The Implications of Adverse Pharmacologic Reactions and Complex Pathogenic Mechanisms in Schizophrenia

Authors

  • Puiu Olivian Stovicek Lecturer, Department of Pharmacology, Faculty of Nursing, Târgu Jiu Subsidiary, “Titu Maiorescu” University, Bucharest, Romania
  • Dragoș Marinescu Professor, Academy of Medical Sciences of Romania, University of Medicine and Pharmacy of Craiova Brunch, Craiova, Romania
  • Liana Păuna-Cristian Department of Radiology, Gral Medical Center, Bucharest, Romania
  • Ileana Marinescu Associate Professor, Discipline of Psychiatry, 5th Department, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania

DOI:

https://doi.org/10.18662/brain/12.2/206

Keywords:

dopamine, extrapyramidal symptoms, homocysteine, prolactin, hypofrontality

Abstract

Schizophrenia is a major health problem in which diversification and increase in the quality of antipsychotic molecules did not yield the anticipated results. that the etiopathogenesis of schizophrenia accounts for a combination of genetic factors forming the genetic spectrum of vulnerability for schizophrenia. The neurodevelopmental anomalies correlated with the gestational period and obstetric traumatisms raises major pharmacological management issues. The two levels of vulnerability (genetic and neurodevelopmental) are the basis of the pathogeny of side effects induced by antipsychotic medication. The most severe side effects are related to extrapyramidal symptoms, hyperhomocysteinemia, hypofrontality, impairment of the neurovascular unit and neuronal metabolic processes. Understanding these particular mechanisms will allow the clinician to identify the pathogenic model of schizophrenia, customized for each specific case. The adverse drug reaction decreases the compliance and adherence to the treatment, determining repeated discontinuations with psychotic relapses, and may trigger psychopathogenic bursts deteriorating the structural and cerebral functional balance. The type of psychotropic medication must be taken into account, as well as the concomitant medication administered for comorbidities associated with schizophrenia. The cerebral vascular modifications are correlated with the metabolic syndrome induced by antipsychotic medication. This complex syndrome, associated also with modifications in the homocysteine metabolism, determines weight gain, obesity, high blood pressure, ischemic cardiopathy, hyperglycemia and dyslipidemia. Identification of possible biological or neuroimaging markers helps and their early correction may prevent the onset of neurodegenerative evolution and irreversible cerebral atrophies, as well as decrease the risk of side effect that may endanger the life of the schizophrenic patient. The complexity of the pathogenic mechanisms requires a prophylactic behavior, not based on therapeutic switch, but on the proactive, customized pharmacologic intervention, addressing the pathogenic chains.

Author Biographies

Puiu Olivian Stovicek, Lecturer, Department of Pharmacology, Faculty of Nursing, Târgu Jiu Subsidiary, “Titu Maiorescu” University, Bucharest, Romania

Lecturer, Department of Pharmacology, Faculty of Nursing, Târgu Jiu Subsidiary, “Titu Maiorescu” University, Bucharest, Romania

Dragoș Marinescu, Professor, Academy of Medical Sciences of Romania, University of Medicine and Pharmacy of Craiova Brunch, Craiova, Romania

Professor, Academy of Medical Sciences of Romania, University of Medicine and Pharmacy of Craiova Brunch, Craiova, Romania

Liana Păuna-Cristian, Department of Radiology, Gral Medical Center, Bucharest, Romania

Department of Radiology, Gral Medical Center, Bucharest, Romania

Ileana Marinescu, Associate Professor, Discipline of Psychiatry, 5th Department, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania

Associate Professor, Discipline of Psychiatry, 5th Department, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania

References

Alberich, S., Fernández-Sevillano, J., González-Ortega, I., Usall, J., Sáenz, M., González-Fraile, E., & González-Pinto, A. (2019). A systematic review of sex-based differences in effectiveness and adverse effects of clozapine. Psychiatry Research, 280, 112506. https://doi.org/10.1016/j.psychres.2019.112506

Andreasen, N. C., O'Leary, D. S., Flaum, M., Nopoulos, P., Watkins, G. L., Boles Ponto, L. L., & Hichwa, R. D. (1997). Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients. Lancet, 349(9067), 1730–1734. https://doi.org/10.1016/s0140-6736(96)08258-x

