Introduction
Among all mental disorders, schizophrenia is one of the most severe mental illnesses in the human population. This is a chronic progressive disease, proceeding with polymorphic symptoms, leading to persistent impairment of social adaptation and the ability to work with patients at a young age (McCutcheon et al., 2020). At the heart of this disorder is a violation of the processes of synaptic transmission, leading to damage to neurons and their pronounced dysfunction (Searles & Knight, 2018).
According to modern concepts, schizophrenia is a multifactorial disease, the etiology, and pathogenesis of which are still represented by various hypotheses, which have not yet been summarized into one complex. It is unambiguous that the pathogenesis of this disease is based on a violation of neurotransmitter processes in the central nervous system (Alanen et al., 2018). In addition, a significant role in schizophrenia is played by a violation of the mutual regulation of the nervous and immune systems (Alanen et al., 2018). This paper analyzes several major current approaches to studying schizophrenia. It specifically focuses on several streams of research. First, it outlines hormonal and genetic mechanisms by reviewing the most recent studies on this matter. Second, it analyzes the role of neurotransmitters and the research on brain processes involved in the development of schizophrenia.
Hormonal and Genetic Mechanisms
Generally accepted modern biological theories of schizophrenia, based on experimental data and supported by clinical studies, include dopamine and glutamate theories. Along with other actively studied hypotheses, studies of the role of sex hormones in the pathogenesis of schizophrenia are of interest. The most famous in the current literature is the estrogen hypothesis of schizophrenia. First, the hypothesis of hypoestrogenism describes chronic estrogen deficiency in women with schizophrenia (Kulkarni et al., 2019). Second, the estrogen-protective hypothesis postulates the protective role of estrogens in women of childbearing age against the development of schizophrenia (Newton-Mann et al., 2017). Scientific research has shown that estradiol has a variety of functions in the brain. Thus, it was found that estradiol regulates gene expression, neuronal viability, the process of differentiation of neurons and glia, and synaptic transmission, and also has anti-inflammatory and reparative properties (Searles et al., 2018). Estrogens can modulate the number and sensitivity of dopamine receptors and monoaminergic transmission and significantly affect dopamine, serotonin, and GABA (Krolick et al., 2018). Thus, estrogen is seen to be the most important factor in schizophrenia development.
Sex hormones play an essential role in the formation and activation of neural connections in the brain. There is an assumption that a violation of the structural connections of the brain, a change in the density of the nervous tissue of the brain regions associated with the provision of attention, working memory, and executive and emotional-volitional functions in schizophrenia may be partially associated with an imbalance of sex hormones (Soria et al., 2018). In a few studies that control both the level of estrogens and the structural features of the brain, in patients with psychotic disorders, an association between reduced levels of estrogen and a decrease in the thickness of the cerebral cortex is found, which is consistent with the estrogen hypothesis of schizophrenia (Jerotic et al., 2021). Although the influence of sex hormones on the development of schizophrenia was known more than a century ago, the mechanisms of this influence are still poorly understood.
The estrogen hypotheses available today are being actively studied and are being confirmed in experimental and clinical studies. The available data indicate that the estrogen hypotheses do not contradict other modern ideas but rather supplement them. This is especially important for the development of a differentiated approach to the treatment of patients, taking into account their age and gender characteristics, and hormonal levels.
It is necessary to distinguish the chronic course of schizophrenia from therapeutically resistant (TR). Despite the chronic course of schizophrenia, a fairly large number of patients respond well to antipsychotic therapy by reducing symptoms and/or improving functioning (Elkis & Buckley, 2016). However, about one-third of patients do not respond to treatment – they are considered therapeutically resistant (Elkis & Buckley, 2016). For practical health care, this form of schizophrenia is associated with significant impairment of the functioning of these patients, longer hospitalization periods, and, accordingly, rather large financial costs (Elkis & Buckley, 2016). Despite the long-term study of the problem of TR-schizophrenia, the etiology of this condition is unknown.
