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Creatine, depression, and brain energetics

The human brain is a powerhouse, consuming tons of fuel to keep all those intricate neural connections going. Brain energetics may play a role in major depression, which makes creatine a potential adjunct to antidepressants and therapy.


Picture this: a small molecule, glutamate, is transported to the surface of a cell and released. A neighboring cell recognizes this small molecule, resulting in a rapid rush of ions into the cell. This voltage change is quickly transferred along the cell until it spreads this chemical message to other neighboring cells. At the end of this complex process, we experience the urge to laugh at a cat video. Thought and mood are complex phenomena that scientists only have the most basic understanding of. Even minor disruptions of these normal signaling processes within the brain can result in changes in mood and wellbeing.

While philosophy and science sometimes disagree about how we identify our self and how our brain chemistry identifies us, there is a clear effect of one on the other. As we have an incomplete understanding of the brain, we must rely primarily on outward symptoms to define numerous mental disorders that affect mood.

For instance, the criteria for a diagnosis of Major Depressive Disorder (MDD) are largely subjective, and counter to common perception don’t necessarily require an individual to feel overwhelmingly sad. The primary indicator used to initially diagnose MDD is a ‘depressed mood,’ which refers to feeling sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, ashamed, or restless. Similar to a few other diseases states discussed in the ERD, MDD appears to have an episodic aspect to it, in which an individual may feel better some weeks than others (similar to the episodic nature of Crohn’s disease). In this case, such an episode is termed a major depressive episode (MDE). So, while an individual event, such as being fired or losing a loved one, can result in MDE, a more persistent state could be diagnosed as MDD.

While the diagnostic criteria for MDD are largely based on perceptions of self and mood, there are several associated measurable biological markers[1]. A frequently observed difference in the brain of people with MDD is a change in brain energetics[2] (as shown in Figure 1), the ability to make and use energy in in the brain. Pharmacological interventions that can treat MDD[3] may have an effect on brain energetics.

Figure 1: How brain energetics differ in people with depression

This may seem pretty specific and odd avenue of research, but keep in mind: the brain is a huge energy sink for the body. The average adult brain uses about 20-25% of our daily energy (or as high as 43% during development![4]). Thus, it’s not surprising that disruptions in brain energy[5] utilization are associated with several medical diagnoses, beyond MDD.

Normally, a Study Deep Dives review only addresses a single study. However, these two studies are two sides of the same coin. They were conducted by largely the same individuals, and involved the same participant group. One was focused on the effects of creatine on symptoms of depression, while the other was trying to explain the mechanism.

The first study was conducted to determine the efficacy of adding five milligrams of daily creatine to a standard antidepressant, in terms of diagnostic criteria of depression, as well as other markers of health (e.g. headaches, dizziness). The second was a mechanistic study designed to explore two things: differences in brain metabolism between healthy people and people with MDD, and an examination of whether creatine and antidepressants helped restore individual biological markers of health.

The two markers researchers examined were levels of N-acetylaspartate (NAA) and rich club connections. NAA is used to assess neuronal viability, integrity, and mitochondrial function. Rich-club-connections occur when neuronal cells have many connections to other local, as well as distant, neurons. These highly ordered brain interconnections expend a large amount of energy to maintain their high degree of interconnectivity and transmit messages over longer distances. They are believed to be play a role in integrating high-level information[6] and their disruption is associated with MDD[7]. Together, these two measures are used to assess the interconnectivity and energy metabolism of the brain.

Researchers have observed that people with major depressive disorder (MDD) have altered brain energetics. Creatine is an important compound that accumulates in the brain and helps buffer depletion of cellular energy. The researchers were attempting to determine if creatine supplementation in individuals with MDD taking antidepressants would be more efficacious than an antidepressant alone. They also examined if there is a measureable difference in brain energetics and brain interconnectivity.

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