorder diagnoses and those with other primary psychiatric disorder diagnoses. The authors also conducted correlation analyses to identify potential correlates for the total RADS-2 scale and the proposed subscale scores.
Osman, A., Gutierrez, P.M., Barrios, F., Wong, J. L., Freedenthal, S., & Lozano, G. (2010). Development and Initial Psychometric Properties of the UTSA Future Disposition Inventory. Journal of Clinical Psychology, 66(4), 1-20.
We describe the development and initial psychometric properties of a 24-item self-report measure, the University of Texas at San Antonio Future Disposition Inventory (UTSA FDI). This instrument is designed to evaluate future related thoughts and feelings that are associated with suicide-related risk behaviors: positive focus, suicide orientation, and negative focus. The items were generated by clinical and nonclinical samples. The structure of the instrument was defined in a sample of 350 university undergraduate students (Study 1). Using CFA, we confirmed the fit of the 3-factor solution in an independent sample of college age students (n=452; Study 2). Scale reliability estimates were good (all rho's>or=.80) in both studies. Known-groups validation analyses showed that scores on each scale were useful in differentiating the responses of the study groups. Correlates for the scales were identified when scores on measures of suicide-related risk and general psychological symptoms were included as validation self-report instruments.
Osman, A., Gutierrez, P.M., Schweers, R., Fang, Q., Holguin-Mills, R. L., & Cashin, M. (2010). Psychometric Evaluation of the Body Investment Scale for Use with Adolescents. Journal of Clinical Psychology, 66(3), 259-276.
We conducted two studies to examine the psychometric properties of the Body Investment Scale (BIS; Orbach & Mikulincer, 1998) in U.S. adolescent samples. The BIS was designed to assess bodily experiences that are associated with suicide-related behaviors. In Study 1, confirmatory factor analysis (CFA) with data from a combined sample of 204 high school adolescents (83 boys, 121 girls) and 197 psychiatric inpatient (101 boys, 96 girls) adolescents provided moderate support for the oblique four-factor solution: Body Feelings (rho=.86, 95% CI=.83-.89), Body Touch (rho=.71, 95% CI=.65-.76), Body Care (rho=.78, 95% CI=.71-.81), and Body Protection (rho=.78, 95% CI=.73-.82); robust comparative fit index=.88 and the robust Tucker Lewis Index=.83. The second-order factor model also provided moderate fit to the data. In Study 2, results of the CFA with data from adolescent psychiatric inpatients (N=205; 101 boys, 104 girls) provided additional support for the four-factor solution. In addition, results of the receiver operating characteristic and logistic regression analyses showed that scores on the Body Feelings and Body Protection scales were most useful in differentiating the responses of suicidal and nonsuicidal adolescents, all Cohen's d values >.30. The study also examined associations between scores on the BIS scales and the validation self-report measures of hopelessness, suicide-related behavior, and reasons for living.
Osman, A., Gutierrez, P.M., Smith, K., Fang, Q., Lozano, G., & Devine, A. (2010). The Anxiety Sensitivity Index-3: Analyses of Dimensions, Reliability Estimates, and Correlates in Nonclinical Samples. Journal of Personality Assessment, 92(1), 45-52.
We investigated the factor structure, reliability estimates, and correlates of the Anxiety Sensitivity Index-3 (ASI-3; Taylor et al., 2007) in 2 studies. We established a bifactor model in Study 1 as an alternative representation of the structure of the ASI-3. Analyses of gender differences on the total ASI-3 and subscale scores were not statistically significant (Study 1, N = 462). In Study 2 (N = 293), results of a series of confirmatory factor analyses provided stronger support for the fit of the bifactor model compared with 2 alternative models. Estimates of scale reliability were adequate (all rho values > or = .80) and not "p" (as in italic p for significance). in the 2 studies. In addition, using simultaneous regression analyses, we found anxiety-specific correlates for the total ASI-3 and subscale scores to include responses on self-report measures of interpersonal sensitivity, obsessive-compulsive anxiety, paranoid ideation, and phobic anxiety.
Osman, A., Gutierrez, P.M., Wong, J. L., Freedenthal, S., Bagge, C. L., & Smith, K. D. (2010). Development and Psychometric Evaluation of the Suicide Anger Expression Inventory--28. Journal of Psychopathology and Behavior Assessment, 32, 595-608.
