Abstract
Major depressive disorder (MDD) often begins during adolescence and is projected to become the leading cause of global disease burden by the year 2030. Yet, approximately 40 % of depressed adolescents fail to respond to standard antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI). Converging evidence suggests that depression is related to brain mitochondrial dysfunction. Our previous studies of MDD in adult and adolescent females suggest that augmentation of SSRI pharmacotherapy with creatine monohydrate (CM) may improve MDD outcomes. Neuroimaging with phosphorus-31 magnetic resonance spectroscopy (31P-MRS) can measure the high-energy phosphorus metabolites in vivo that reflect mitochondrial function. These include phosphocreatine (PCr), a substrate for the creatine kinase reaction that produces adenosine triphosphate. As part of the National Institute of Mental Health’s experimental medicine initiative, we conducted a placebo-controlled dose-ranging study of adjunctive CM for adolescent females with SSRI-resistant MDD. Participants were randomized to receive placebo or CM 2, 4 or 10 g daily for 8 weeks. Pre- and post-treatment 31P-MRS scans were used to measure frontal lobe PCr, to assess CM’s target engagement with cerebral energy metabolism. Mean frontal lobe PCr increased by 4.6, 4.1 and 9.1 % in the 2, 4 and 10 g groups, respectively; in the placebo group, PCr fell by 0.7 %. There was no group difference in adverse events, weight gain or serum creatinine. Regression analysis of PCr and depression scores across the entire sample showed that frontal lobe PCr was inversely correlated with depression scores (p = 0.02). These results suggest that CM achieves target engagement with brain bioenergetics and that the target is correlated with a clinical signal. Further study of CM as a treatment for adolescent females with SSRI-resistant MDD is warranted.
Highlights
Depressive disorders are the second leading cause of years lived with disability as of 2010 (Ferrari et al 2013) and major depressive disorder (MDD) is projected to become the leading cause of global disease burden by 2030 (Lepine and Briley 2011)
Our previous studies of MDD in adult and adolescent females suggest that augmentation of selective serotonin reuptake inhibitor (SSRI) pharmacotherapy with creatine monohydrate (CM) may improve MDD outcomes
Regression analysis of PCr and depression scores across the entire sample showed that frontal lobe PCr was inversely correlated with depression scores (p = 0.02). These results suggest that CM achieves target engagement with brain bioenergetics and that the target is correlated with a clinical signal
Summary
Depressive disorders are the second leading cause of years lived with disability as of 2010 (Ferrari et al 2013) and major depressive disorder (MDD) is projected to become the leading cause of global disease burden by 2030 (Lepine and Briley 2011). In a placebo-controlled study of healthy adults, we found that cerebral PCr and Pi increased and β-NTP decreased, in subjects receiving oral CM versus placebo (Lyoo et al 2003) This reproduced the alterations in 31P-MRS metabolites that predict responsiveness, in two distinct groups of MDD patients: (1) treatment-naïve subjects receiving initial pharmacotherapy with an SSRI (Renshaw et al 2001); and (2) SSRI-resistant subjects who receive hormonal augmentation of their existing antidepressant (Iosifescu et al 2008). More recent data suggest CM’s antidepressant-like effects are sex hormone dependent (Allen et al 2015) The aims of this R21 were: to demonstrate that CM targets and alters brain energy metabolism in female adolescents with SSRI-resistant MDD in a dose-responsive manner, compared with placebo; and to determine the dose of CM offering the best combination of safety, tolerability and target engagement with mitochondrial function in these participants
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