Psychological illnesses have serious clinical manifestations that can be debilitating. It has been known for a while now that endogenous derangements in the dopaminergic and serotonergic system contribute to the phenotypic manifestation of psychological illness, hence selective serotonin reuptake inhibitors and typical/atypical antipsychotics (D2 dopamine receptor blockers) are used for treatment. However, this is merely a simple explanation for the dysfunction occurring in the central nervous system, which is highly complex, dynamic, and interactive. Exogenous biochemical assaults to the chemistry of the brain can also heavily influence the progression and severity of psychiatric diseases, as well as the response to common pharmacotherapies. Evolving knowledge of the complex interplay of the biochemical pathways of the brain has created new avenues for molecular diagnostics and monitoring of response to pharmacotherapy.
A commonly abused hallucinogen, delta-9-tetrahydrocannabinol (THC) found in marijuana, is an exogenous form of endocannabinoids, which are endogenous neurotransmitters that bind to cannabinoid receptors. The endocannabinoid system has an important role in the vulnerability-stress-inflammation model of schizophrenia pathogenesis, modulating inflammatory processes and cortisol release through the hypothalamic-pituitary axis. An example of an endogenous cannabinoid, anandamide, reduces inflammation by blocking microglial activation and stimulates neurogenesis. A study showed that Schizophrenic low-frequency cannabis users exhibited a 10-fold higher cerebrospinal fluid (CSF) anandamide levels than did schizophrenic high-frequency users, indicating that frequent cannabis exposure may down-regulate anandamide signaling in the CNS of schizophrenic patients1. This can serve as a prognostic tool in treatment refractive forms of schizophrenia, with the downside being the frequent lumbar punctures in order to trend anandamide values.
Leading the charge in innovative biochemical analysis of brain signaling as it pertains to mental health is Dr. Deveroux Ferguson with the UA College of Medicine – Phoenix. His team’s current study of anxiety and depression in mouse models has identified a dysregulation in expression of the SIRT1 gene, which codes for the protein NAD-dependent deacetylase sirtuin-1. The function of this protein is to regulate gene expression through the acetylation of histones and non-histone proteins associated with DNA molecules. They noticed that when the mice were subjected to different stressful and anxiety-provoking stimuli such as a maze test or force swim test, there was overexpression of SIRT1 in the nucleus accumbens (NAc) of the brain. This same reaction was also elicited without the previous stimuli by increasing SIRT1 levels directly in NAc through the use of viral vector-mediated gene transfer. Conversely, ablation of SIRT1 expressing neurons in the NAc eradicated the depressive and anxious symptoms. This has ultimately led to a novel signaling pathway for the development of innovative antidepressants to treat depression and other stress-related disorders2. Other research efforts by Dr. Ferguson also look into how stimulant drugs drive the addiction process in the brain3.
Research efforts such as these are paving the the way for the next generation of therapeutics in the field of psychiatry, which is in need of similar model of personalized medicine seen in the other medical fields. It may be possible that some of these efforts may lead to development of routinely screened markers diagnostic of different mental health issues.
- Leweke, F. Markus et al. Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: Impact of cannabis use. Schizophrenia Research , Volume 94 , Issue 1 , 29 – 36
- Kim, H.-D., Hesterman, J., Call, T., Magazu, S., Keeley, E., Armenta, K., … Ferguson, D. (2016). SIRT1 Mediates Depression-Like Behaviors in the Nucleus Accumbens. The Journal of Neuroscience, 36(32), 8441–8452. http://doi.org/10.1523/JNEUROSCI.0212-16.2016
- Feng, J., Wilkinson, M., Liu, X., Purushothaman, I., Ferguson, D., Vialou, V., … Shen, L. (2014). Chronic cocaine-regulated epigenomic changes in mouse nucleus accumbens. Genome Biology, 15(4), R65. http://doi.org/10.1186/gb-2014-15-4-r65
Ogaga Ojameruaye is a medical student at The University of Arizona College of Medicine – Phoenix. He completed his BS in physiology at The University of Arizona and completed his MS in psychology at Grand Canyon University. Ogaga is passionate about translational medicine, bench-to-bedside research, and the discovery of new diagnostic tools as they contribute to the model of precision medicine.