William T. Regenold

Increased prevalence of type 2 diabetes mellitus among psychiatric inpatients with bipolar I affective and schizoaffective disorders independent of psychotropic drug use

BACKGROUND There are numerous reports of abnormal glucose metabolism, including increased rates of type 2 diabetes mellitus, in psychiatric patients. It remains unclear, however, whether there is an intrinsic relationship between abnormal glucose metabolism and particular psychiatric disorders, because the relationship is complicated by treatment with psychotropic medications that promote weight gain and hyperglycemia. This study aimed to clarify this relationship. METHODS The medical records of 243 inpatients, aged 50-74 years, with diagnoses of major depression, bipolar I disorder, schizoaffective disorder, schizophrenia, and dementia were reviewed. Psychiatric and type 2 diabetes mellitus diagnoses, medications, body mass index (BMI), age, gender, and race were recorded. Diabetes rates were compared to age, race, and gender-matched rates in the US general population. RESULTS Rates of type 2 diabetes mellitus were: schizoaffective (50%) > bipolar I (26%) > major depression (18%) = dementia (18%) > schizophrenia (13%) (p < 0.006). Diabetic patients had a higher mean BMI (p = 0.01), but not a significantly higher use of psychotropic medications previously reported to be associated with new-onset type 2 diabetes (e.g., phenothiazines, clozapine, olanzapine). Logistic regression revealed that psychiatric diagnosis and BMI were the only significant and independent predictors of diabetes diagnosis. Compared to national norms, diabetes rates were significantly elevated only in bipolar I affective and schizoaffective patients. LIMITATIONS This study was a retrospective chart review of older, hospitalized patients. CONCLUSIONS This is the first published study to show an increased prevalence of type 2 diabetes mellitus among psychiatric patients with particular psychiatric illnesses independent of the effects of age, race, gender, medication, and body mass. This finding, which requires replication in a larger scale, prospective study, suggests an intrinsic relationship between abnormal glucose metabolism and bipolar I affective and schizoaffective disorders.

Myelin staining of deep white matter in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and unipolar major depression

Neuroimaging and postmortem studies suggest the involvement of white matter disease in schizophrenia, bipolar disorder, and unipolar major depression. To date there is no published, collective study of myelin staining in these three psychiatric disorders. Deep white matter lesions, potentially affecting corticolimbic circuits, have been particularly implicated in late life depression and poor outcome bipolar disorder. We hypothesized that individuals with these disorders would manifest reduced deep white matter myelin staining compared to normal controls. Sixty transverse sections of fixed dorsolateral prefrontal cortex - 15 from individuals with each psychiatric disorder and 15 from normal controls - were stained according to the method of Kluver and Barrera. Myelin staining intensity was quantified by digital image analysis and expressed as a percent of grey matter staining for a given section. Mean deep (but not gyral) white matter myelin staining was less intense in all three psychiatric groups compared to control. This difference was statistically significant for the bipolar and unipolar groups, with a strong trend toward attenuated staining in the schizophrenic group. Our findings are consistent with postmortem and neuroimaging studies of affective disorders that indicate an increased prevalence of deep white matter lesions in unipolar and bipolar affective disorders.

Elevated Cerebrospinal Fluid Lactate Concentrations in Patients with Bipolar Disorder and Schizophrenia: Implications for the Mitochondrial Dysfunction Hypothesis

BACKGROUND Evidence is accumulating that mitochondrial dysfunction is involved in the pathophysiology of bipolar disorder and schizophrenia. Cerebrospinal fluid (CSF) concentration of lactate, a product of extra-mitochondrial glucose metabolism, is commonly elevated in individuals with mitochondrial disorders, especially those with neuropsychiatric symptoms. We tested the hypothesis that patients with bipolar disorder and schizophrenia would, on average, have elevated CSF lactate concentrations compared with healthy control subjects. METHODS The CSF lactate and CSF and plasma glucose concentrations were measured with a YSI (YSI, Yellow Springs, Ohio) 2300 STAT Plus Glucose & Lactate Analyzer in 15 samples from each of three groups of subjects: bipolar I disorder patients, schizophrenic patients, and healthy control subjects. RESULTS Mean CSF lactate concentrations were significantly higher in bipolar (1.76 +/- .38) and schizophrenic subjects (1.61 +/- .31) compared with control subjects (1.31 +/- .21 mmol/L). These differences persisted after adjusting means for CSF glucose concentration, which correlated positively with CSF lactate concentration. CONCLUSIONS This is the first report of increased CSF lactate concentrations in patients with bipolar disorder and schizophrenia. Elevated CSF lactate indicates increased extra-mitochondrial and anaerobic glucose metabolism and is consistent with impaired mitochondrial metabolism. Measuring CSF lactate concentration might help identify bipolar and schizophrenic patients with mitochondrial dysfunction who might benefit from research to elucidate and ultimately rectify possible mitochondrial pathology underlying these disorders.

