Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study. J Affect Disord 135(1-3):354-361

The Brain Institute, University of Utah, 383 Colorow Drive, Salt Lake City, UT 84108, USA.
Journal of Affective Disorders (Impact Factor: 3.38). 08/2011; 135(1-3):354-61. DOI: 10.1016/j.jad.2011.07.010
Source: PubMed


Adolescent major depressive disorder (MDD) is a life-threatening brain disease with limited interventions. Treatment resistance is common, and the illness burden is disproportionately borne by females. 31-Phosphorus magnetic resonance spectroscopy ((31)P MRS) is a translational method for in vivo measurement of brain energy metabolites.
We recruited 5 female adolescents who had been on fluoxetine (Prozac®) for ≥ 8 weeks, but continued meet diagnostic criteria for MDD with a Children's Depression Rating Scale-Revised (CDRS-R) raw score ≥ 40. Treatment response was measured with the CDRS-R. (31)P MRS brain scans were performed at baseline, and repeated following adjunctive creatine 4 g daily for 8 weeks. For comparison, 10 healthy female adolescents underwent identical brain scans performed 8 weeks apart.
The mean CDRS-R score declined from 69 to 30.6, a decrease of 56%. Participants experienced no Serious Adverse Events, suicide attempts, hospitalizations or intentional self-harm. There were no unresolved treatment-emergent adverse effects or laboratory abnormalities. MDD participants' baseline CDRS-R score was correlated with baseline pH (p=0.04), and was negatively correlated with beta-nucleoside triphosphate (β-NTP) concentration (p=0.03). Compared to healthy controls, creatine-treated adolescents demonstrated a significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up (31)P MRS brain scans.
Lack of placebo control; and small sample size.
Further study of creatine as an adjunctive treatment for adolescents with SSRI-resistant MDD is warranted.

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    • "A growing number of reports have provided evidence for the importance of the creatine kinase/phosphocreatine system in the pathophysiology of depression: (1) brain phosphocreatine , detected by phosphorus-31 magnetic resonance spectroscopy, was shown to be decreased in severely depressed patients (Kato et al. 1992); (2) an inverse correlation between Hamilton Depression Rating Scale scores and white matter creatine levels was shown (Dager et al. 2004); (3) single prolonged stress and forced swimming stress decreased creatine concentrations in the rat prefrontal cortex (Herring et al. 2008; Kim et al. 2010; Knox et al. 2010); (4) learned helplessness, a well-validated animal model of depression, decreased the expression of hippocampal creatine transporter (Lugenbiel et al. 2010); (5) the acute administration of the fast-acting antidepressant ketamine increased creatine kinase activity in rats (Assis et al. 2009); (6) clinical trials show that creatine augmentation in antidepressant treatment-resistant patients may be a promising therapeutic approach that exhibits more rapid and efficacious responses (Kondo et al. 2011; Lyoo et al. 2012); (7) creatine administration in mice produced an anti-immobility effect in the tail suspension test (TST) and forced swimming test (FST), two widely used tests for screening antidepressants (Allen et al. 2010, Cunha et al. 2012, 2013a, b). The mechanisms underlying the neuroprotective and antidepressant actions may be different, although antidepressant agents commonly exhibit neuroprotective properties . "
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    ABSTRACT: The modulation of N-methyl-D-aspartate receptor (NMDAR) and l-arginine/nitric oxide (NO) pathway is a therapeutic strategy for treating depression and neurologic disorders that involves excitotoxicity. Literature data have reported that creatine exhibits antidepressant and neuroprotective effects, but the implication of NMDAR and l-arginine/nitric oxide (NO) pathway in these effects is not established. This study evaluated the influence of pharmacological agents that modulate NMDAR/l-arginine-NO pathway in the anti-immobility effect of creatine in the tail suspension test (TST) in mice. The NOx levels and cellular viability in hippocampal and cerebrocortical slices of creatine-treated mice were also evaluated. The anti-immobility effect of creatine (10 mg/kg, po) in the TST was abolished by NMDA (0.1 pmol/mouse, icv), d-serine (30 µg/mouse, icv, glycine-site NMDAR agonist), arcaine (1 mg/kg, ip, polyamine site NMDAR antagonist), l-arginine (750 mg/kg, ip, NO precursor), SNAP (25 μg/mouse, icv, NO donor), L-NAME (175 mg/kg, ip, non-selective NOS inhibitor) or 7-nitroindazole (50 mg/kg, ip, neuronal NOS inhibitor), but not by DNQX (2.5 µg/mouse, icv, AMPA receptor antagonist). The combined administration of sub-effective doses of creatine (0.01 mg/kg, po) and NMDAR antagonists MK-801 (0.001 mg/kg, po) or ketamine (0.1 mg/kg, ip) reduced immobility time in the TST. Creatine (10 mg/kg, po) increased cellular viability in hippocampal and cerebrocortical slices and enhanced hippocampal and cerebrocortical NOx levels, an effect potentiated by l-arginine or SNAP and abolished by 7-nitroindazole or L-NAME. In conclusion, the anti-immobility effect of creatine in the TST involves NMDAR inhibition and enhancement of NO levels accompanied by an increase in neural viability.
    Amino Acids 01/2015; 47(4). DOI:10.1007/s00726-014-1910-0 · 3.29 Impact Factor
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    • "Compared to healthy controls, creatinetreated adolescents demonstrated a significant increase in brain PCr concentration on follow-up 31 P MRS. Kondo et al. (2011) Creatine monohydrate 5 g daily "
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    ABSTRACT: 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.
    Journal of Bioenergetics 09/2014; 47(1-2). DOI:10.1007/s10863-014-9584-6 · 3.21 Impact Factor
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    • "Several clinical trials (Amital et al., 2006; Kondo et al., 2011; Lyoo et al., 2012) and studies with animal models (Allen et al., 2010, 2012; Cunha et al., 2012) have reported that creatine supplementation exerts antidepressant effects. Specifically, it was recently demonstrated that the administration of creatine produces an antidepressant-like effect in the tail suspension test, a predictive test of antidepressant properties frequently used to evaluate the efficacy of drugs designed to treat depression, and this effect was shown to be mediated by a dopaminergic activation (Cunha et al., 2012). "
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    ABSTRACT: Creatine was previously shown to produce an antidepressant-like effect in the tail suspension test through a modulation of the dopaminergic system. In this study, the mechanisms underlying its antidepressant-like effect were further evaluated by investigating the involvement of the serotonergic system in its effect. The anti-immobility effect of creatine (1mg/kg) was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100mg/kg, i.p., for 4 consecutive days, an inhibitor of serotonin (5-HT) synthesis). Creatine (0.01mg/kg, sub-effective dose) in combination with sub-effective doses of WAY100635 (0.1mg/kg, s.c., a 5-HT(1A) receptor antagonist), 8-OH-DPAT (0.1mg/kg, i.p., a 5-HT(1A) receptor agonist) or selective serotonin reuptake inhibitors fluoxetine (5mg/kg, p.o.), paroxetine (0.1mg/kg, p.o.), citalopram (0.1mg/kg, p.o.) and sertraline (3mg/kg, p.o.) reduced the immobility time in the tail suspension test as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an interaction with 5-HT(1A) receptors. Of note, the present results also indicate that creatine improves the effectiveness of the selective serotonin reuptake inhibitors, a finding that may have therapeutic implications for the treatment of depressive disorders.
    Brain research bulletin 06/2013; DOI:10.1016/j.brainresbull.2013.01.005 · 2.72 Impact Factor
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