Post-stroke fatigue as an indicator of underlying bioenergetics alterations.

Approximately half of stroke survivors suffer from clinically significant fatigue, contributing to poor quality of life, depression, dependency, and increased mortality. The etiology of post-stroke fatigue is not well understood and treatment is limited. This study tested the hypothesis that systemic aerobic energy metabolism, as reflected by platelet oxygen consumption, is negatively associated with fatigue and systemic inflammation is positively associated with fatigue in chronic ischemic stroke survivors. Data on self-reported level of fatigue, platelet oxygen consumption rates (OCR) and plasma inflammatory markers were analyzed from 20 ischemic stroke survivors. DNA copy number for two mitochondrial genes was measured as a marker of platelet mitochondrial content. Basal and protonophore-stimulated maximal platelet OCR showed a biphasic relationship to fatigue. Platelet OCR was negatively associated with low to moderate fatigue but was positively associated with moderate to high fatigue. DNA copy number was not associated with either fatigue or platelet OCR. Fatigue was negatively associated with C-reactive protein but not with other inflammatory markers. Post-stroke fatigue may be indicative of a systemic cellular energy dysfunction that is reflected in platelet energy metabolism. The biphasic relationship of fatigue to platelet OCR may indicate an ineffective bioenergetic compensatory response that has been observed in other pathological states.

Nonconvulsive Electrotherapy for Treatment Resistant Unipolar and Bipolar Major Depressive Disorder: A Proof-of-concept Trial.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective therapy for treatment resistant major depressive disorder (TRD); however, some individuals with TRD refuse ECT over concern about adverse cognitive effects. Clinical observation of two patients with TRD who had a therapeutic response to intended ECT despite having only one or no seizure suggested that nonconvulsive electrical stimulation may be effective in some patients. OBJECTIVE/HYPOTHESIS: This study tested the hypothesis that electrical brain stimulation applied like standard ECT, but below seizure threshold, can have therapeutic effects on TRD with fewer adverse cognitive effects. METHODS: Thirteen outpatients with TRD (6 unipolar, 7 bipolar) who refused ECT participated in this open label adjunctive treatment study of nonconvulsive electrotherapy (NET) at the University of Maryland Medical Center. Brief pulse bifrontal electrical stimulation was given thrice weekly with a Thymatron System IV Integrated ECT Instrument. RESULTS: Seizure-free data were obtained from 11 of 13 subjects. Group mean Hamilton Depression Rating Scale 17-item version scores declined significantly (P = 0.001) from 20.3 to 8.6. Response and remission rates were 73% (8) and 55% (6), respectively. Cognitive testing using the Mini-Mental State Exam and the Autobiographical Memory Inventory-Short Form did not show declines typically observed with ECT. CONCLUSIONS: The therapeutic effect of NET on TRD was similar to that of ECT. Serious adverse effects and adverse cognitive effects were not observed. These results challenge the widespread belief that a seizure is necessary for the antidepressant effect of ECT and merit further investigation to determine whether NET is a viable alternative to ECT in some patients with TRD. Clinical trial posted on www.clinicaltrials.gov, identifier: NCT01065597.

A mitochondrial bioenergetic basis of depression.

Major depressive disorder (MDD) is an important public health problem affecting 350 million people worldwide. After decades of study, the pathophysiology of MDD remains elusive, resulting in treatments that are only 30-60% effective. This review summarizes the emerging evidence that implicates impaired mitochondrial bioenergetics as a basis for MDD. It is suggested that impaired mitochondrial bioenergetic function contributes to the pathophysiology of MDD via several potential pathways including: genetics/genomics, inflammation, oxidative stress, and alterations in neuroplasticity. A discussion of mitochondrial bioenergetic pathways that lead to MDD is provided. Evidence is reviewed regarding the mito-toxic or mito-protective impact of various antidepressant medications currently in use. Opportunities for further research on novel therapeutic approaches, including mitochondrial modulators, as stand-alone or adjunct therapy for reducing depression are suggested. In conclusion, while there is substantial evidence linking mitochondrial bioenergetics and MDD, there are currently no clear mitochondrial phenotypes or biomarkers to use as guides in targeting therapies beyond individuals with MDD and known mitochondrial disorders toward the general population of individuals with MDD. Further study is needed to develop these phenotypes and biomarkers, to identify therapeutic targets, and to test therapies aimed at improving mitochondrial function in individuals whose MDD is to some extent symptomatic of impaired mitochondrial bioenergetics.

