Abstract
Clozapine displays stronger systemic metabolic side effects than haloperidol and it has been hypothesized that therapeutic antipsychotic and adverse metabolic effects of these drugs are related. Considering that cerebral disconnectivity through oligodendrocyte dysfunction has been implicated in schizophrenia, it is important to determine the effect of these drugs on oligodendrocyte energy metabolism and myelin lipid production. Effects of clozapine and haloperidol on glucose and myelin lipid metabolism were evaluated and compared in cultured OLN-93 oligodendrocytes. First, glycolytic activity was assessed by measurement of extra- and intracellular glucose and lactate levels. Next, the expression of glucose (GLUT) and monocarboxylate (MCT) transporters was determined after 6 and 24 h. And finally mitochondrial respiration, acetyl-CoA carboxylase, free fatty acids, and expression of the myelin lipid galactocerebroside were analyzed. Both drugs altered oligodendrocyte glucose metabolism, but in opposite directions. Clozapine improved the glucose uptake, production and release of lactate, without altering GLUT and MCT. In contrast, haloperidol led to higher extracellular levels of glucose and lower levels of lactate, suggesting reduced glycolysis. Antipsychotics did not alter significantly the number of functionally intact mitochondria, but clozapine enhanced the efficacy of oxidative phosphorylation and expression of galactocerebroside. Our findings support the superior impact of clozapine on white matter integrity in schizophrenia as previously observed, suggesting that this drug improves the energy supply and myelin lipid synthesis in oligodendrocytes. Characterizing the underlying signal transduction pathways may pave the way for novel oligodendrocyte-directed schizophrenia therapies.
Highlights
Schizophrenia is a devastating mental disorder affecting about 1% of the population worldwide (Saha et al, 2005)
We have shown that haloperidol and clozapine attenuate glucosedeprivation induced necrotic cell death in oligodendrocyte culture, suggesting that antipsychotic drugs may exert a protective effect on oligoendrocytes during a glucose/energy deprived state (Steiner et al, 2011)
This effect was evident after 6 h in the extracellular medium [main effect (TREAT) F(4, 18) = 46.25, P < 0.001, low clozapine (LC) n.s., high clozapine (HC) P < 0.01, low haloperidol (LH) P < 0.001, high haloperidol (HH) P < 0.001] and within cells [effect of treatment (TREAT) F(4, 18) = 11.30, P < 0.001, low clozapine vs. control (LC) n.s., high clozapine vs. control (HC) P < 0.01, low haloperidol vs. control (LH) n.s., high haloperidol vs. control (HH) n.s.]
Summary
Schizophrenia is a devastating mental disorder affecting about 1% of the population worldwide (Saha et al, 2005). Absolute or relative energy insufficiency due to abnormal glucose metabolism can lead to abnormal behavior and cognition. When applying insulin therapy in patients with psychiatric disorders, psychotic patients required higher doses of insulin compared to non-psychotic subjects, indicating some degree of insulin resistance (Sakel, 1938). Several recent studies show elevated rates of either diabetes or impaired glucose tolerance (insulin) resistance in first-episode, drug-naive subjects and in non-psychotic relatives of patients, suggesting that altered glucose metabolism might be related to schizophrenia itself, rather than only to treatment, or lifestyle factors related to it (Kirkpatrick et al, 2012; Van Welie et al, 2013)
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