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Pharmacotherapy of schizophrenia: toward a metabolomic-based approach

Published online by Cambridge University Press:  05 June 2018

Haythum O. Tayeb ,
Hussam A. Murad ,
Misbahuddin M. Rafeeq  and
Frank I. Tarazi Open the ORCID record for Frank I. Tarazi [Opens in a new window]
Haythum O. Tayeb
Affiliation:
Department of Medicine, Division of Neurology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
Hussam A. Murad*
Affiliation:
Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Misbahuddin M. Rafeeq
Affiliation:
Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia
Frank I. Tarazi
Affiliation:
Department of Psychiatry and Neuroscience Program, Harvard Medical School and McLean Hospital, Boston, Massachusetts, USA
*
*Address for correspondence: Dr. Hussam A. Murad, Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia. (Email: hamurad@kau.edu.sa)
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Abstract

Approximately 20%–30% of schizophrenia patients are resistant to current standard pharmacotherapies. Recent schizophrenia research aims to identify specific pathophysiological abnormalities and novel targets in the disease, with the goals of identifying at-risk individuals, facilitating diagnosis, prompting early and personalized interventions, and helping predict response to treatment. Metabolomics involves the systematic study of the profile of biochemical alterations early in the course of a given disorder. Major aspects of the schizophrenia metabolome have been characterized, uncovering potential selective biomarkers for the disease that may change how the disorder is diagnosed, and how patients are stratified and treated. This review focuses on the most common metabolomic fingerprints of the different pathways involved in the pathophysiology of schizophrenia, and the potential development of novel metabolomic-related pharmacotherapies for improved treatment of schizophrenia and other related idiopathic psychotic disorders.

Keywords

Antipsychoticsbiomarkersmetabolomicspharmacotherapiesschizophrenia
Type
Review
Information
CNS Spectrums , Volume 24 , Issue 3 , June 2019 , pp. 281 - 286
Copyright
© Cambridge University Press 2018 