Osman A, Wong JL, Bagge CL, Freedenthal S, Gutierrez PM, Lozano G. The Depression Anxiety Stress Scales-21 (DASS-21): Further Examination of Dimensions, Scale Reliability, and Correlates. J Clin Psychol. 2012 Dec;68(12):1322-38.
OBJECTIVES: We conducted two studies to examine the dimensions, internal consistency reliability estimates, and potential correlates of the Depression Anxiety Stress Scales-21 (DASS-21; Lovibond & Lovibond, 1995). METHOD: Participants in Study 1 included 887 undergraduate students (363 men and 524 women, aged 18 to 35 years; mean [M] age = 19.46, standard deviation [SD] = 2.17) recruited from two public universities to assess the specificity of the individual DASS-21 items and to evaluate estimates of internal consistency reliability. Participants in a follow-up study (Study 2) included 410 students (168 men and 242 women, aged 18 to 47 years; M age = 19.65, SD = 2.88) recruited from the same universities to further assess factorial validity and to evaluate potential correlates of the original DASS-21 total and scale scores. RESULTS: Item bifactor and confirmatory factor analyses revealed that a general factor accounted for the greatest proportion of common variance in the DASS-21 item scores (Study 1). In Study 2, the fit statistics showed good fit for the bifactor model. In addition, the DASS-21 total scale score correlated more highly with scores on a measure of mixed depression and anxiety than with scores on the proposed specific scales of depression or anxiety. Coefficient omega estimates for the DASS-21 scale scores were good. CONCLUSIONS: Further investigations of the bifactor structure and psychometric properties of the DASS-21, specifically its incremental and discriminant validity, using known clinical groups are needed.
Ross, R. G., Stevens, K. E., Proctor, W. R., Leonard, S., Kisley, M. A., Hunter, S. K., et al. (Freedman, R.) (2010). Research review: Cholinergic mechanisms, early brain development, and risk for schizophrenia. Child Psychology and Psychiatry, 51, 535-549.
The onset of diagnostic symptomology for neuropsychiatric diseases is often the end result of a decades-long process of aberrant brain development. Identification of novel treatment strategies aimed at normalizing early brain development and preventing mental illness should be a major therapeutic goal. However, there are few models for how this goal might be achieved. This review uses the development of a psychophysiological correlate of attentional deficits in schizophrenia to propose a developmental model with translational primary prevention implications. Review of genetic and neurobiological studies suggests that an early interaction between alpha7 nicotinic receptor density and choline availability may contribute to the development of schizophrenia-associated attentional deficits. Therapeutic implications, including perinatal dietary choline supplementation, are discussed.
Sanders, A. R., Levinson, D. F., Duan J., Dennis, J. M., Li, R., et al. (Freedman, R.) (2010). An internet-based NIMH control sample for genetic studies: Self report of mental illness. American Journal of Psychiatry, 167(7), 854-865.
OBJECTIVE: The Molecular Genetics of Schizophrenia (MGS2) project recruited an adult control sample of non-Hispanic European-ancestry (N=3,364) and African American (N=1,301) subjects. METHOD: Subjects gave consent to deposit phenotypic data and blood samples into a repository for general research use, with full anonymization of the sample. The authors compared the control sample with population census data for demographic data and with previous population surveys for anthropometrics and prevalences of psychiatric disorders as estimated by an Internet-administered questionnaire. RESULTS: The full MGS2 control sample includes 4,665 subjects (European-ancestry: N=3,364; African American: N=1,301), of whom 3,626 were included in the MGS2 genome-wide association study (GWAS). The sample is generally demographically representative of the U.S. population, except for being older and more female, educated, and affluent, although all strata are represented. Self-reported ancestry was consistent with genotypic and census data. Lifetime prevalences for depressive, anxiety, and substance use diagnoses were higher than in previous population-based surveys, probably due to use of an abbreviated self-report instrument. However, patterns such as sex ratios, comorbidity, and demographic associations were consistent with previous reports. DNA quality for the Internet collected/evaluated control sample was comparable to that of the face-to-face case sample. CONCLUSIONS: The Internet-based methods facilitated the rapid collection of large and anonymized non-Hispanic European-ancestry and African American control samples that have been validated as being generally representative for many aspects of demography, ancestry, and morbidity. Utilization of clinical screening data shared with the scientific community may permit investigators to select appropriate controls for some studies.