The genes for receptors and SLC6A4, the main serotonin transporter, are the most fully studied in the aspect of TP-schizophrenia. In addition to the receptors proper (DRD1-5), the dopamine system also includes carrier proteins (DAT – dopamine transporter), metabolic enzymes (COMT – catechol-methyltransferase, MAO – monoamine oxidase) (Baou et al., 2016). A special gene, disrupted in schizophrenia, is also highlighted – DISC1 (Disrupted-in-Schizophrenia-1). The most intriguing information about this gene is that its exact function in the body is unknown, but its role has been shown as a genetic marker of schizophrenic spectrum disorders (Shao et al., 2017). Naturally, its role in the development of TR-schizophrenia is also being studied.
Neurotransmitters and Brain Processes
Previously, the development of schizophrenia was mainly associated with dopaminergic system dysfunction. However, the accumulated data suggested that the pathogenesis of schizophrenia may include dysfunction in the dopaminergic, glutamatergic, serotonergic, and GABAergic systems, which can lead to aberrant functioning of interneurons and manifest itself in the form of cognitive, behavioral, and social dysfunction (Yang & Tsai, 2017). According to graph theory, interactions between neurotransmitters can be depicted as “nodes” and “edges” (Yang & Tsai, 2017). The oxidative balance, immune and glutamatergic systems can be multiple nodes that block the “central hub” (Yang & Tsai, 2017). Thus, an imbalance in any node’s part can impact the whole system.
It was suggested that positive symptomatology in schizophrenia develops due to hyperactivity of dopaminergic neurotransmission. The classical dopaminergic hypothesis is based on the identification of high concentrations of dopamine in the terminals and D2 receptors of the subcortical region of the brain and the nucleus accumbens (Foley, 2019). With the accumulation of knowledge in this area, a hypothesis was formulated that a deficiency of dopamine neurotransmission in dopamine receptors DRD1 in the prefrontal cortex can result in cognitive impairment and other schizophrenia symptoms (Rice et al., 2016). Thus, dopamine is also seen as an essential factor in schizophrenia development.
Glutamate is the primary excitatory neurotransmitter of the central nervous system, and it is used by all neurons of the cerebral cortex, projecting axons beyond its limits (Uno & Coyle, 2019). It is known that glutamate plays a vital role in synaptic plasticity, one of the manifestations of which is long-term potentiation and the formation of new synapses (Uno & Coyle, 2019). An increasing number of publications indicate the involvement of glutamate signaling in the neurobiology of schizophrenia and other psychiatric disorders such as major depression and bipolar disorder (Uno & Coyle, 2019). Posthumous studies show an altered density of dendritic spines in the brains of patients with schizophrenia, indicating that remodeled neural networks may be involved in the disease development (Berdenis van Berlekom et al., 2020). Drugs that interact with the glutamate system tend to attract attention because they show efficacy in animal models and potential therapeutic effects in a clinical setting.
Serotonin is an important neurotransmitter involved in regulating cognitive functions, memory, learning ability, appetite, vascular tone, coagulation, functioning of the immune system, dopamine release, and sexual desire (Stahl, 2018). Serotonin signaling in the brain through cAMP and CREB activates the expression of many genes that encode proteins required for neuronal growth and brain cell viability (Wang et al., 2018). In addition, the signaling pathways of serotonin interact with the signaling pathways of dopamine, glutamate, acetylcholine, and gamma-aminobutyric acid. Dysfunction of serotonergic neurotransmission is a critical link in the pathogenesis of schizophrenia (Yang & Tsai, 2017). Serotonin receptors are involved in various neurobiological manifestations such as aggressiveness, anxiety, increased appetite, decreased learning ability, and memory impairment; they are also targets for antipsychotics. According to the serotonin theory, the development of schizophrenia is due to a deficiency in serotonergic neurotransmission (Stahl, 2018). Thus, serotonin is also included in the explanation of schizophrenia development.