Anghelescu A. (2018). Uncommon association of two anatomical variants of cerebral circulation: A fetal-type posterior cerebral artery and inferred artery of percheron, complicated with paramedian thalamomesencephalic stroke-case presentation and literature review. Case Reports in Neurological Medicine, 2018, 4567206. https://doi.org/10.1155/2018/4567206

Blair, D. T., & Dauner, A. (1992). Extrapyramidal symptoms are serious side-effects of antipsychotic and other drugs. The Nurse Practitioner, 17(11), 56–67. https://doi.org/10.1097/00006205-199211000-00018

Bodranghien, F., Bastian, A., Casali, C., Hallett, M., Louis, E. D., Manto, M., Mariën, P., Nowak, D. A., Schmahmann, J. D., Serrao, M., Steiner, K. M., Strupp, M., Tilikete, C., Timmann, D., & van Dun, K. (2016). Consensus paper: Revisiting the symptoms and signs of cerebellar syndrome. Cerebellum, 15(3), 369–391. https://doi.org/10.1007/s12311-015-0687-3

Brugada, P., & Brugada, J. (1992). Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. Journal of the American College of Cardiology, 20(6), 1391–1396. https://doi.org/10.1016/0735-1097(92)90253-j

Burada, E., Marinescu, I., Rogoveanu, O. C., Dobrescu, A., Taisescu, C., Burada, F., Sfredel, V., & Balseanu, T. A. (2019). Vitamin B12 blood level is correlated with drug-induced extrapyramidal symptoms in schizophrenic patients. Revista de Chimie, 70(2), 630-632. https://doi.org/10.37358/RC.19.2.6972

Caldani, S., Bucci, M. P., Lamy, J. C., Seassau, M., Bendjemaa, N., Gadel, R., Gaillard, R., Krebs, M. O., & Amado, I. (2017). Saccadic eye movements as markers of schizophrenia spectrum: Exploration in at-risk mental states. Schizophrenia Research, 181, 30–37. https://doi.org/10.1016/j.schres.2016.09.003

Campdelacreu J. (2014). Parkinson disease and Alzheimer disease: environmental risk factors. Neurologia, 29(9), 541–549. https://doi.org/10.1016/j.nrl.2012.04.001

Canham, P. B., Korol, R. M., Finlay, H. M., Hammond, R. R., Holdsworth, D. W., Ferguson, G. G., & Lucas, A. R. (2006). Collagen organization and biomechanics of the arteries and aneurysms of the human brain. In G. A. Holzapfel & R. W. Ogden (Eds.), Mechanics of biological tissue (pp. 307-322). Springer.

Chan, H. Y., Chang, C. J., Chiang, S. C., Chen, J. J., Chen, C. H., Sun, H. J., Hwu, H. G., & Lai, M. S. (2010). A randomised controlled study of risperidone and olanzapine for schizophrenic patients with neuroleptic-induced acute dystonia or parkinsonism. Journal of Psychopharmacology, 24(1), 91–98. https://doi.org/10.1177/0269881108096070

Chirita, R, Sacuiu, I, Burlea, A, & Chirita, V. (2012). The role of nitric oxide inhibitors in treatment on symptom severity and cognitive deficits in schizophrenia. International Journal Of Neuropsychopharmacology, 15, 113-113.

Ciubara, A., Cartas, N., Burlea, L. S., Chirita, R., Ciubara, B. A., Untu, I., & Iliescu, D. B. (2015). The relationship between schizophrenia and criminality. European Psychiatry, 30(S1), 1-1. https://doi.org/10.1016/s0924-9338(15)30603-9

Coletti, A. M., Singh, D., Kumar, S., Shafin, T. N., Briody, P. J., Babbitt, B. F., Pan, D., Norton, E. S., Brown, E. C., Kahle, K. T., Del Bigio, M. R., & Conover, J. C. (2018). Characterization of the ventricular-subventricular stem cell niche during human brain development. Development, 145(20), dev170100. https://doi.org/10.1242/dev.170100