Tregellas, J. R., Olincy, A., Johnson, L., Tanabe, J., Shatti, S., Martin, L. F., Singel, D., Du, Y. P., Soti, F., Kern, W. R., & Freedman, R. (2010). Functional magnetic resonance imaging of effects of a nicotinic agonist in schizophrenia. Neuropsychopharmacology, 35(4), 938-942.
3-(2,4-Dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at alpha7-nicotinic acetylcholine receptors and is now in early clinical development for treatment of deficits in neurocognition and sensory gating in schizophrenia. During its initial phase 2 test, functional magnetic resonance imaging (fMRI) studies were conducted to determine whether the drug had its intended effect on hippocampal inhibitory interneurons. Increased hemodynamic activity in the hippocampus in schizophrenia is found during many tasks, including smooth pursuit eye movements, and may reflect inhibitory dysfunction. Placebo and two doses of drug were administered in a random, double-blind crossover design. After the morning drug/placebo ingestion, subjects underwent fMRI while performing a smooth pursuit eye movement task. Data were analyzed from 16 nonsmoking patients, including 7 women and 9 men. The 150-mg dose of DMXB-A, compared with placebo, diminished the activity of the hippocampus during pursuit eye movements, but the 75-mg dose was ineffective. The effect at the 150-mg dose was negatively correlated with plasma drug levels. The findings are consistent with the previously established function of alpha7-nicotinic receptors on inhibitory interneurons in the hippocampus and with genetic evidence for deficits in these receptors in schizophrenia. Imaging of drug response is useful in planning future clinical tests of this compound and other nicotinic agonists for schizophrenia.
Waldo, M. C., Woodward, L., & Adler, L. E. (2010). Varenicline and p50 auditory gating in medicated schizophrenic patients: A pilot study. Psychiatry Research.
Most schizophrenic patients have a deficit in auditory sensory gating that appears to be mediated by the alpha-7 nicotinic receptor. This pilot study examines the effects of varenicline, an alpha-7 agonist, on the P50 auditory evoked potential in six schizophrenic patients. The study was canceled because of concerning side effects consistent with those reported by the FDA. However, in this small group of subjects, varenicline did not consistently enhance P50 auditory gating.
Yildiz, A., Gokmen, N., Kucukguctu, S., Yurt, A., Olson, D., Rouse, E. D., & Renshaw, P.F. (2010). In vivo proton magnetic resonance spectroscopic examination of benzodiazepine action in humans. Psychiatry Research, 184(3), 162-170.
In an examination of the effect of benzodiazepines on brain chemistry, 44 healthy controls underwent a short echo-time proton magnetic resonance spectroscopy ((1)H MRS) session after induced sedation with intravenous midazolam (0.03mg/kg) plus fentanyl (2μg/kg). The regions of interest were the anterior cingulate cortex, right basal ganglia, right frontal lobe, and right hippocampus. Twenty-five of these subjects underwent the second (1)H MRS session while awake. The measured (1)H MRS metabolites included N-acetyl-aspartate, creatine-containing compounds (PCr+Cr), choline-containing compounds, myo-inositol, and glutamate plus glutamine, which were quantified both as absolute values and metabolite/PCr+Cr ratios. The results were analyzed using independent group t tests and repeated measures analysis of variance (ANOVA, with alpha values set at 0.025 to minimize the risk of false-positive findings arising from multiple comparisons. No significant difference between subjects under midazolam plus fentanyl induced sedation and awake could be detected with unpaired analyses. Paired comparisons by ANOVA with repeated measures found that neither drug (midazolam plus fentanyl) nor the drug by time (interval between two scan times) interaction had a significant effect on the quantified metabolites. These findings encourage utilization of benzodiazepine-induced brief sedation during in vivo (1)H MRS experiments of the brain, and may help with elucidation of state-dependent neurochemical alterations during the course of bipolar and schizoaffective disorders.
Osman A, Wong JL, Bagge CL, Freedenthal S, 
