Kious 2019: Creatine Augmentation for Depression

Study Overview

Citation: Kious BM, Kondo DG, Renshaw PF. (2019). Creatine for the treatment of depression. Biomolecules, 9(9), 406.

This comprehensive 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.

Important Caveats

1. Not a standalone treatment — Creatine is being studied as an adjunct to standard antidepressant therapy
2. Early-stage research — Larger randomised controlled trials are needed
3. Gender differences — Most positive results have been in female participants
4. Dose uncertainty — Optimal dosing for mental health effects is not yet established
5. Bipolar caution — Risk of manic switching in bipolar disorder needs monitoring
6. 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.

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:

1. Storage: Approximately 95% of the body’s creatine is stored in skeletal muscle, with the remaining 5% in the brain, kidneys, and liver
2. Conversion: The enzyme creatine kinase attaches a high-energy phosphate group to free creatine, creating phosphocreatine (PCr)
3. Energy release: During high-intensity activity, PCr rapidly donates its phosphate group to ADP, regenerating ATP within milliseconds
4. 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.

Practical Application

Translating the science into actionable steps:

Dosing Protocol

• Standard maintenance: 3-5g creatine monohydrate daily, taken with any meal
• Optional loading phase: 20g/day split into 4 x 5g doses for 5-7 days (faster saturation but not required)
• Body-weight adjustment: Individuals over 80kg may benefit from the upper range (5g); those under 60kg can use the lower range (3g)

What to Expect

Combining with Other Strategies

Creatine works best as part of an integrated approach:

• Progressive resistance training — creatine amplifies the results of structured training programmes
• Adequate protein intake — 1.6-2.2g/kg/day supports the muscle-building effects of creatine
• Sufficient sleep — 7-9 hours per night for optimal recovery and muscle protein synthesis
• Consistent nutrition — creatine is not a substitute for a well-balanced diet

Evidence Quality Assessment

When evaluating claims about creatine, consider the hierarchy of evidence:

1. Systematic reviews and meta-analyses — the strongest evidence, pooling data from multiple studies. Creatine has numerous favourable meta-analyses
2. Randomised controlled trials (RCTs) — well-designed experiments with control groups. Creatine has 500+ published RCTs
3. Observational studies — useful for identifying associations but cannot prove causation
4. Case reports and anecdotes — the weakest evidence, useful for generating hypotheses but not for making recommendations

The recommendations in this article are based on level 1-2 evidence wherever possible.

Malaysian Context

For readers in Malaysia, several local factors are worth considering:

• Climate: Malaysia’s tropical heat (27-33 degrees Celsius average) and high humidity increase fluid requirements. Supplement creatine with 2.5-3.5 litres of daily water intake, more during intense outdoor activity
• Halal considerations: Unflavoured creatine monohydrate powder is synthetically produced and generally considered permissible. See our halal creatine guide for brand-specific verification
• Affordability: Creatine is one of the most cost-effective supplements available in Malaysia, starting from RM0.50 per serving. See our price comparison guide for current pricing
• Availability: Widely available through Shopee, Lazada, and specialty supplement shops across Peninsular Malaysia, Sabah, and Sarawak

For personalised dosage recommendations, try our creatine dosage calculator.

Sources & References

Full citations available in our Research Library.