Brandon Scott Pruett, MD, PhD

Association between schizophrenia and altered energy metabolism

Many people are familiar with the fact that some of the antipsychotic drugs used to treat schizophrenia such as olanzapine can cause weight gain, disruptions of glucose regulation, and may predispose to diabetes1. However, what is less commonly known is that schizophrenia itself is actually associated with similar changes2. In fact, multiple studies have found elevated blood glucose and insulin resistance, hallmarks of prediabetes/diabetes, even in first-episode schizophrenia patients with little to no prior antipsychotic use3. While the significance of this association is debated, there is evidence to suggest that these disruptions may actually play an etiological role in schizophrenia and its development4.

Importance of energy metabolism to brain function

So, how are energy metabolism disruptions relevant to brain function? Well, it turns out that the brain consumes a lot of energy. In fact, while accounting for only 2% of body weight, the brain consumes about 20% of energy intake5. Despite this, it has very little capacity to store energy, and thus is very vulnerable to even minor changes in energy delivery5. Most of the energy consumed in the brain goes toward maintaining synapses5, the connections between neurons that allow them to communicate. Importantly, dysfunction of synapses is heavily implicated in schizophrenia6.

Brain energy metabolism changes in schizophrenia

In schizophrenia, there appears to be a shift in the way the brain utilizes energy with an increased reliance on a process for generating energy from glucose that is much less efficient and generates much less energy overall7. Furthermore, this process leads to a buildup of lactate (AKA lactic acid), which causes increased tissue acidity. Indeed, a number of studies have shown evidence of increased acidity in the brains of schizophrenia patients7,8. Thus, in addition to less efficient energy production, which directly impacts the brain’s ability to maintain synapses, the brain energy metabolism changes associated with schizophrenia further stress the brain through increased acidity.

Schizophrenia brain energy metabolism changes as a potential treatment target

One group looking into this very issue first identified brain energy changes associated with schizophrenia, and then attempted to identify drugs that could reverse these changes. One of the most promising class of drugs they identified includes pioglitazone, which is an FDA-approved medication that increases the body’s sensitivity to insulin and is a commonly used treatment for type II diabetes9. Since as mentioned above insulin resistance is often associated with schizophrenia, use of drugs in this class may be particularly beneficial in people with schizophrenia. This group then treated a mouse model of schizophrenia with pioglitazone and found that it improved memory9.

Of note, pioglitazone has also been studied as an add-on treatment to traditional antipsychotic agents in schizophrenia in two clinical trials though they were both relatively small studies10,11. In addition to improvements in measures of energy metabolism (e.g. decreased glucose, improved insulin sensitivity, and improved lipid profiles), schizophrenia patients receiving pioglitazone also had improvements in depressive and negative symptom scores10,11. While there is often a focus on treating the positive symptoms of schizophrenia, which include delusions and hallucinations, the depressive and negative symptoms of schizophrenia, which include things like social withdrawal, decreased motivation, decreased speech, and diminished ability to experience pleasure, are often the most debilitating symptoms and the least responsive to traditional antipsychotic medications12. Thus, improvement in these symptoms is a really important finding.

Future Directions

While the clinical studies of pioglitazone are promising, as mentioned above, they are relatively small and need to be replicated in larger study samples. Still, they offer a glimpse and demonstrate the importance of targeting brain energy metabolism changes in the treatment of schizophrenia. For one, it may prove an effective way of improving negative and depressive symptoms of schizophrenia. Furthermore, it may also improve broad metabolic changes such as elevated glucose and decreased insulin sensitivity associated not only with schizophrenia but also many of the antipsychotic agents that are the current mainstays of treatment. This is incredibly important as these metabolic changes likely contribute to the greatly increased rate of premature death seen in individuals with schizophrenia13. Thus, continued studies targeting the reversal of metabolic changes in schizophrenia have great potential for not only improving the treatment of this illness but also for reducing its associated early mortality.

Brandon Scott Pruett, MD, PhD
Assistant Professor
Department of Psychiatry & Behavioral Neurobiology
The University of Alabama at Birmingham Heersink School of Medicine

References

1        Pillinger, T. et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry 7, 64-77, doi:10.1016/S2215-0366(19)30416-X (2020).

2        Mitchell, A. J. et al. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders–a systematic review and meta-analysis. Schizophr Bull 39, 306-318, doi:10.1093/schbul/sbr148 (2013).

3        Pillinger, T. et al. Impaired Glucose Homeostasis in First-Episode Schizophrenia: A Systematic Review and Meta-analysis. JAMA Psychiatry 74, 261-269, doi:10.1001/jamapsychiatry.2016.3803 (2017).

4        Li, Z. et al. Glucose and Insulin-Related Traits, Type 2 Diabetes and Risk of Schizophrenia: A Mendelian Randomization Study. EBioMedicine 34, 182-188, doi:10.1016/j.ebiom.2018.07.037 (2018).

5        Pulido, C. & Ryan, T. A. Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals. Sci Adv 7, eabi9027, doi:10.1126/sciadv.abi9027 (2021).

6        Trubetskoy, V. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature 604, 502-508, doi:10.1038/s41586-022-04434-5 (2022).

7        Pruett, B. S. & Meador-Woodruff, J. H. Evidence for altered energy metabolism, increased lactate, and decreased pH in schizophrenia brain: A focused review and meta-analysis of human postmortem and magnetic resonance spectroscopy studies. Schizophr Res 223, 29-42, doi:10.1016/j.schres.2020.09.003 (2020).

8        Hagihara, H. et al. Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders. Neuropsychopharmacology 43, 459-468, doi:10.1038/npp.2017.167 (2018).

9        Sullivan, C. R. et al. Connectivity Analyses of Bioenergetic Changes in Schizophrenia: Identification of Novel Treatments. Mol Neurobiol 56, 4492-4517, doi:10.1007/s12035-018-1390-4 (2019).

10      Smith, R. C. et al. Effects of pioglitazone on metabolic abnormalities, psychopathology, and cognitive function in schizophrenic patients treated with antipsychotic medication: a randomized double-blind study. Schizophr Res 143, 18-24, doi:10.1016/j.schres.2012.10.023 (2013).

11      Iranpour, N. et al. The effects of pioglitazone adjuvant therapy on negative symptoms of patients with chronic schizophrenia: a double-blind and placebo-controlled trial. Hum Psychopharmacol 31, 103-112, doi:10.1002/hup.2517 (2016).

12      Buckley, P. F. & Stahl, S. M. Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or cul-de-sac? Acta Psychiatr Scand 115, 93-100, doi:10.1111/j.1600-0447.2007.00992.x (2007).

13      Olfson, M., Gerhard, T., Huang, C., Crystal, S. & Stroup, T. S. Premature Mortality Among Adults With Schizophrenia in the United States. JAMA Psychiatry 72, 1172-1181, doi:10.1001/jamapsychiatry.2015.1737 (2015).