Increased breath ethane and pentane concentrations in currently unmedicated patients with schizophrenia

Brian M. Ross, Sandeep Shah, Malcolm Peet

.

DOI: 10.4236/ojpsych.2011.11001                

Abstract

Schizophrenia is a common and debilitating mental illness. The disorder is thought to be developmental in origin, with oxidative stress being implicated as possible pathophysiological mechanism. Breath alkanes provide a non-invasive means to assess oxidative stress, with ethane levels reportedly increased in medicated patients with schizophrenia. It is possible, however, that the psychotropic medications used to treat the disorder result in elevated breath ethane levels. We have therefore measured the concentration of ethane and pentane, markers of oxidative stress, in the breath of currently unmedicated patients with schizophrenia. Alveolar breath samples were collected, applied to thermal desorption tubes, and analyzed using a combination of two-stage thermal de-sorption, gas chromatography and mass spectrometry. Compared to healthy controls ethane and pentane levels were found to be elevated in patients with schizophrenia, while levels of butane were normal. Our data support the notion that oxidative stress is increased in schizophrenia and that this is unlikely to be a consequence of antipsychotic medications. In addition, breath alkane analysis may represent a rapid and non-invasive means to monitor oxidative stress occurring in schizophrenia.

Keywords

Breath Analysis; Alkane, Schizophrenia; Ethane; Pentane

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Van Os, J. and Kapur, S. (2009) Schizophrenia. Lancet, 374, 635-645. doi:10.1016/S0140-6736(09)60995-8 Saha, S., Chant, D., Welham, J. and McGrath, J. (2005) A systematic review of the prevalence of schizophrenia. PLoS Medicine, 2, e141. doi:10.1371/journal.pmed.0020141
[2]	Akyol, O., Herken, H., Uz, E., Fadillio?lu, E., Unal, S., S??üt, S., Ozyurt, H. and Sava?, H.A. (2002) The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients. The possible role of oxidant/antioxidant imbalance. Progress in Neuropsycho-pharmacology and Biological Psychiatry, 26, 995-1005. doi:10.1016/S0278-5846(02)00220-8
[3]	Halliwell, B. and Gutteridge, J.M. (1999) Free radicals in biology and medicine. 3rd Edition, Oxford University Press, UK.
[4]	Reddy, R., Sahebarao, M.P., Mukherjee, S. and Murthy, J.N. (1991) Enzymes of the antioxidant defense system in chronic schizophrenic patients. Biological Psychiatry, 30, 409-412. doi:10.1016/0006-3223(91)90298-Z
[5]	Mahadik, S.P. and Mukherjee, S. (1996) Free radical pathology and antioxidant defense in schizophrenia: A review. Schizophrenia Research, 19, 1-17. doi:10.1016/0920-9964(95)00049-6
[6]	Kuloglu, M., Ustundag, B., Atmaca, M., Canatan, B., Tezcan, A.E. and Cinkilinc, N. (2002) Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochemistry and Function, 20, 171-175. doi:10.1002/cbf.940
[7]	Yao, J.K., Reddy, R., McElhinny, L.G. and van Kammen, D.P. (1998) Effects of haloperidol on antioxidant defense system enzymes in schizophrenia. Journal of Psychiatry Research, 32, 385-391. doi:10.1016/S0022-3956(98)00028-4
[8]	Mukerjee, S., Mahadik, S.P., Scheffer, R., Correnti, E.E. and Kelkar, H. (1996) Impaired antioxidant defense at the onset of psychosis. Schizophrenia Research, 19, 19-26. doi:10.1016/0920-9964(95)00048-8
