Creatine monohydrate in resistant depression: a preliminary study

Roitman, Susana; Green, Tamar; Osher, Yamima; Karni, N.; Levine, Joseph

doi:10.1111/j.1399-5618.2007.00532.x

Cited by 96 publications

(79 citation statements)

References 26 publications

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“…Creatine, a well-known energy enhancer compound, has shown promise as a safe, effective, and tolerable adjunct to medication for the treatment of depression [18][19][20]. The present study extends the literature data by showing that creatine also elicits antidepressant-like effect in the TST through an interaction with the neuromodulatory system operated by adenosine and its receptors.…”

Section: Discussionsupporting

confidence: 81%

“…In this context, creatine administered both systemic and centrally produces antidepressant-like effects in behavioral despair models like the TST [16][17][18]. In addition to the preclinical data, clinical trials have also demonstrated that creatine supplementation produces antidepressant effect and that creatine could be a new approach in the treatment of depression [21,19,20]. However, the mechanisms underlying the homeostatic versus neuromodulatory roles of creatine in the brain still need to be explored.…”

Section: Discussionmentioning

confidence: 99%

“…Both clinical and preclinical evidence have demonstrated that creatine (N-aminoiminomethyl-N-methylglycine, a substrate of creatine kinase enzyme) improves mood, possibly by restoring brain energy levels and homeostasis [16][17][18][19][20][21][22]. Of note, creatine supplementation has been reported to improve depressive symptoms in 1-2 weeks of treatment in depressive patients, faster than the currently available antidepressants, which require 4-5 weeks to produce their therapeutic effects [19,21].…”

Section: Introductionmentioning

confidence: 99%

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Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation

Cunha

Pazini

Rosa

et al. 2015

Purinergic Signalling

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The benefits of creatine supplementation have been reported in a broad range of central nervous systems diseases, including depression. A previous study from our group demonstrated that creatine produces an antidepressant-like effect in the tail suspension test (TST), a predictive model of antidepressant activity. Since depression is associated with a dysfunction of the adenosinergic system, we investigated the involvement of adenosine A 1 and A 2A receptors in the antidepressant-like effect of creatine in the TST. The anti-immobility effect of creatine (1 mg/kg, po) or ketamine (a fast-acting antidepressant, 1 mg/kg, ip) in the TST was prevented by pretreatment of mice with caffeine (3 mg/kg, ip, nonselective adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (2 mg/kg, ip, selective adenosine A 1 receptor antagonist), and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-ylamino]ethyl)-phenol (ZM241385) (1 mg/kg, ip, selective adenosine A 2A receptor antagonist). In addition, the combined administration of subeffective doses of creatine and adenosine (0.1 mg/kg, ip, nonselective adenosine receptor agonist) or inosine (0.1 mg/kg, ip, nucleoside formed by the breakdown of adenosine) reduced immobility time in the TST. Moreover, the administration of subeffective doses of creatine or ketamine combined with N-6-cyclohexyladenosine (CHA) (0.05 mg/kg, ip, selective adenosine A 1 receptor agonist), N-6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine (DPMA) (0.1 mg/kg, ip, selective adenosine A 2A receptor agonist), or dipyridamole (0.1 μg/mouse, icv, adenosine transporter inhibitor) produced a synergistic antidepressant-like effect in the TST. These results indicate that creatine, similarly to ketamine, exhibits antidepressant-like effect in the TST probably mediated by the activation of both adenosine A 1 and A 2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation

Cunha

Pazini

Rosa

et al. 2015

Purinergic Signalling

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“…Creatine monohydrate had been tested in a small case series study as an augmenting agent for SSRI-resistant depression in adolescents with encouraging results [155]. Similarly, creatine augmentation was tested in a small open-label trial of patients with treatment-resistant MDD and bipolar depression with positive results [156]. An RCT of creatine augmentation for TRD is under way (online suppl.…”

Section: Resultsmentioning

confidence: 99%

The Integrative Management of Treatment-Resistant Depression: A Comprehensive Review and Perspectives