Coppedè, F. (2012). Genetics and epigenetics of Parkinson's disease. The Scientific World Journal, 2012, 489830. https://doi.org/10.1100/2012/489830

Enokido, Y., Suzuki, E., Iwasawa, K., Namekata, K., Okazawa, H., & Kimura, H. (2005). Cystathionine beta-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS. FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 19(13), 1854–1856. https://doi.org/10.1096/fj.05-3724fje

Fleiss, B., Wong, F., Brownfoot, F., Shearer, I. K., Baud, O., Walker, D. W., Gressens, P., & Tolcos, M. (2019). Knowledge gaps and emerging research areas in intrauterine growth restriction-associated brain injury. Frontiers in Endocrinology, 10, 188. https://doi.org/10.3389/fendo.2019.00188

Hassan, A., Hunt, B. J., O'Sullivan, M., Bell, R., D'Souza, R., Jeffery, S., Bamford, J. M., & Markus, H. S. (2004). Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain, 127(1), 212–219. https://doi.org/10.1093/brain/awh023

Higashi, K., Medic, G., Littlewood, K. J., Diez, T., Granström, O., & De Hert, M. (2013). Medication adherence in schizophrenia: factors influencing adherence and consequences of nonadherence, a systematic literature review. Therapeutic Advances in Psychopharmacology, 3(4), 200–218. https://doi.org/10.1177/2045125312474019

Höistad, M., Segal, D., Takahashi, N., Sakurai, T., Buxbaum, J. D., & Hof, P. R. (2009). Linking white and grey matter in schizophrenia: oligodendrocyte and neuron pathology in the prefrontal cortex. Frontiers in Neuroanatomy, 3, 9. https://doi.org/10.3389/neuro.05.009.2009

Hyde, T. M., Deep-Soboslay, A., Iglesias, B., Callicott, J. H., Gold, J. M., Meyer-Lindenberg, A., Honea, R. A., Bigelow, L. B., Egan, M. F., Emsellem, E. M., & Weinberger, D. R. (2008). Enuresis as a premorbid developmental marker of schizophrenia. Brain: A Journal of Neurology, 131(9), 2489–2498. https://doi.org/10.1093/brain/awn167

Iosifescu, D. V., Renshaw, P. F., Lyoo, I. K., Lee, H. K., Perlis, R. H., Papakostas, G. I., Nierenberg, A. A., & Fava, M. (2006). Brain white-matter hyperintensities and treatment outcome in major depressive disorder. The British Journal of Psychiatry, 188, 180–185. https://doi.org/10.1192/bjp.188.2.180

Jardri, R., Hugdahl, K., Hughes, M., Brunelin, J., Waters, F., Alderson-Day, B., Smailes, D., Sterzer, P., Corlett, P. R., Leptourgos, P., Debbané, M., Cachia, A., & Denève, S. (2016). Are hallucinations due to an imbalance between excitatory and inhibitory influences on the brain? Schizophrenia Bulletin, 42(5), 1124–1134. https://doi.org/10.1093/schbul/sbw075

Kaar, S. J., Angelescu, I., Marques, T. R., & Howes, O. D. (2019). Pre-frontal parvalbumin interneurons in schizophrenia: a meta-analysis of post-mortem studies. Journal of Neural Transmission, 126(12), 1637–1651. https://doi.org/10.1007/s00702-019-02080-2

Kapczinski, F., & Streb, L. G. (2014). Neuroprogression and staging in psychiatry: Historical considerations. Revista Brasileira de Psiquiatria, 36(3), 187–188. https://doi.org/10.1590/1516-4446-2014-3605

Krzystanek, M., & Pałasz, A. (2019). NMDA receptor model of antipsychotic drug-induced hypofrontality. International Journal of Molecular Sciences, 20(6), 1442. https://doi.org/10.3390/ijms20061442

Lambert, M., Karow, A., Leucht, S., Schimmelmann, B. G., & Naber, D. (2010). Remission in schizophrenia: validity, frequency, predictors, and patients' perspective 5 years later. Dialogues in Clinical Neuroscience, 12(3), 393–407. https://doi.org/10.31887/DCNS.2010.12.3/mlambert

