Beyond Serotonin: Deepening Our Understanding of Glutamates Role in Psychotic Conditions and Applying It

    In pop star Sia's song Unstoppable she says, "I'm unstoppable, I'm A Porsche with no brakes" (Sia, 2016).  Based on groundbreaking research expanding our understanding of GABA and glutamates roles in neurotransmission, these lyrics may be the perfect analogy for someone experiencing a psychotic episode. For years the bulk of mental health research has focused on the physiological pathways of dopamine and serotonin. These "feel good" neurotransmitters are what most of us think about when considering chemical imbalances that can manifest symptoms associated with behavioral disorders. More recently however, there is exciting new research exploring GABA and glutamate's role in disorders such as schizophrenia and bipolar disorder that could transform the way we diagnose and treat those affected, and possibly even prevent these conditions altogether. 

    Beyond being one of the 20 amino acids found in our body, glutamate is an important excitatory neurotransmitter (Tsapakis, 2020). This role is balanced by GABA which is an inhibitory neurotransmitter. In other words, glutamate is like the gas pedal and GABA is the brakes in regard to brain activity. Using advanced techniques to measure these neurotransmitters, such as magnetic resonance spectroscopy, we have been able to closely associate elevated brain levels of glutamate with bipolar disorder (Shen, 2021). In the case of bipolar disorder, this elevation in glutamate is often accompanied by a disruption in GABAergic response (Brady, 2013).  If there is insufficient GABAergic activity to regulate this excessive glutamergic activity your brain becomes, as Sia would say, "A Porsche with no brakes" with a cascade of excitatory brain activity that can cause mania, hallucinations, sleep disturbances, and psychosis. In fact, glutamate excitotoxicity, an example of positive feedback, is a severe condition resulting from excessive glutamergic activity which can cause brain cells to die. It is triggered by excessive glutamate which then leads to excessive glutamate receptor activity. Many neurodegenerative diseases are associated with glutamate excitotoxicity such as Huntington's, MS, Parkinson's, ALS, and Alzheimer's. Another clue is that those with bipolar disorder or schizophrenia are much more likely to develop these neurodegenerative disorders. This means that repairing the suppression of the GABAergic pathway (i.e. not having brakes) should most likely be the focus of intervention in schizophrenia, anxiety, and bipolar disorder, because this is what makes them physiologically distinct from other neuropsychological disorders. It should be noted that glutamate is actually the direct precursor to GABA, so applying this knowledge is more complicated than simply decreasing glutamate levels and most likely involves the receptors of these ligands to a greater extent than the amount of ligand itself. Because of this, excess glutamate shouldn't necessarily be considered the cause of these disorders, but it certainly seems to be a measurable physiological marker for them. Based on these recent research revelations, it would seem that a disruption of this delicate physiological interaction could be the root cause of bipolar disorder and schizophrenia. The establishment of a measurable physiological biomarker for DSM5 classified mental disorders would be absolutely transformative in the diagnosis and treatment of these conditions. If the MRS (magnetic resonance spectroscopy) test can be used to measure these neurotransmitters clinically (Reddy 2020), then diagnosing mental disorders with questionnaires and smiley face pictures could become a thing of the past. 

   

     Another exciting element of our growing understanding of these conditions is that there are a variety of lifestyle factors that have been shown to have an impact on the GABA/glutamate pathways. These can be implemented to more ethically treat or even prevent related conditions. Alcohol is known to enhance GABA receptor activity leading to a more relaxed state, but its long-term use can suppress this system and actually increase glutamate activity. This is why alcohol withdrawal and psychotic mental disorders share many of the same symptoms and are often included in the same differential diagnosis. Nicotine, caffeine, and cannabis also have a potentially harmful effect on this pathway. Poor sleep, chronic stress and being sedentary can also increase glutamate and decrease GABAergic activity. Diet also plays an important role in maintaining and healing GABAergic tone. Magnesium acts as an NMDA receptor blocker which can reduce the overactivity of the glutamergic pathway. Vitamin B6 is crucial as well because it is actually involved in the process of converting glutamate into GABA. Ever heard of MSG and how bad it is? MSG is monosodium glutamate. It's literally glutamate salt. Another thing to be cautious of is whey protein powder isolate which contains an incredibly high amount of glutamate and can lead to supraphysiological levels. Excessive sugar can also cause glutamate overactivity. Interestingly, fasting has also been shown to improve the conversion of glutamate into GABA (Delgado, 2013). There has also been limited research on the keto diet being able to decrease glutamate in individuals with bipolar disorder, but this research was performed by someone who has bipolar disorder and who is a personal proponent of the keto diet (Campbell, 2025). This research does however support the idea that medical nutrition therapy can be an effective means of treating these disorders in regard to this specific pathway (Onaolopo, 2021). 

    The application of these lifestyle factors provides a mountain of evidence-based intervention options for the treatment of bipolar disorder and schizophrenia without the need for the long-term use of psychoactive substances. Lithium has traditionally been used in the treatment of psychotic conditions but while effective, has some negative metabolic and even cognitive effects (Volkmann, 2020). Historically, we haven't even understood how Lithium causes a reduction in symptoms. Recently we have learned that it decreases glutamate and supports GABAergic pathways, but for whatever reason, scientists still haven't put two and two together. Essentially every current pharmacological intervention for these disorders has some sort of known negative secondary effect, especially when used chronically. These negative effects are comparable to those experienced by the use of alcohol to "self-medicate." It can cause a physiological dependency that only treats the symptoms without ever addressing the cause. This is a grave ethical concern because these medications are sometimes forcibly administered to individuals who are deemed incapable of caring for themselves. Antipsychotic medications have an indirect effect on GABA and glutamate as they effect parallel neurotransmitter pathways, but they do not directly modulate what I believe to be the core cause of these conditions. This more nuanced understanding can guide the development of new medications that can be more directly involved in improving GABAergic tone while minimizing harmful side effects. 