Carvalho

Berk

Hyphantis

et al. 2014

Psychother Psychosom

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Background: Major depressive disorder is a prevalent and disabling illness. Notwithstanding numerous advances in the pharmacological treatment of depression, approximately 70% of patients do not remit after first-line antidepressant treatment. Methods: The MEDLINE/PubMed, EMBASE and ClinicalTrials.gov electronic databases were searched from inception to October 1, 2013, for randomized controlled trials (RCT), relevant open-label trials, meta-analyses and ongoing trials of pharmacological and psychotherapeutic approaches to treatment-resistant depression (TRD). Results: Switching to a different antidepressant is a useful option following nonresponse to a first-line agent. Although widely used in clinical practice, there is limited evidence to support antidepressant combination for TRD. Notwithstanding evidence for lithium or T₃ augmentation to be successful in TRD, most studies were carried out when participants were treated with tricyclic antidepressants (TCA). Of the available strategies to augment the response to new-generation antidepressants, the use of some atypical antipsychotics is best supported by evidence. Several novel therapeutic options are currently discussed. Evidence suggests that cognitive therapy (CT) is an effective strategy for TRD. Conclusions: The success of switching to a different antidepressant following a first-line agent is supported by evidence, but there is limited evidence for effective combination strategies. Lithium and T₃ augmentation of TCA have the strongest evidence base for successful treatment of TRD. The use of augmentation of newer-generation antidepressants with atypical antipsychotics is supported by a growing evidence base. Current evidence supports CT as an effective strategy for TRD. There is a need for additional large-scale RCT of TRD. The development of new antidepressants targeting novel pathways opens a promising perspective for the management of TRD.

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“…Consistent with this role, energy metabolism in the brain and changes thereof have been shown to be closely associated with the pathophysiology of depressive disorder in patients. 37) In the event of an external stressful stimulus, allostasis occurs through the initiation of physiological responses and coping behaviors to achieve adaptation of the living organism to the environment, whereas allostatic overload leads to chronic disease. 38) In our rat model of depression-like symptoms, the energy-producing activity in the TCA cycle was abnormal, which is considered to have caused the increases in NAA and creatine in order to complement the loss of energy resulting from disease development.…”

Section: )mentioning

confidence: 99%

High-Resolution Magic-Angle Spinning-<sup>1</sup>H-NMR Spectroscopy-Based Metabolic Profiling of Hippocampal Tissue in Rats with Depression-Like Symptoms

Akimoto

Oshima

Ohara

et al. 2017

Biological & Pharmaceutical Bulletin

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Depressive disorders cause large socioeconomic effects influencing not only the patients themselves but also their family and broader community as well. To better understand the physiologic factors underlying depression, in this study, we performed metabolomics analysis, an omics technique that comprehensively analyzes small molecule metabolites in biological samples. Specifically, we utilized high-resolution magic-angle spinning-1 H-NMR (HRMAS-1 H-NMR) spectroscopy to comprehensively analyze the changes in metabolites in the hippocampal tissue of rats exposed to chronic stress (CS) via multi-step principal component analysis (multi-step PCA). The rats subjected to CS exhibited obvious depression-like behaviors. High correlations were observed between the first principal component (PC1) score in the score plot obtained using multi-step PCA and measurements from depression-like behavioral testing (body weight, sucrose preference test, and open field test). Alanine, glutamate, glutamine, and aspartate levels in the hippocampal tissue were significantly lower, whereas N-acetylaspartate, myo-inositol, and creatine were significantly higher in the CS group compared to the control (non-CS) group. As alanine, glutamate, and glutamine are known to be involved in energy metabolism, especially in the tricarboxylic acid cycle, chronic exogenous stress may have induced abnormalities in energy metabolism in the brains of the rats. The results suggest that N-acetylaspartate and creatine levels may have increased in order to complement the loss of energy-producing activity resulting from the development of the depression-like disorder. Multi-step PCA therefore allowed an exploration of the degree of depression-like symptoms as represented by changes in intrinsic metabolites.

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Creatine monohydrate in resistant depression: a preliminary study

Abstract: This small, preliminary, open study of creatine monohydrate suggests a beneficial effect of creatine augmentation in unipolar depression, but possible precipitation of a manic switch in bipolar depression.

Cited by 96 publications

References 26 publications

Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation

Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation

The Integrative Management of Treatment-Resistant Depression: A Comprehensive Review and Perspectives

High-Resolution Magic-Angle Spinning-<sup>1</sup>H-NMR Spectroscopy-Based Metabolic Profiling of Hippocampal Tissue in Rats with Depression-Like Symptoms

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