Lewerenz, J., & Maher, P. (2015). Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence? Frontiers in Neuroscience, 9, 469. https://doi.org/10.3389/fnins.2015.00469

Marek, G. J., Behl, B., Bespalov, A. Y., Gross, G., Lee, Y., & Schoemaker, H. (2010). Glutamatergic (N-methyl-D-aspartate receptor) hypofrontality in schizophrenia: Too little juice or a miswired brain? Molecular Pharmacology, 77(3), 317–326. https://doi.org/10.1124/mol.109.059865

Marinescu, I., Marinescu, D., Pauna-Cristian, L., & Stovicek, P. O., (2021) Particularities of cerebral small vessel disease in schizophrenia. In A. Gonzalez-Quevedo, S. Dambinova & K. Bettermann (Eds.), Understanding and treating cerebral small vessel disease (pp 383-428). Nova Science Publishers Inc.

Marinescu, I., Stovicek, P. O., Marinescu, D., Papacocea, M. T., Manea, M. C., Ionescu, E., Badarau, I. A., Manea, M., Papacocea, I. R., & Ciobanu, A. M. (2019). Cinnarizine - Potential trigger of the dopamine supersensitivity psychosis in patients with paranoid schizophrenia particular neurobiochemical model. Revista de Chimie, 70(8), 3003-3007. https://doi.org/10.37358/RC.19.8.7474

Miller, S. L., Huppi, P. S., & Mallard, C. (2016). The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome. The Journal of Physiology, 594(4), 807–823. https://doi.org/10.1113/JP271402

Mufaddel, A. A., & Al-Hassani, G. A. (2014). Familial idiopathic basal ganglia calcification (Fahr`s disease). Neurosciences, 19(3), 171–177. https://pubmed.ncbi.nlm.nih.gov/24983277/

Muntjewerff, J. W., Kahn, R. S., Blom, H. J., & den Heijer, M. (2006). Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Molecular Psychiatry, 11(2), 143–149. https://doi.org/10.1038/sj.mp.4001746

Nachimuthu, S., Assar, M. D., & Schussler, J. M. (2012). Drug-induced QT interval prolongation: mechanisms and clinical management. Therapeutic Advances in Drug Safety, 3(5), 241–253. https://doi.org/10.1177/2042098612454283

Nishioka, M., Bundo, M., Kasai, K., & Iwamoto, K. (2012). DNA methylation in schizophrenia: progress and challenges of epigenetic studies. Genome Medicine, 4(12), 96. https://doi.org/10.1186/gm397

Obyedkov, I., Skuhareuskaya, M., Skugarevsky, O., Obyedkov, V., Buslauski, P., Skuhareuskaya, T., & Waszkiewicz, N. (2019). Saccadic eye movements in different dimensions of schizophrenia and in clinical high-risk state for psychosis. BMC Psychiatry, 19, 110. https://doi.org/10.1186/s12888-019-2093-8

Orefici, G., Cardona, F., Cox, C. J., & Cunningham, M. W. (2016) Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). In J. J. Ferretti, D. L. Stevens & V. A. Fischetti, (Eds.), Streptococcus pyogenes: Basic biology to clinical manifestations (pp. 827-868). University of Oklahoma Health Sciences Center.

Owega, A., Klingelhöfer, J., Sabri, O., Kunert, H. J., Albers, M., & Sass, H. (1998). Cerebral blood flow velocity in acute schizophrenic patients. A transcranial Doppler ultrasonography study. Stroke, 29(6), 1149–1154. https://doi.org/10.1161/01.str.29.6.1149

Pinault D. (2011). Dysfunctional thalamus-related networks in schizophrenia. Schizophrenia Bulletin, 37(2), 238–243. https://doi.org/10.1093/schbul/sbq165

Revheim, N., Corcoran, C. M., Dias, E., Hellmann, E., Martinez, A., Butler, P. D., Lehrfeld, J. M., DiCostanzo, J., Albert, J., & Javitt, D. C. (2014). Reading deficits in schizophrenia and individuals at high clinical risk: relationship to sensory function, course of illness, and psychosocial outcome. The American Journal of Psychiatry, 171(9), 949–959. https://doi.org/10.1176/appi.ajp.2014.13091196