Effect of Vagus Nerve Stimulation on Cerebrospinal Fluid Monoamine Metabolites, Norepinephrine, and Gamma-Aminobutyric Acid Concentrations in Depressed Patients

BACKGROUND Vagus nerve stimulation (VNS) has shown promising antidepressant effects in treatment-resistant depression, but the mechanisms of action are not known. Cerebrospinal fluid (CSF) studies in epilepsy patients show that VNS alters concentrations of monamines and gamma-aminobutyric acid (GABA), neurotransmitter systems possibly involved in the pathogenesis of depression. METHODS Twenty-one adults with treatment-resistant, recurrent, or chronic major depression underwent standardized lumbar puncture for collection of 12 mL CSF on three separate but identical procedure days during participation in the VNS D-02 clinical trial. All subjects remained on stable regimens of mood medications. Collections were made at baseline (2 weeks after surgical implantation but before device activation), week 12 (end of the acute-phase study), and week 24. Cerebrospinal fluid concentrations of norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined with high-performance liquid chromatography. Concentrations of GABA were assayed with mass spectrometry. RESULTS Comparison of sham versus active VNS revealed a significant (mean 21%) VNS-associated increase in CSF HVA. Mean CSF concentrations of NE, 5-HIAA, MHPG, and GABA did not change significantly. Higher baseline HVA/5-HIAA ratio predicted worse clinical outcome. CONCLUSIONS Although several of the CSF neurochemical effects we observed in this VNS study were similar to those described in the literature for antidepressants and electroconvulsive therapy, the results do not suggest a putative antidepressant mechanism of action for VNS.

Cerebrospinal fluid evidence of increased extra-mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis disease progression

In contrast to relapse, the mechanisms of multiple sclerosis (MS) disease progression are less understood and appear not to be exclusively inflammatory in nature. In this pilot study we investigated the relationship between disturbed CNS energy metabolism and MS disease progression. We tested the hypothesis that cerebrospinal fluid (CSF) concentrations of sorbitol, fructose, and lactate, all metabolites of extra-mitochondrial glucose metabolism, would be elevated in secondary progressive (SP) MS patients and would be associated with worsening neurologic disability. We measured metabolite concentrations by gas chromatographic/mass spectrometric and enzymatic methods in archived CSF samples from 85 MS patients [31 relapsing-remitting (RR) and 54 SP patients] and 18 healthy controls. We found that concentrations of all three metabolites, but not concentrations of glucose or myoinositol, were significantly increased in CSF from SP and, to a lesser degree, RR patients, compared to controls. Furthermore, CSF concentrations of sorbitol and fructose (polyol pathway metabolites), but not lactate (anaerobic glycolysis metabolite), correlated positively and significantly with Expanded Disability Status Scale (EDSS) score, an index of neurologic disability in MS patients. We conclude that extra-mitochondrial glucose metabolism is increased in MS patients and is associated with disease progression evidenced by increasing EDSS score. As extra-mitochondrial glucose metabolism increases with impaired mitochondrial metabolism of glucose, these findings implicate mitochondrial dysfunction in the pathogenesis of MS disease progression. CSF metabolic profiling may be useful in clarifying the role of mitochondrial pathology in progression and in targeting and monitoring therapies for disease progression that aim to preserve or boost mitochondrial glucose metabolism.

Electroconvulsive Therapy for Epilepsy and Major Depression

In this first report of electroconvulsive therapy (ECT) for the simultaneous treatment of seizures and depressive episodes, the authors discuss the use of ECT in the treatment of complex-partial seizures and major depression in a geriatric patients who refused antidepressant and antiepileptic medication. ECT has numerous anticonvulsant effects, including elevated seizure threshold and decreased seizure duration, which make it a useful adjunctive therapy in epilepsy that is refractory or not amenable to treatment with medication.

GSK-3β in cerebrospinal fluid of schizophrenia patients

Summary.Cerebrospinal fluid contains proteins and metabolites of brain origin and was extensively studied in psychiatry in the 1970’s with few definitive results. We have recently found 40% reduced protein levels of GSK-3β in schizophrenia in postmortem prefrontal cortex, but our attempt to develop a diagnostic marker using peripheral lymphocyte GSK-3β was not successful. In this study we aimed to find whether the reduction in brain GSK-3β is reflected in CSF of schizophrenia patients. We report a significant reduction in CSF GSK-3β protein levels in six schizophrenia patients compared to seventeen healthy subjects. Our results corroborate other studies in which CSF protein levels reflect the alteration found in these proteins in schizophrenia patients’ postmortem brain.

