ABSTRACT
OBJECTIVES: Extensive preclinical and clinical evidence suggests mitochondrial dysfunction in bipolar disorder. Studies of brain energy metabolism in bipolar disorder suggest an impairment of energy generation by mitochondrial oxidative phosphorylation. Lithium is an effective drug widely used in treating bipolar disorder, but its mechanism of action has remained uncertain. The aim of this study was to clarify the effect of lithium on mitochondrial oxidative phosphorylation. METHODS: We spectrophotometrically determined the activities of the respiratory chain complexes I + III [antimycin A-sensitive nicotinamide adenine dinucleotide (NADH) cytochrome c oxidorductase], complexes II + III (succinate cytochrome c oxidoreductase), succinate dehydrogenase, and complex IV [cytochrome c oxidase (COX)], and of the mitochondrial matrix enzyme citrate synthase in postmortem human brain cortex homogenates following exposure to lithium (up to 10 mM). RESULTS: Activities of complexes I + III and of complexes II + III were dose-dependently increased by lithium with maximum values at 1 mM (165%, p = 0.03, and 146%, p = 0.00002, of controls). Activity of succinate dehydrogenase remained unchanged up to 2 mM, but was raised at higher drug concentrations (maximum 220%, p = 0.01, of controls). In contrast, activity of COX was not significantly affected by the drug (decrease of 12% at 1 mM, p = 0.4). CONCLUSIONS: Our study suggests that lithium stimulates mitochondrial respiratory chain enzyme activities at clinically relevant concentrations. Lithium's effect on the mitochondrial respiratory chain presents further evidence of the pathophysiological significance of mitochondrial dysfunction in bipolar disorder. The effect may be relevant to the therapeutic efficacy of the drug by potentially reversing a disease-related alteration.
Subject(s)
Antimanic Agents/pharmacology , Brain/drug effects , Lithium Chloride/pharmacology , Mitochondria/drug effects , Oxidative Phosphorylation/drug effects , Brain Chemistry/drug effects , Dose-Response Relationship, Drug , Electron Transport Chain Complex Proteins/metabolism , Electron Transport Complex IV/metabolism , Female , Humans , Male , Mitochondria/enzymology , Postmortem Changes , Succinate Dehydrogenase/metabolismABSTRACT
BACKGROUND: An inverse association either between depression or impaired functional status and quality of life (QoL) has been reported for cancer patients, but the independent effect of depression or depressive symptoms and of functional impairment on QoL is unclear. PATIENTS AND METHODS: We investigated the prevalence of depression or depressive symptoms with the Beck Depression Inventory (BDI), the functional impairment with the ECOG-Performance-Status (ECOG-PS) and the QoL with the EORTC-QLQ-C30 questionnaire in a sample of 175 hospitalised cancer patients prior to the start of chemotherapy. RESULTS: Sixteen of 175 patients (9.1%) screened positive for major depression, 29 (16.6%) had mild to moderate depressive symptoms. In 11 of 15 scales of the EORTC-QLQ-C30 questionnaire depression or depressive symptoms were significantly associated with worse QoL in univariate analysis and in 12 of 15 scales poor ECOG-PS was significantly associated with worse QoL. In multivariate analysis including ECOG-PS and BDI, the effect of depression and/ or depressive symptoms on QoL was persistent in seven scales: global QoL, physical- and role functioning, fatigue, nausea & vomiting, pain, and constipation, that of ECOG-PS in five scales: global QoL, emotional functioning, nausea & vomiting, pain, and appetite loss. CONCLUSIONS: Signs of major depression or depressive symptoms and impaired functional status contribute independently to poorer QoL in cancer patients prior to chemotherapy.