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References

1. Chong, HY, Teoh, SL, Wu, DB-C, et al. Global economic burden of schizophrenia: a systematic review. Neuropsychiatr Disease Treat. 2016; 12: 357–373.Google Scholar
2. Emsley, R, Chiliza, B, Asmal, L, et al. The nature of relapse in schizophrenia. BMC Psychiatry. 2013; 13(1): 50.Google Scholar
3. Hosák, L, Hosakova, J. The complex etiology of schizophrenia—general state of the art. Neuro Endocrinol Lett. 2015; 36(7): 631–637.Google Scholar
4. Karlsgodt, KH, Sun, D, Cannon, TD. Structural and functional brain abnormalities in schizophrenia. Curr Dir Psychol Sci. 2010; 19(4): 226–231.Google Scholar
5. Baldessarini, RJ, Tarazi, FI. Pharmacotherapy of Psychosis and Mania. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill; 2005; 11: 461–500.Google Scholar
6. Lewis, DA, Sweet, RA. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. J Clin Invest. 2009; 119(4): 706–716.Google Scholar
7. Lieberman, J, Stroup, T, McEvoy, J, et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005; 353(12): 1209–1223.Google Scholar
8. Davidson, M, Galderisi, S, Weiser, M, et al. Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: a randomized, open-label clinical trial (EUFEST). Am J Psychiatry. 2009; 166(6): 675–682.Google Scholar
9. Haddad, PM, Brain, C, Scott, J. Nonadherence with antipsychotic medication in schizophrenia: challenges and management strategies. Patient Relat Outcome Meas. 2014; 5: 43–62.Google Scholar
10. Jones, KA, Menniti, FS, Sivarao, DV. Translational psychiatry—light at the end of the tunnel. Ann N Y Acad Sci. 2015; 1344(1): 1–11.Google Scholar
11. Atkinson, AJ, Colburn, WA, DeGruttola, VG, et al. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69(3): 89–95.Google Scholar
12. Weickert, CS, Weickert, TW, Pillai, A, et al. Biomarkers in schizophrenia: a brief conceptual consideration. Disease Markers. 2013; 35(1): 3–9.Google Scholar
13. Pickard, BS. Schizophrenia biomarkers: translating the descriptive into the diagnostic. J Psychopharmacol. 2015; 29(2): 138–143.Google Scholar
14. Sethi, S, Brietzke, E. Omics-based biomarkers: application of metabolomics in neuropsychiatric disorders. Int J Neuropsychopharmacol. 2016; 19(3): pyv096.Google Scholar
15. Holmes, E, Wilson, ID, Nicholson, JK. Metabolic phenotyping in health and disease. Cell. 2008; 134(5): 714–717.Google Scholar
16. Griffiths, WJ, Koal, T, Wang, Y, et al. Targeted metabolomics for biomarker discovery. Angew Chem Int Ed Engl. 2010; 49(32): 5426–5445.Google Scholar
17. Orešič, M, Tang, J, Seppänen-Laakso, T, et al. Metabolome in schizophrenia and other psychotic disorders: a general population-based study. Genome Med. 2011; 3(3): 19.Google Scholar
18. Yang, J, Chen, T, Sun, L, et al. Potential metabolite markers of schizophrenia. Mol Psychiatry. 2013; 18(1): 67–78.Google Scholar
19. He, Y, Yu, Z, Giegling, I, et al. Schizophrenia shows a unique metabolomics signature in plasma. Transl Psychiatry. 2012; 2(8): e149.Google Scholar
20. Gan, JL, Cheng, ZX, Duan, HF, et al. Atypical antipsychotic drug treatment for 6 months restores N-acetylaspartate in left prefrontal cortex and left thalamus of first-episode patients with early onset schizophrenia: a magnetic resonance spectroscopy study. Psychiatry Res. 2014; 223(1): 23–27.Google Scholar
21. Xuan, J, Pan, G, Qiu, Y, et al. Metabolomic profiling to identify potential serum biomarkers for schizophrenia and risperidone action. J Proteome Res. 2011; 10(12): 5433–5443.Google Scholar
22. Tkachev, D, Mimmack, ML, Huffaker, SJ, et al. Further evidence for altered myelin biosynthesis and glutamatergic dysfunction in schizophrenia. Int J Neuropsychopharmacol. 2007; 10(4): 557–563.Google Scholar
23. Holmes, E, Tsang, TM, Huang, JT, et al. Metabolic profiling of CSF: evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Med. 2006; 3(8): e327.Google Scholar
24. Kaddurah-Daouk, R, McEvoy, J, Baillie, R, et al. Metabolomic mapping of atypical antipsychotic effects in schizophrenia. Mol Psychiatry. 2007; 12(10): 934–945.Google Scholar
25. Cai, HL, Li, HD, Yan, XZ, et al. Metabolomic analysis of biochemical changes in the plasma and urine of first-episode neuroleptic-naive schizophrenia patients after treatment with risperidone. J Proteome Res. 2012; 11(8): 4338–4350.Google Scholar
26. Fukushima, T, Iizuka, H, Yokota, A, et al. Quantitative analyses of schizophrenia-associated metabolites in serum: serum D-lactate levels are negatively correlated with gamma-glutamylcysteine in medicated schizophrenia patients. PLoS One. 2014; 9(7): e101652.Google Scholar
27. Guest, PC, Schwarz, E, Krishnamurthy, D, et al. Altered levels of circulating insulin and other neuroendocrine hormones associated with the onset of schizophrenia. Psychoneuroendocrinology. 2011; 36(7): 1092–1096.Google Scholar
28. Palomino, A, González-Pinto, A, Martinez-Cengotita, , et al. Relationship between negative symptoms and plasma levels of insulin-like growth factor 1 in first-episode schizophrenia and bipolar disorder patients. Prog Neuropsychopharmacol Biol Psychiatry. 2013; 44: 29–33.Google Scholar
29. Beckmann, H, Gattaz, W. Multidimensional analysis of the concentrations of 17 substances in the CSF of schizophrenics and controls. J Neural Transm. 2002; 109(5): 931–938.Google Scholar
30. Linderholm, KR, Skogh, E, Olsson, SK, et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull. 2010; 38(3): 426–432.Google Scholar
31. Ohrmann, P, Kugel, H, Bauer, J, et al. Learning potential on the WCST in schizophrenia is related to the neuronal integrity of the anterior cingulate cortex as measured by proton magnetic resonance spectroscopy. Schizophr Res. 2008; 106(2): 156–163.Google Scholar
32. Liu, P, Jing, Y, Collie, N, et al. Altered brain arginine metabolism in schizophrenia. Transl Psychiatry. 2016; 6(8): e871.Google Scholar
33. Yao, J, Zhou, X, Keshavan, M. Homeostatic imbalance of adenosine signaling and uric acid production in schizophrenia. Schizophr Bull. 2017; 43(Suppl 1): S89.Google Scholar
34. Chan, MK, Gottschalk, MG, Haenisch, F, et al. Applications of blood-based protein biomarker strategies in the study of psychiatric disorders. Prog Neurobiol. 2014; 122: 45–72.Google Scholar
35. Harris, LW, Guest, PC, Wayland, MT, et al. Schizophrenia: metabolic aspects of aetiology, diagnosis and future treatment strategies. Psychoneuroendocrinology. 2013; 38(6): 752–766.Google Scholar
36. Harris, LW, Pietsch, S, Cheng, TM, et al. Comparison of peripheral and central schizophrenia biomarker profiles. PloS One. 2012; 7(10): e46368.Google Scholar
37. Plitman, E, Nakajima, S, de la Fuente-Sandoval, C, et al. Glutamate-mediated excitotoxicity in schizophrenia: a review. Eur Neuropsychopharmacol. 2014; 24(10): 1591–1605.Google Scholar
38. Lisman, JE, Coyle, JT, Green, RW, et al. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 2008; 31(5): 234–242.Google Scholar
39. Chen, Y, Guillemin, GJ. Kynurenine pathway metabolites in humans: disease and healthy states. Int J Tryptophan Res. 2009; 2: 1–19.Google Scholar
40. Muller, N, Myint, AM, Schwarz, MJ. Kynurenine pathway in schizophrenia: pathophysiological and therapeutic aspects. Curr Pharm Design. 2011; 17(2): 130–136.Google Scholar
41. Volk, DW, Gonzalez-Burgos, G, Lewis, DA. l-Proline, GABA synthesis and gamma oscillations in schizophrenia. Trends Neurosci. 2016; 39(12): 797–798.Google Scholar
42. Najjar, S, Pearlman, DM. Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res. 2015; 161(1): 102–112.Google Scholar
43. Calabrese, V, Giordano, J, Crupi, R. Hormesis, cellular stress response and neuroinflammation in schizophrenia: early onset versus late onset state. J Neurosci Res. 2017; 95(5): 1182–1193.Google Scholar
44. Bou Khalil, R. Recombinant human IGF-1 for patients with schizophrenia. Med Hypotheses. 2011; 77(3): 427–429.Google Scholar
45. Liu, F, Guo, X, Wu, R, et al. Minocycline supplementation for treatment of negative symptoms in early-phase schizophrenia: a double blind, randomized, controlled trial. Schizophr Res. 2014; 153(1): 169–176.Google Scholar
46. Ghanizadeh, A, Dehbozorgi, S, OmraniSigaroodi, M, et al. Minocycline as add-on treatment decreases the negative symptoms of schizophrenia; a randomized placebo-controlled clinical trial. Recent Pat Inflamm Allergy Drug Discov. 2014; 8(3): 211–215.Google Scholar
47. Zhang, L, Zhao, J. Profile of minocycline and its potential in the treatment of schizophrenia. Neuropsychiatr Dis Treat. 2014; 10: 1103–1111.Google Scholar
48. Shim, S, Shuman, M, Duncan, E. An emerging role of cGMP in the treatment of schizophrenia: a review. Schizophr Res. 2016; 170(1): 226–231.Google Scholar
49. Breier, A, Hummer, T, Liffick, E, et al. The effects of 12-month, double-blind N-acetyl cysteine treatment on symptoms and brain structures in early phase psychosis. Biol Psychiatry. 2017; 81(10): S164.Google Scholar
50. Harvey, PD. Pharmacological cognitive enhancement in schizophrenia. Neuropsychol Rev. 2009; 19(3): 324–335.Google Scholar
51. Goff, DC, Romero, K, Paul, J, et al. Biomarkers for drug development in early psychosis: current issues and promising directions. Eur Neuropsychopharmacol. 2016; 26(6): 923–937.Google Scholar
52. Kegel, ME, Bhat, M, Skogh, E, et al. Imbalanced kynurenine pathway in schizophrenia. Int J Tryptophan Res. 2014; 7: 15–22.Google Scholar
53. Schwarcz, R, Bruno, JP, Muchowski, PJ, et al. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012; 13(7): 465–477.Google Scholar
54. Wonodi, I, Schwarcz, R. Cortical kynurenine pathway metabolism: a novel target for cognitive enhancement in schizophrenia. Schizophr Bull. 2010; 36(2): 211–218.Google Scholar
55. Wonodi, I, Stine, OC, Sathyasaikumar, KV, et al. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Arch Gen Psychiatry. 2011; 68(7): 665–674.Google Scholar
56. Goff, DC, Lamberti, JS, Leon, AC, et al. A placebo-controlled add-on trial of the Ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology. 2008; 33(3): 465–472.Google Scholar
57. Goff, DC, Hill, M, Barch, D. The treatment of cognitive impairment in schizophrenia. Pharmacol Biochem Behav. 2011; 99(2): 245–253.Google Scholar
58. Beinat, C, Banister, SD, Herrera, M, et al. The therapeutic potential of α7 nicotinic acetylcholine receptor (α7 nAChR) agonists for the treatment of the cognitive deficits associated with schizophrenia. CNS Drugs. 2015; 29(7): 529–542.Google Scholar
59. Javitt, DC, Carter, CS, Krystal, JH, et al. Utility of imaging-based biomarkers for glutamate-targeted drug development in psychotic disorders: a randomized clinical trial. JAMA Psychiatry. 2018; 75(1): 11–19.Google Scholar