According to the kynurenic hypothesis, schizophrenia is considered the result of an imbalance in the metabolism pathways of tryptophan (Plitman et al., 2017). Kynurenic acid (KA) is a neuroactive metabolite of tryptophan, formed in the brain and peripherally, which is known to block ionotropic glutamate and α7-nicotinic acetylcholine receptors (α7nAChR), acting as a ligand for the GPR35 receptor for the G-linked protein and the receptor human (AHR) (Plitman et al., 2017). KA appears to modulate several mechanisms that lead to schizophrenia development, including dopaminergic transmission in the mesolimbic and mesocortical regions or glutamatergic neurotransmission (Plitman et al., 2017). The kynurenic hypothesis discusses the appearance of various symptoms of schizophrenia and cognitive impairments characteristic of the disease.
There is also evidence of the relationship between cognitive impairment in schizophrenia and changes in brain structures. Structural changes in the brain, such as a decrease in the volume of gray matter and a violation of the integrity of the white matter, are considered a substrate for the development of cognitive impairments in schizophrenia (Mouchliantis et al., 2016). The data of functional brain imaging methods revealed abnormal neural activity in solving cognitive tasks associated with the function of working and long-term memory, decision-making, and emotional response to relevant situations (Keshavan et al., 2017). At the level of structural and functional connectomes, one can see the differences in the interaction of neural networks in schizophrenic patients and healthy ones (Sun et al., 2019). These differences are especially noticeable when constructing dynamic connectomes at rest.
The influence of a decrease in the volume of the prefrontal cortex and anterior cingulate gyrus on the development of disorders of emotional intelligence and social functioning is also shown, which is reflected in the concept of the theory of mind or the concept of cognitive dysmetria (Mothersill et al., 2016). It is assumed that rest networks can be used as a biomarker for preserving the cognitive-affective sphere in the study of neurodegenerative processes (Mouchliantis et al., 2016). Further research in this direction is required; in particular, conducting a comprehensive neurophysiological, immunological and clinical examination of patients in dynamics is crucial. It will make it possible to establish stable relationships between the studied parameters, as well as the clinical significance of changes detected in patients with fMRI and assessment of immunological parameters, to determine the possibility of research results implementation into clinical practice.
References
Alanen, Y. O., Fleck, S., Jackson, M., & Leinonen, S. L. (2018). Schizophrenia: Its origins and need-adapted treatment. Routledge.
Baou, M., Boumba, V. A., Petrikis, P., Rallis, G., Vougiouklakis, T., & Mavreas, V. (2016). A review of genetic alterations in the serotonin pathway and their correlation with psychotic diseases and response to atypical antipsychotics. Schizophrenia Research, 170(1), 18-29.
Berdenis van Berlekom, A., Muflihah, C. H., Snijders, G. J., MacGillavry, H. D., Middeldorp, J., Hol, E. M., Kahn, R. S., & De Witte, L. D. (2020). Synapse pathology in schizophrenia: A meta-analysis of postsynaptic elements in postmortem brain studies. Schizophrenia Bulletin, 46(2), 374-386.
Elkis, H., & Buckley, P. F. (2016). Treatment-resistant schizophrenia. Psychiatric Clinics, 39(2), 239-265.
Foley, P. B. (2019). Dopamine in psychiatry: a historical perspective. Journal of Neural Transmission, 126(4), 473-479.
Jerotic, S., Lalovic, N., Pejovic, S., Mihaljevic, M., Pavlovic, Z., Britvic, D., Risimic, D., Soldatovic, I., Silverstein, S.M., & Maric, N. P. (2021). Sex differences in macular thickness of the retina in patients with psychosis spectrum disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 110, 110280-110293.
Keshavan, M. S., Eack, S. M., Prasad, K. M., Haller, C. S., & Cho, R. Y. (2017). Longitudinal functional brain imaging study in early course schizophrenia before and after cognitive enhancement therapy. NeuroImage, 151, 55-64.
Krolick, K. N., Zhu, Q., & Shi, H. (2018). Effects of estrogens on central nervous system neurotransmission: Implications for sex differences in mental disorders. Progress in Molecular Biology and Translational Science, 160, 105-171.