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

OBJECTIVE: An association between allergic disease and depression has been consistently reported, but whether the key mediating ingredients are predominantly biological, psychological, or mere artifacts remains unknown. In the current study, we examined a hypothesized relationship between allergen-specific immunoglobulin E (IgE) status and changes in allergy symptoms with worsening in depression scores. METHODS: In patients with recurrent mood disorders, we individually coupled sensitization to specific seasonal aeroallergens (as assessed by allergen-specific IgE) with temporal windows of exposure to aeroallergens (low versus high tree or ragweed pollen counts, measured according to the National Allergy Bureau guidelines). We compared Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD) depression score changes in 41 patients with mood disorders [25 with major depression and 16 with bipolar I disorder, diagnosed by Structured Clinical Interview for DSM (SCID)] seropositive for tree or ragweed pollen-specific IgE antibody versus 53 patients with mood disorders (30 with major depression and 23 with bipolar I disorder) seronegative for aeroallergen-specific IgE. RESULTS: Worsening in total depressive scores from low to high pollen exposure was greater in allergen-specific IgE-positive patients as compared to allergen-specific IgE antibody-negative patients (p = 0.01). When stratified by polarity, the association was significant only in patients with bipolar I disorder (p = 0.004). This relationship was resilient to adjustment for changes in allergy symptom scores. CONCLUSION: To our knowledge, this is the first report of coupling a molecular marker of vulnerability (allergen-specific IgE) with a specific environmental trigger (airborne allergens) leading to exacerbation of depression in patients with bipolar I disorder.

Inositol deficiency diet and lithium effects.

OBJECTIVES: A major hypothesis explaining the therapeutic effect of lithium (Li) in mania is depletion of inositol via inhibition of inositol monophosphatase. However, inositol is also present in the diet. Restriction of dietary inositol could theoretically enhance the effects of Li. METHODS: We used dietary inositol restriction in animal studies and also devised a palatable diet for humans that is 90% free of inositol. RESULTS: Dietary inositol restriction significantly augmented the inositol-reducing effect of Li in rat frontal cortex. Li reduced inositol levels by 4.7%, inositol-deficient diet by 5.1%, and Li plus inositol-deficient diet by 10.8%. However, feeding with the inositol-deficient diet did not enhance the behavioral effect of Li in the Li-pilocarpine seizure model. Fifteen patients participated in an open clinical study of the inositol-deficient diet: six rapid cycling bipolar patients responding inadequately to Li or valproate in different phases of illness; two Li-treated bipolar outpatients with residual symptomatology, and seven inpatient Li-treated bipolar patients in non-responding acute mania. The diet had a major effect in reducing the severity of affective disorder in 10 of the patients within the first 7-14 days of treatment. CONCLUSION: These results suggest that dietary inositol restriction may be useful in some bipolar patients, but controlled replication is necessary.

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.

Inhibition of aldose reductase enhances HeLa cell sensitivity to chemotherapeutic drugs and involves activation of extracellular signal-regulated kinases.

Changes in glucose metabolism during diabetes are linked to an increased risk for the development of cancer. Increased activity of aldose reductase, the rate-limiting polyol pathway enzyme that converts glucose into sorbitol, mediates pathologies associated with diabetes and is thought to be involved in increased resistance to chemotherapeutic drugs. Thus, increased intracellular sorbitol levels may serve a protective function in cancer cells. In these studies we determined whether an inhibitor of aldose reductase could enhance the effectiveness of anticancer agents. Our findings indicate that treatment with the aldose reductase inhibitor, ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate (EBPC), enhances the cytotoxic effects of the anticancer agents doxorubicin and cisplatin in HeLa cervical carcinoma cells. To establish a mechanistic basis for the increased cytotoxicity by EBPC, we examined the activity of the extracellular signal-regulated kinase (ERK) pathway, which is an important regulator of cell growth. Interestingly, treatment with EBPC in combination with the chemotherapeutic drugs increased ERK activity as compared to treatment with the chemotherapeutic drugs, suggesting a possible role for the ERK pathway in mediating doxorubicin- or cisplatin-induced cell death. Consistent with this possibility, inhibition of ERK activation by the MEK inhibitor, U0126, reversed the EBPC-mediated enhancement of cell death. In summary, these data provide evidence that adjuvant therapy with aldose reductase inhibitors improves the effectiveness of chemotherapeutic drugs, possibly through an ERK pathway-mediated mechanism.