Relationship of cerebrospinal fluid glucose metabolites to MRI deep white matter hyperintensities and treatment resistance in bipolar disorder patients

OBJECTIVES Both diabetes mellitus and magnetic resonance image (MRI) deep white matter hyperintensities (WMHs) are more common in bipolar disorder (BD) patients than in matched controls. Deep-as opposed to periventricular--WMHs and diabetes are associated with treatment resistance and poorer outcome. This study investigated whether brain glucose metabolism by the polyol pathway--a pathway linked to nervous tissue disease in diabetes--is related to deep WMH volume and treatment resistance in BD patients. METHODS Volumes of fluid-attenuated inversion recovery WMHs were quantified and correlated with cerebrospinal fluid (CSF) concentrations of glucose metabolites in 20 nondiabetic patients with BD and nondiabetic comparison subjects with schizophrenia (n = 15) or transient neurologic symptoms (neurologic controls, n = 15). RESULTS BD patients, but not schizophrenic patients, had significantly greater volumes of deep but not periventricular WMHs compared to neurologic controls. BD subjects also had significantly greater CSF concentrations of sorbitol and fructose (the polyol pathway metabolites of glucose) compared to controls. Significant positive correlations between CSF metabolites and WMH volumes were found only in the BD group and were between deep WMH volumes and CSF sorbitol (rho = 0.487, p = 0.029) and fructose (rho = 0.474, p = 0.035). An index of treatment resistance correlated significantly with deep WMH volume (rho = 0.578, p = 0.008), sorbitol (rho = 0.542, p = 0.013), and fructose (rho = 0.692, p = 0.001) in BD subjects but not in other subjects. CONCLUSIONS This is the first reported evidence of relationships between abnormal brain glucose metabolism and both deep WMHs and treatment resistance in a group of BD patients. Further studies are necessary to determine the significance of these findings to BD pathophysiology.

Pollen-specific immunoglobulin E positivity is associated with worsening of depression scores in bipolar disorder patients during high pollen season

Manalai P, Hamilton RG, Langenberg P, Kosisky SE, Lapidus M, Sleemi A, Scrandis D, Cabassa JA, Rogers CA, Regenold WT, Dickerson F, Vittone BJ, Guzman A, Balis T, Tonelli LH, Postolache TT. Pollen‐specific immunoglobulin E positivity is associated with worsening of depression scores in bipolar disorder patients during high pollen season. Bipolar Disord 2012: 14: 90–98.

Association of Electroconvulsive Therapy With Psychiatric Readmissions in US Hospitals

Importance Although electroconvulsive therapy (ECT) is considered the most efficacious treatment available for individuals with severe affective disorders, ECT’s availability is limited and declining, suggesting that information about the population-level effects of ECT is needed. Objective To examine whether inpatient treatment with ECT is associated with a reduction in 30-day psychiatric readmission risk in a large, multistate sample of inpatients with severe affective disorders. Design, Setting, and Participants A quasi-experimental instrumental variables probit model of the association correlation of ECT administration with patient risk of 30-day readmission was estimated using observational, longitudinal data on hospital inpatient discharges from US general hospitals in 9 states. From a population-based sample of 490 252 psychiatric inpatients, a sample was drawn that consisted of 162 691 individuals with a principal diagnosis of major depressive disorder (MDD), bipolar disorder, or schizoaffective disorder. The key instrumental variable used in the analysis was ECT prevalence in the prior calendar year at the treating hospital. To examine whether ECT’s association with readmissions was heterogeneous across population subgroups, analyses included interactions of ECT with age group, sex, race/ethnicity, and diagnosis group. The study was conducted from August 27, 2015, to March 7, 2017. Main Outcome and Measures Readmission within 30 days of being discharged. Results Overall, 2486 of the 162 691 inpatients (1.5%) underwent ECT during their index admission. Compared with other inpatients, those who received ECT were older (mean [SD], 56.8 [16.5] vs 45.9 [16.5] years; P < .001) and more likely to be female (65.0% vs 54.2%; P < .001) and white non-Hispanic (85.3% vs 62.1%; P < .001), have MDD diagnoses (63.8% vs 32.0%; P < .001) rather than bipolar disorder (29.0% vs 40.0%; P < .001) or schizoaffective disorder (7.1% vs 28.0%; P < .001), have a comorbid medical condition (31.3% vs 26.6%; P < .001), have private (39.4% vs 21.7%; P < .001) or Medicare (49.2% vs 39.4%; P < .001) insurance coverage, and be located in urban small hospitals (31.2% vs 22.3%; P < .001) or nonurban hospitals (9.0% vs 7.6%; P = .02). Administration of ECT was associated with a reduced 30-day readmission risk among psychiatric inpatients with severe affective disorders from an estimated 12.3% among individuals not administered ECT to 6.6% among individuals administered ECT (risk ratio [RR], 0.54; 95% CI, 0.28-0.81). Significantly larger associations with ECT on readmission risk were found for men compared with women (RR, 0.44; 95% CI, 0.20-0.69 vs 0.58; 95% CI, 0.30-0.88) and for individuals with bipolar disorder (RR, 0.42; 95% CI, 0.17-0.69) and schizoaffective disorder (RR, 0.44; 95% CI, 0.11-0.79) compared with those who had MDD (RR, 0.53; 95% CI, 0.26-0.81). Conclusions and Relevance Electroconvulsive therapy may be associated with reduced short-term psychiatric inpatient readmissions among psychiatric inpatients with severe affective disorders. This potential population health effect may be overlooked in US hospitals’ current decision making regarding the availability of ECT.