Robinson D. A. (1964). The mechanics of human saccadic eye movement. The Journal of Physiology, 174(2), 245–264. https://doi.org/10.1113/jphysiol.1964.sp007485

Saalmann, Y. B., & Kastner, S. (2015). The cognitive thalamus. Frontiers in Systems Neuroscience, 9, 39. https://doi.org/10.3389/fnsys.2015.00039

Sachdev, P. S. (2005). Homocysteine and brain atrophy. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 29(7), 1152–1161. https://doi.org/10.1016/j.pnpbp.2005.06.026

Schmahmann, J. D., & Sherman, J. C. (1998). The cerebellar cognitive affective syndrome. Brain: A Journal of Neurology, 121(4), 561–579. https://doi.org/10.1093/brain/121.4.561

Sacuiu, I., Chirita, V., Burlea, A., & Chirita, R. (2012). The effect of the atypical antipsychotics on cognitive deficit in schizophrenia. International Journal OF Neuropsychopharmacology, 15, 61.

Sears, L. L., Andreasen, N. C., & O'Leary, D. S. (2000). Cerebellar functional abnormalities in schizophrenia are suggested by classical eyeblink conditioning. Biological Psychiatry, 48(3), 204–209. https://doi.org/10.1016/s0006-3223(00)00247-x

Shetty, A. S., Bhatia, K. P., & Lang, A. E. (2019). Dystonia and Parkinson's disease: What is the relationship? Neurobiology of disease, 132, 104462. https://doi.org/10.1016/j.nbd.2019.05.001

Simeone, J. C., Ward, A. J., Rotella, P., Collins, J., & Windisch, R. (2015). An evaluation of variation in published estimates of schizophrenia prevalence from 1990─2013: A systematic literature review. BMC Psychiatry, 15, 193. https://doi.org/10.1186/s12888-015-0578-7

Siniscalchi, A., Mancuso, F., Gallelli, L., Ferreri Ibbadu, G., Biagio Mercuri, N., & De Sarro, G. (2005). Increase in plasma homocysteine levels induced by drug treatments in neurologic patients. Pharmacological Research, 52(5), 367–375. https://doi.org/10.1016/j.phrs.2005.05.013

Stovicek, P. O., Friedmann, C., Marinescu, D., Văduva, I. A., Bondari, S., Trifu, S. C., & Marinescu, I. (2020). Mild TBI in the elderly - Risk factor for rapid cognitive impairment in Alzheimer's disease. Romanian Journal of Morphology and Embryology, 61(1), 61–72. https://doi.org/10.47162/RJME.61.1.07

Untu, I., Chirita, R., Bulgaru-Iliescu, D., Chirila, B. D., Ciubara, A., & Burlea, S. L. (2015). Ethical implications of bio-psycho-social transformations entailed by the aging process. Revista de Cercetare si Interventie Sociala, 48, 216-225. https://www.rcis.ro/ro/section1/136-volumul-482015martie/2161-ethical-implications-of-bio-psycho-social-transformations-entailed-by-the-aging-process.html

Varambally, S., Venkatasubramanian, G., & Gangadhar, B. N. (2012). Neurological soft signs in schizophrenia - The past, the present and the future. Indian Journal of Psychiatry, 54(1), 73–80. https://doi.org/10.4103/0019-5545.94653

Wenzel-Seifert, K., Wittmann, M., & Haen, E. (2011). QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Deutsches Arzteblatt International, 108(41), 687–693. https://doi.org/10.3238/arztebl.2011.0687

Wysokiński, A., & Kłoszewska, I. (2013). Homocysteine levels in patients with schizophrenia on clozapine monotherapy. Neurochemical Research, 38(10), 2056–2062. https://doi.org/10.1007/s11064-013-1113-1

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Published

2021-07-19

How to Cite

Stovicek, P. O. ., Marinescu, D. ., Păuna-Cristian, L. ., & Marinescu, I. . (2021). The Implications of Adverse Pharmacologic Reactions and Complex Pathogenic Mechanisms in Schizophrenia. BRAIN. Broad Research in Artificial Intelligence and Neuroscience, 12(2), 279-302. https://doi.org/10.18662/brain/12.2/206

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