[Show abstract][Hide abstract] ABSTRACT: Both nonaffective and affective psychoses are associated with deficits in social functioning across the course of the illness. However, it is not clear how social functioning varies among diagnostic groups as a function of age. The current study examined the relationship between social functioning and age in schizophrenia (SZ), schizoaffective disorder (SZA), and psychotic bipolar disorder (PBD). We found that individuals with PBD had the highest functioning, whereas individuals with SZ had the poorest. The functioning of individuals with SZA fell in between those of other groups. We also found that older ages were associated with poorer functioning. Although there was not a significant diagnostic group by age interaction, visual inspection of our data suggests a subtly steeper trajectory of decline in PBD. Overall, these results indicate that early interventions targeting social functioning may benefit individuals with either non-affective or affective psychoses to slow a projected decline.
Full-text · Article · Dec 2014 · Journal of Nervous & Mental Disease
[Show abstract][Hide abstract] ABSTRACT: White matter (WM) abnormalities are among the most commonly reported neuroimaging findings in bipolar disorder. Nonetheless, the specific nature and pathophysiology of these abnormalities remains unclear. Use of a combination of magnetization transfer ratio (MTR) and diffusion tensor spectroscopy (DTS) permits examination of myelin and axon abnormalities separately. We aimed to examine myelination and axon geometry in euthymic patients with bipolar disorder with psychosis (BDP) by combining these two complementary non-invasive MRI techniques. We applied a combined MRI approach using MTR to study myelin content and DTS to study metabolite (NAA) diffusion within axons in patients with BDP (n=21) and healthy controls (n=24). Data were collected from a 1 × 3 × 3 cm voxel within the right prefrontal cortex WM at 4 Tesla. Clinical and cognitive data were examined in association with MTR and DTS data. MTR was significantly reduced in BDP, suggesting reduced myelin content. The apparent diffusion coefficient of N-acetylaspartate (NAA) did not differ from healthy controls, suggesting no changes in axon geometry in patients with BDP. These findings suggest that patients with BDP exhibit reduced myelin content, but no changes in axon geometry compared to controls. These findings are in contrast with our recent findings, using the same techniques, in patients with schizophrenia (SZ), which suggest both myelination and axon abnormalities in SZ. This difference may indicate that alterations in WM in BDP may have unique causes and may be less extensive than WM abnormalities seen in SZ.Neuropsychopharmacology accepted article preview online, 20 November 2014. doi:10.1038/npp.2014.310.
No preview · Article · Nov 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
[Show abstract][Hide abstract] 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.
No preview · Article · Nov 2014 · Harvard Review of Psychiatry
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
No preview · Article · Dec 2013 · Harvard Review of Psychiatry
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
No preview · Article · Nov 2013 · Comprehensive psychiatry
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Full-text · Article · Jun 2013 · Schizophrenia Research
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Full-text · Article · May 2013 · Bipolar Disorders
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
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.
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.
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.
No preview · Article · Apr 2013 · Biological psychiatry
[Show abstract][Hide abstract] 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.
Full-text · Article · Mar 2013 · Schizophrenia Research
[Show abstract][Hide abstract] 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.
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.
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%).
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.
No preview · Article · Jan 2013 · Comprehensive psychiatry
[Show abstract][Hide abstract] 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.
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).
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.
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.
Full-text · Article · Dec 2012 · Schizophrenia Research
[Show abstract][Hide abstract] ABSTRACT: Several lines of evidence implicate dysfunction in brain energy production as a key component of bipolar disorder. In particular, elevated brain lactate levels observed in this condition suggest a shift from aerobic to anaerobic metabolism, possibly as a result of mitochondrial abnormalities. Most prior imaging studies of brain metabolites were performed in either euthymic or depressed bipolar patients or compared different populations in different mood states. We sought to measure brain metabolite concentrations in the same patients in both manic and euthymic states. Given the dramatic changes in clinical state of bipolar disorder patients, we hypothesized that previously observed abnormalities in lactate concentrations in bipolar disorder might show state dependent changes. In this study 15 patients (mean age 36.1 years) diagnosed with bipolar I disorder underwent proton magnetic resonance spectroscopy of the anterior cingulate cortex and parieto-occipital cortex during hospitalization for acute mania (mean Young Mania Rating Scale (YMRS) 22.1). Seven of these subjects returned (mean interval 21.16 months) to have imaging repeated while euthymic (mean YMRS 2.0). A group of age- and gender-matched control participants (N=6) were scanned as well. We report that during mania, bipolar disorder subjects had lactate levels comparable to healthy control subjects but during euthymia these levels were significantly reduced. No significant change was observed for other metabolites. These results implicate mood dependent alterations in energy metabolism in the biology of bipolar disorder. Additionally, this finding has potential use as a biomarker for both evaluating novel treatments as well as diagnostic clarification between mood disorders.