Kulkarni, J., Butler, S., & Riecher-Rössler, A. (2019). Estrogens and SERMS as adjunctive treatments for schizophrenia. Frontiers in Neuroendocrinology, 53, 100743-100758.
McCutcheon, R. A., Marques, T. R., & Howes, O. D. (2020). Schizophrenia—An overview. JAMA Psychiatry, 77(2), 201-210.
Mothersill, O., Knee-Zaska, C., & Donohoe, G. (2016). Emotion and theory of mind in schizophrenia—Investigating the role of the cerebellum. The Cerebellum, 15(3), 357-368.
Mouchlianitis, E., McCutcheon, R., & Howes, O. D. (2016). Brain-imaging studies of treatment-resistant schizophrenia: A systematic review. The Lancet Psychiatry, 3(5), 451-463.
Newton-Mann, E., Finney, C., Purves-Tyson, T., & Gogos, A. (2017). Estrogen receptors: Mechanism of action and relevance to schizophrenia. Current Psychiatry Reviews, 13(1), 55-64.
Plitman, E., Iwata, Y., Caravaggio, F., Nakajima, S., Chung, J. K., Gerretsen, P., Kim, J., Takeuchi, H., Chakravarty, M., Remington, G., & Graff-Guerrero, A. (2017). Kynurenic acid in schizophrenia: A systematic review and meta-analysis. Schizophrenia Bulletin, 43(4), 764-777.
Rice, M. W., Roberts, R. C., Melendez-Ferro, M., & Perez-Costas, E. (2016). Mapping dopaminergic deficiencies in the substantia nigra/ventral tegmental area in schizophrenia. Brain Structure and Function, 221(1), 185-201.
Searles, H. F., & Knight, R. P. (2018). Collected papers on schizophrenia and related subjects. Routledge.
Searles, S., Makarewicz, J. A., & Dumas, J. A. (2018). The role of estradiol in schizophrenia diagnosis and symptoms in postmenopausal women. Schizophrenia Research, 196, 35-38.
Shao, L., Lu, B., Wen, Z., Teng, S., Wang, L., Zhao, Y., Ishizuka, K., Xu, X., Sawa, A., Song, H., Ming, G., & Zhong, Y. (2017). Disrupted-in-Schizophrenia-1 (DISC1) protein disturbs neural function in multiple disease-risk pathways. Human Molecular Genetics, 26(14), 2634-2648.
Soria, V., González-Rodríguez, A., Huerta-Ramos, E., Usall, J., Cobo, J., Bioque, M., Barbero, J. D., García-Rizo, C., Tost, M., Monreal, J. A., PNECAT Group & Labad, J. (2018). Targeting hypothalamic-pituitary-adrenal axis hormones and sex steroids for improving cognition in major mood disorders and schizophrenia: A systematic review and narrative synthesis. Psychoneuroendocrinology, 93, 8-19.
Stahl, S. M. (2018). Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: Dopamine, serotonin, and glutamate. CNS Spectrums, 23(3), 187-191.
Sun, Y., Collinson, S. L., Suckling, J., & Sim, K. (2019). Dynamic reorganization of functional connectivity reveals abnormal temporal efficiency in schizophrenia. Schizophrenia bulletin, 45(3), 659-669.
Uno, Y., & Coyle, J. T. (2019). Glutamate hypothesis in schizophrenia. Psychiatry and Clinical Neurosciences, 73(5), 204-215.
Wang, H., Xu, J., Lazarovici, P., Quirion, R., & Zheng, W. (2018). CAMP response element-binding protein (CREB): A possible signaling molecule link in the pathophysiology of schizophrenia. Frontiers in Molecular Neuroscience, 11, 255-271.
Yang, A. C., & Tsai, S. J. (2017). New targets for schizophrenia treatment beyond the dopamine hypothesis. International Journal of Molecular Sciences, 18(8), 1689-1701.