     The onset of bipolar disorder and schizophrenia at about the age of adulthood coincides with the societal expectations of independence and freedom associated with these ages. When considered alongside the variety of lifestyle factors that can impact the glutamate/GABA balance, it is possible that related conditions may manifest as a result of a culmination of inadequate self-care such as deficiencies in sleep, exercise, nutrition, and substance abuse. Could it be possible that the age of onset of these conditions can be explained by young adults simply no longer having someone to buy them groceries or remind them to eat their vegetables and go to sleep at a reasonable time? There has been extensive research into a potential genetic explanation for psychotic disorders with an established association between certain genes and the expression of these disorders but the search for this gene seems fueled by a potentially false assumption about the very nature of these conditions (Henriksen, 2017). We generally think of mental illness as the cause of someone being unable to care for themselves, but what if the inverse is true? What if the lack of self-care is what has led to the physiological disruptions that have manifested psychiatric symptoms creating a positive feedback loop? The other paradigm shattering aspect of this information is that it could mean that psychotic disorders may be entirely preventable in the same way that cardiovascular disease and hypertension are. It could also mean that, at least at certain stages, these conditions could be entirely reversible through lifestyle changes in a similar manner to someone who is prediabetic or prehypertensive. In fact, the prevalence of psychotic disorders in individuals with obesity is similar to the prevalence of diabetes and cardiovascular disease further suggesting a causative relationship between lifestyle factors and the onset of these conditions (Chouinard, 2016). Traditionally, this relationship is blamed on antipsychotics which are known to cause metabolic problems. To simply manage these conditions with medications that can have harmful effects on the body without making relevant lifestyle changes seems imbecilic with respect to our more recent understanding of the relevant physiological pathways. I believe that there is adequate evidence that the treatment of these conditions should focus on healing the GABAergic pathway through lifestyle change and that medication should only be used transiently or in the most severe cases instead of being the status quo for intervention in psychotic disorders. It is my prediction that in a few decades we will think about psychotic conditions and glutamate in a similar fashion to how we think about hypertension and sodium. 

Citations

Brady Jr, R. O., McCarthy, J. M., Prescot, A. P., Jensen, J. E., Cooper, A. J., Cohen, B. M., Renshaw, P. F., & Öngür, D. (2013). Brain gamma-aminobutyric acid (GABA) abnormalities in bipolar disorder. Bipolar Disorders, 15(4), 434–439. https://doi.org/10.1111/bdi.12074

Campbell, I. H., Needham, N., Grossi, H., Kamenska, I., Luz, S., Sheehan, S., Thompson, G., Thrippleton, M. J., Gibbs, M. C., Leitao, J., Moses, T., Burgess, K., Rigby, B. P., Simpson, S. A., McIntosh, E., Brown, R., Meadowcroft, B., Creasy, F., Mitchell-Grigorjeva, M., … Smith, D. J. (2025). A pilot study of a ketogenic diet in bipolar disorder: Clinical, metabolic, and magnetic resonance spectroscopy findings. BJPsych Open, 11(2), Article e34. https://doi.org/10.1192/bjo.2024.841

Chouinard, V.-A., Pingali, S. M., Chouinard, G., Henderson, D. C., Mallya, S. G., Cypess, A. M., Cohen, B. M., & Öngür, D. (2016). Factors associated with overweight and obesity in schizophrenia, schizoaffective and bipolar disorders. Psychiatry Research, 237, 304–310. https://doi.org/10.1016/j.psychres.2016.01.024

Delgado, T. C. (2013). Glutamate and GABA in appetite regulation. Frontiers in Endocrinology, 4, Article 103. https://doi.org/10.3389/fendo.2013.00103

Henriksen, M. G., Nordgaard, J., & Jansson, L. B. (2017). Genetics of schizophrenia: Overview of methods, findings and limitations. Frontiers in Human Neuroscience, 11, Article 322. https://doi.org/10.3389/fnhum.2017.00322

Onaolapo, O. J., & Onaolapo, A. Y. (2021). Nutrition, nutritional deficiencies, and schizophrenia: An association worthy of constant reassessment. World Journal of Clinical Cases, 9(28), 8295–8311. https://doi.org/10.12998/wjcc.v9.i28.8295

Reddy-Thootkur, M., Kraguljac, N. V., & Lahti, A. C. (2022). The role of glutamate and GABA in cognitive dysfunction in schizophrenia and mood disorders: A systematic review of magnetic resonance spectroscopy studies. Schizophrenia Research, 249, 74–84. https://doi.org/10.1016/j.schres.2020.02.001

Shen, J., & Tomar, J. S. (2021, February 23). Elevated brain glutamate levels in bipolar disorder and pyruvate carboxylase-mediated anaplerosis. Frontiers in Psychiatry, 12, Article 640977. https://doi.org/10.3389/fpsyt.2021.640977

Sia. (2016). Unstoppable [Song]. On This is Acting. Monkey Puzzle Records; RCA Records.

Tsapakis, E. M., & Travis, M. J. (2002). Glutamate and psychiatric disorders. Advances in Psychiatric Treatment, 8(3), 189–197. https://doi.org/10.1192/apt.8.3.189

Volkmann, C., Bschor, T., & Köhler, S. (2020). Lithium treatment over the lifespan in bipolar disorders. Frontiers in Psychiatry, 11, Article 377. https://doi.org/10.3389/fpsyt.2020.00377