Affective disorders, antidepressant drugs and brain metabolism

Abstract

There is increasing evidence that affective disorders are associated with dysfunction of neurotransmitter postsynaptic transduction pathways and that chronic treatment with clinically active drugs results in adaptive modification of these pathways. Despite the close dependence of signal transduction on adenosine triphosphate (ATP) availability, the changes in energy metabolism in affective disorders are largely unknown. This question has been indirectly dealt with through functional imaging studies (PET, SPECT, MRS). Despite some inconsistencies, PET and SPECT studies suggest low activity in cortical (especially frontal) regions in depressed patients, both unipolar and bipolar, and normal or increased activity in the manic pole. Preliminary MRS studies indicate some alterations in brain metabolism, with reduced creatine phosphate and ATP levels in the brain of patients with affective disorders. However, the involvement of the energy metabolism in affective disorders is still debated. We propose direct neurochemical investigations on mitochondrial functional parameters of energy transduction, such as the activities of (a) the enzymatic systems of oxidative metabolic cycle (Kreb's cycle); (b) the electron transfer chain; (c) oxidative phosphorylation, and (d) the enzyme activities of ATP-requiring ATPases. These processes should be studied in affective disorders and in animals treated with antidepressant drugs or lithium.

Type 1 diabetes mellitus and major depressive disorder: evidence for a biological link

“…Both ROS levels and total antioxidant reactivity improved towards non-diabetic values on administration of a drug that produces an antidepressant effect in these animals (clonazepam) [63,64]. These findings are consistent with previous reports suggesting that the mitochondrial electron transport chain may be an overlooked target of antidepressant action [65]. Thus, the evidence to date suggests that oxidative stress may be a key element in the pathophysiology of comorbid type 1 diabetes and MDD, and this requires further investigation.…”

Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis

“…Apart from an imbalance of the neurotransmitter homeostasis, aberrant metabolic as well as immune-related functions are thought to contribute to the pathogenesis of affective disorders. A hypothetical deficit of energy as indicated by reduced levels of ATP and creatine phosphate in the brain of many patients (Moretti et al, 2003) as well as an over-reactive immune system as mirrored by increases in cytokine levels are features that occur during disease manifestation (Penninx et al, 2003;Thomas et al, 2005). Here, drug-induced autophagy might serve several functions: first, energy metabolism might be partly reconstituted Figure 11 A model of the autophagy-and cholesterol-related effects of AMI on astrocytes.…”

Hyperforin promotes mitochondrial function and development of oligodendrocytes

“…Several studies have shown that SJW and hyperforin can upregulate gene expressions related to increasing glycolysis and cellular glucose uptake in the hippocampus and other tissue (Krusekopf and Roots, 2005;Pennington et al, 2009). A recent 31 P-MRS study suggests that agents with the ability to increase brain ATP levels may show antidepressant effect (Moretti et al, 2003). A variety of antidepressants including imipramine, amitriptyline and clomipramine increase the ATP generation of astrocytes in vitro and this may affect the differentiation of astrocytes (Trzeciak et al, 1995).…”