Skip to main content Accessibility help

Pharmacotherapy of schizophrenia: toward a metabolomic-based approach

  • Haythum O. Tayeb (a1), Hussam A. Murad (a2) (a3), Misbahuddin M. Rafeeq (a2) and Frank I. Tarazi (a4)


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.


Corresponding author

*Address for correspondence: Dr. Hussam A. Murad, Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia. (Email:


Hide All
1. Chong, HY, Teoh, SL, Wu, DB-C, et al. Global economic burden of schizophrenia: a systematic review. Neuropsychiatr Disease Treat. 2016; 12: 357373.
2. Emsley, R, Chiliza, B, Asmal, L, et al. The nature of relapse in schizophrenia. BMC Psychiatry. 2013; 13(1): 50.
3. Hosák, L, Hosakova, J. The complex etiology of schizophrenia—general state of the art. Neuro Endocrinol Lett. 2015; 36(7): 631637.
4. Karlsgodt, KH, Sun, D, Cannon, TD. Structural and functional brain abnormalities in schizophrenia. Curr Dir Psychol Sci. 2010; 19(4): 226231.
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: 461500.
6. Lewis, DA, Sweet, RA. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. J Clin Invest. 2009; 119(4): 706716.
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): 12091223.
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): 675682.
9. Haddad, PM, Brain, C, Scott, J. Nonadherence with antipsychotic medication in schizophrenia: challenges and management strategies. Patient Relat Outcome Meas. 2014; 5: 4362.
10. Jones, KA, Menniti, FS, Sivarao, DV. Translational psychiatry—light at the end of the tunnel. Ann N Y Acad Sci. 2015; 1344(1): 111.
11. Atkinson, AJ, Colburn, WA, DeGruttola, VG, et al. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69(3): 8995.
12. Weickert, CS, Weickert, TW, Pillai, A, et al. Biomarkers in schizophrenia: a brief conceptual consideration. Disease Markers. 2013; 35(1): 39.
13. Pickard, BS. Schizophrenia biomarkers: translating the descriptive into the diagnostic. J Psychopharmacol. 2015; 29(2): 138143.
14. Sethi, S, Brietzke, E. Omics-based biomarkers: application of metabolomics in neuropsychiatric disorders. Int J Neuropsychopharmacol. 2016; 19(3): pyv096.
15. Holmes, E, Wilson, ID, Nicholson, JK. Metabolic phenotyping in health and disease. Cell. 2008; 134(5): 714717.
16. Griffiths, WJ, Koal, T, Wang, Y, et al. Targeted metabolomics for biomarker discovery. Angew Chem Int Ed Engl. 2010; 49(32): 54265445.
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.
18. Yang, J, Chen, T, Sun, L, et al. Potential metabolite markers of schizophrenia. Mol Psychiatry. 2013; 18(1): 6778.
19. He, Y, Yu, Z, Giegling, I, et al. Schizophrenia shows a unique metabolomics signature in plasma. Transl Psychiatry. 2012; 2(8): e149.
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): 2327.
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): 54335443.
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): 557563.
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.
24. Kaddurah-Daouk, R, McEvoy, J, Baillie, R, et al. Metabolomic mapping of atypical antipsychotic effects in schizophrenia. Mol Psychiatry. 2007; 12(10): 934945.
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): 43384350.
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.
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): 10921096.
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: 2933.
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): 931938.
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): 426432.
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): 156163.
32. Liu, P, Jing, Y, Collie, N, et al. Altered brain arginine metabolism in schizophrenia. Transl Psychiatry. 2016; 6(8): e871.
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.
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: 4572.
35. Harris, LW, Guest, PC, Wayland, MT, et al. Schizophrenia: metabolic aspects of aetiology, diagnosis and future treatment strategies. Psychoneuroendocrinology. 2013; 38(6): 752766.
36. Harris, LW, Pietsch, S, Cheng, TM, et al. Comparison of peripheral and central schizophrenia biomarker profiles. PloS One. 2012; 7(10): e46368.
37. Plitman, E, Nakajima, S, de la Fuente-Sandoval, C, et al. Glutamate-mediated excitotoxicity in schizophrenia: a review. Eur Neuropsychopharmacol. 2014; 24(10): 15911605.
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): 234242.
39. Chen, Y, Guillemin, GJ. Kynurenine pathway metabolites in humans: disease and healthy states. Int J Tryptophan Res. 2009; 2: 119.
40. Muller, N, Myint, AM, Schwarz, MJ. Kynurenine pathway in schizophrenia: pathophysiological and therapeutic aspects. Curr Pharm Design. 2011; 17(2): 130136.
41. Volk, DW, Gonzalez-Burgos, G, Lewis, DA. l-Proline, GABA synthesis and gamma oscillations in schizophrenia. Trends Neurosci. 2016; 39(12): 797798.
42. Najjar, S, Pearlman, DM. Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res. 2015; 161(1): 102112.
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): 11821193.
44. Bou Khalil, R. Recombinant human IGF-1 for patients with schizophrenia. Med Hypotheses. 2011; 77(3): 427429.
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): 169176.
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): 211215.
47. Zhang, L, Zhao, J. Profile of minocycline and its potential in the treatment of schizophrenia. Neuropsychiatr Dis Treat. 2014; 10: 11031111.
48. Shim, S, Shuman, M, Duncan, E. An emerging role of cGMP in the treatment of schizophrenia: a review. Schizophr Res. 2016; 170(1): 226231.
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.
50. Harvey, PD. Pharmacological cognitive enhancement in schizophrenia. Neuropsychol Rev. 2009; 19(3): 324335.
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): 923937.
52. Kegel, ME, Bhat, M, Skogh, E, et al. Imbalanced kynurenine pathway in schizophrenia. Int J Tryptophan Res. 2014; 7: 1522.
53. Schwarcz, R, Bruno, JP, Muchowski, PJ, et al. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012; 13(7): 465477.
54. Wonodi, I, Schwarcz, R. Cortical kynurenine pathway metabolism: a novel target for cognitive enhancement in schizophrenia. Schizophr Bull. 2010; 36(2): 211218.
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): 665674.
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): 465472.
57. Goff, DC, Hill, M, Barch, D. The treatment of cognitive impairment in schizophrenia. Pharmacol Biochem Behav. 2011; 99(2): 245253.
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): 529542.
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): 1119.



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed