The Forgotten Role of Creatine and Exercise in Depression

Nicholas reviewed two key trials: one where 5g/day creatine added to an antidepressant showed faster response by week 2 compared to placebo + antidepressant; another where creatine paired with CBT over 8 weeks improved outcomes. He stressed that 5g/day is the standard fitness dose and may be too low for significant brain effects, as most creatine goes to muscle. Higher doses (10g/day) used in TBI and schizophrenia showed benefits, and longer duration (>8 weeks) is likely needed. He also mentioned that dosing should ideally be based on muscle mass (DEXA) but is complex. For depression, it's still an emerging area, and they are seeking funding for a trial combining creatine with resistance training.

Nicholas argued that physicians typically say 'go exercise' without specifics, which is condescending and ineffective. They need to prescribe exercise like a drug, using the F.I.T. principle (Frequency, Intensity, Type, Time) and track progress. He emphasized that while higher intensity gives greater antidepressant benefit, for depressed, sedentary individuals starting low and gradually increasing is key because the initial improvement from complete inactivity to light movement is exponential. For older adults, mild-to-moderate is safer. The literature shows no clear winner among resistance, aerobics, or mind-body; the patient's preference and adherence determine success. He noted that dance emerged in one meta-analysis likely due to social interaction.

Nicholas highlighted that over 50% of American calorie intake is from ultra-processed foods. He cited the SMILES trial and others demonstrating that dietary improvement alone can significantly alleviate depressive symptoms, even without medication changes. He explained that ultra-processed foods not only contribute to depression through inflammation and metabolic dysfunction, but depression itself rewires the brain to crave more of these foods, creating a vicious cycle. He also pointed out the nutrient-dilution effect: a 500-calorie donut replaces a large volume of nutrient-dense whole foods. He stressed that while depression isn't solely caused by diet, it's a critical modifiable factor that can fill the 'stress bucket' and tip someone into a full-blown episode.

Nicholas explained that some people exercise to feel a high, but over time that high diminishes and they need to exercise just to feel normal, mirroring substance dependence. If this one pillar is removed (injury, travel), they lack resilience. He drew from personal experience when he broke his arm and realized he had overly relied on exercise, leaving a void. He emphasized that just as we diversify investments, we need multiple pillars of happiness, including relationships, purpose, and relaxation. This also applies within exercise: have different physical activities so that if you can't run, you can walk or swim.

As his final piece of advice, Nicholas said he wished he had implemented this sooner: treating exercise as part of the day's structure rather than an addition. Life only gets busier with age and responsibilities, so cementing that hour early is crucial. He argued that many people know they should exercise but fail because it's not scheduled. This approach is preventative, building a habit that protects mental health and fills the stress bucket less. It also aligns with his multiple pillars philosophy—making that hour a ritual of self-care that remains even when other areas fluctuate.

Nicholas described how depression imposes a high metabolic demand on the brain, akin to sleep deprivation. In this state, ATP synthesis is compromised, leading to symptoms like low energy and poor concentration. Creatine, stored as phosphocreatine in muscle and brain, serves as a rapid backup energy system by regenerating ATP. He framed depression not as a creatine deficiency but as a condition where this energy buffer could provide meaningful relief. Emerging literature is exploring depression subtypes, including inflammatory depression, where creatine's anti-inflammatory effects might also play a role. This bioenergetic perspective is generating interest across disorders from TBI to schizophrenia.

Nicholas argued that while exercise is known to upregulate neuroplasticity for learning new things, its role in unlearning is equally crucial. In a depressed state, the brain wires automatic negative associations — seeing someone laugh automatically triggers thoughts of being ridiculed. Exercise puts the brain into a neuroplastic state where it becomes more amenable to shedding these wired thought patterns. This may amplify the benefits of therapy like CBT, as the brain is primed to let go of rumination loops. He tied this to the psychological component of the bio-psycho-social model, emphasizing that unlearning is a way to break the cycle of depression.

Nicholas cited the SMILES trial and similar studies where depressed individuals with poor diets had their ultra-processed food intake reduced, leading to significant drops in depression scores even without medication changes. He noted that over 50% of US energy intake comes from ultra-processed foods. The causal link is strengthened because depression also increases cravings for these foods, creating a vicious cycle. He emphasized that replacing nutrients from whole foods with poor-quality, high-calorie ultra-processed foods contributes to inflammation, insulin resistance, and metabolic dysfunction, all of which feed into the bioenergetic model of depression.

After a 2025 Nature Medicine paper found microplastics (primarily nanoplastics) in post-mortem brains, with higher loads in dementia patients, Nicholas co-authored a paper exploring whether microplastic content in ultra-processed foods could mediate the association between diet and depression. He highlighted that chicken nuggets contain 30 times the microplastics of chicken breasts, demonstrating orders-of-magnitude differences. Because studying microplastic exposure is difficult, they proposed creating a dietary microplastic index to estimate intake from food frequency questionnaires and reanalyze existing trials like SMILES to see if microplastic reduction drove mood improvements. He stressed that no direct causal human studies exist yet, but mechanisms from animal studies (inflammation, oxidative stress) align with those of ultra-processed foods.

Nicholas wrote a paper asking whether exercise can be a form of self-harm. He noted that while exercise is largely positive, some individuals — particularly those with exercise dependence or eating disorders — use intense exercise to feel physical pain as a way to cope with emotional distress. Society and even doctors reinforce 'more exercise is better', missing the pathology. He described cases where people need to exercise just to feel normal, akin to substance use where the high diminishes and they require it to avoid a low. He shared a personal anecdote about breaking his arm arm-wrestling in medical school, realizing he was overly reliant on the exercise pillar for wellbeing, which taught him the importance of multiple pillars and not making exercise the sole source of mood regulation.