Study Overview
Citation: Kious BM, Kondo DG, Renshaw PF. (2019). Creatine for the treatment of depression. Biomolecules, 9(9), 406.
This thorough review examined the evidence for creatine supplementation as a potential adjunct treatment for depressive disorders.
It represents one of the most thorough analyses of creatine’s role in mental health, bridging the gap between basic neuroscience and clinical application.
The Brain Energy Hypothesis
The review centres on the bioenergetic hypothesis of depression — the idea that impaired brain energy metabolism contributes to depressive symptoms.
Key evidence supporting this includes brain imaging studies (MRS) showing reduced phosphocreatine and ATP levels in depressed patients, altered creatine kinase activity in depression, and the high energy demands of brain regions involved in mood regulation (prefrontal cortex, amygdala).
Creatine supplementation may address this energy deficit by increasing brain phosphocreatine stores, supporting ATP regeneration in neurons, enhancing mitochondrial function, and providing neuroprotective effects against oxidative stress.
Clinical Evidence Reviewed
Open-Label Studies
Several open-label studies showed promising results when creatine was added to SSRI treatment in women with major depressive disorder.
Improvements were seen in depression rating scales within 2-4 weeks of creatine augmentation at doses of 3-5g daily.
Adolescent Depression
A pilot study in adolescent females with treatment-resistant depression showed significant improvement when creatine (4g/day) was added to fluoxetine treatment.
Brain phosphocreatine levels increased, correlating with clinical improvement.
Bipolar Depression
Preliminary evidence also suggested potential benefits in bipolar depression, though with a caution about possible manic switching.
Toniolo et al. (2017) found benefits in bipolar II depression with creatine augmentation.
(Kreider et al., 2017)Important Caveats
- Not a standalone treatment — Creatine is being studied as an adjunct to standard antidepressant therapy
- Early-stage research — Larger randomised controlled trials are needed
- Gender differences — Most positive results have been in female participants
- Dose uncertainty — Optimal dosing for mental health effects is not yet established
- Bipolar caution — Risk of manic switching in bipolar disorder needs monitoring
- Not a replacement for professional care — Depression requires proper medical treatment
Malaysian Relevance
Mental health awareness is growing in Malaysia, with depression affecting an estimated 2.3% of the population.
While creatine should never replace professional mental health care, this research opens an interesting avenue for future investigation.
Malaysian patients on antidepressant treatment could discuss creatine supplementation with their psychiatrists as research develops.
Where This Fits in the Evidence
Kious, Kondo and Renshaw (2019) is a review rather than a trial, and it reads best as a bridge between mechanism and clinic: it pulls together the bioenergetic hypothesis of depression with the open-label and pilot data on creatine added to SSRIs. The signal is consistent but preliminary, drawn mostly from small studies and weighted towards female participants, with an explicit caution about manic switching in bipolar depression. This places creatine’s mood role well behind its established muscle and exercise evidence, where the ISSN position stand sets the baseline, and firmly in adjunct rather than standalone territory. Related brain and mental-health studies are collected in our research library.
Sources and References
- Kious BM, Kondo DG, Renshaw PF. (2019). Creatine for the treatment of depression. Biomolecules, 9(9), 406.
- Toniolo RA, et al. (2017). Creatine augmentation for bipolar disorder. JAD, 215, 108-113.
- Kreider RB, et al. (2017). ISSN position stand. JISSN, 14, 18.
Further Reading
- creatine dosage guide
- creatine safety profile
- creatine for brain health
- how creatine works
- buying creatine in Malaysia
- creatine for women
Mechanism of Action
Understanding the biochemistry behind creatine's effects provides context for the practical recommendations in this guide. Creatine functions primarily through the ATP-phosphocreatine (ATP-PCr) system:
- Storage: Approximately 95% of the body's creatine is stored in skeletal muscle, with the remaining 5% in the brain, kidneys, and liver
- Conversion: The enzyme creatine kinase attaches a high-energy phosphate group to free creatine, creating phosphocreatine (PCr)
- Energy release: During high-intensity activity, PCr rapidly donates its phosphate group to ADP, regenerating ATP within milliseconds
- Resynthesis: During rest periods, the process reverses — ATP donates a phosphate back to creatine, replenishing PCr stores
This cycle operates continuously in all metabolically active tissues. Supplementation increases the total creatine pool by 20-40%, expanding the energy buffer available for intense physical and cognitive work.