[9]	Evans, D.R., Parikh, V.V., Khan, M.M., Coussons, C., Buckley, P.E. and Mahadik, S.P. (2003) Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment. Prostaglandins Leukotrienes and Essential Fatty Acids, 69, 393-399. doi:10.1016/j.plefa.2003.08.010
[10]	Herken, H., Uz, E., Ozyurt, H., Sogut, S., Virit, O. and Akyol, O. (2001) Evidence that the activities of erythrocyte free radical scavenging enzymes and the products of lipid peroxidation are increased in different forms of schizophrenia. Molecular Psychiatry, 6, 66-73. doi:10.1038/sj.mp.4000789
[11]	Yao, J.K., Reddy, R.D. and van Kammen, D.P. (1999) Human plasma glutathione peroxidase and symptom severity in schizophrenia. Biological Psychiatry, 45, 1512-1515. doi:10.1016/S0006-3223(98)00184-X
[12]	Ranjekar, P.K., Hinge, A., Hegde, M.V., Ghate, M., Kale, A., Sitasawad, S., Wagh, U.V., Debsikdar, V.B. and Mahadik, S.P. (2003) Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schiz- ophrenic and bipolar mood disorder patients. Psychiatry Research, 121, 109-122. doi:10.1016/S0165-1781(03)00220-8
[13]	Ustundag, B., Atmaca, M., Kirtas, O., Selek, S., Metin, K. and Tezcan, E. (2006) Total antioxidant response in patients with schizophrenia. Psychiatry and Clinical Neuroscience, 60, 458-464. doi:10.1111/j.1440-1819.2006.01532.x
[14]	Yao, J.K., Reddy, R., McElhinny, L.G. and van Kammen, D.P. (1998) Reduced status of plasma total antioxidant capacity in schizophrenia. Schizophrenia Research, 32, 1-8. doi:10.1016/S0920-9964(98)00030-9
[15]	Virit, O., Altindag, A., Yumru, M., Dalkilic, A., Savas, H.A., Selek, S., Erel, O. and Herken, H. (2009) A defect in the antioxidant defense system in schizophrenia. Neur- opsychobiology, 60, 87-93. doi:10.1159/000239684
[16]	Nishioka, N. and Arnold, S.E. Evidence for oxidative DNA damage in the hippocampus of elderly patients with chronic schizophrenia. American Journal of Geriatric Psychiatry, 12, 167-175.
[17]	Young, J., McKinney, S.B., Ross, B.M., Wahle, K.W. and Boyle, S.P. (2007) Biomarkers of oxidative stress in schizophrenic and control subjects. Prostaglandins Leukotrienes and Essential Fatty Acids, 76, 73-85.
[18]	Dietrich-Muszalska, A., Olas, B., G?owacki, R. and Bald, E. (2009) Oxidative/nitrative modifications of plasma proteins and thiols from patients with schizophrenia. Neuropsychobiology, 59, 1-7. doi:10.1159/000202822
[19]	Dietrich-Muszalska, A. and Olas, B. (2007) Isoprostenes as indicators of oxidative stress in schizophrenia. World Journal of Biological Psychiatry, 11, 1-7.
[20]	Wang, J.F., Shao, L., Sun, X. and Young, L.T. (2009) Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia. Bip- olar Disorders, 11, 523-529. doi:10.1111/j.1399-5618.2009.00717.x
[21]	Steullet, P., Cabungcal, J.H., Kulak, A., Kraftsik, R., Chen, Y., Dalton, T.P., Cuénod, M. and Do, K.Q. (2010) Redox dysregulation affects the ventral but not dorsal hippocampus: Impairment of parvalbumin neurons, gam- ma oscillations, and related behaviors. Journal of Neuroscience, 30, 2547-2558. doi:10.1523/JNEUROSCI.3857-09.2010
[22]	Cabungcal, J.H., Nicolas, D., Kraftsik, R., Cuénod, M., Do, K.Q. and Hornung, J.P. (2006) Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons. Neurobiology of Dise- ase, 22, 624-637.
[23]	Puri, B.K., Counsell, S.J., Ross, B.M., Hamilton, G., Bustos, M.G. and Treasaden, I.H. (2008) Evidence from in vivo 31-phosphorus magnetic resonance spectroscopy phosphodiesters that exhaled ethane is a biomarker of cerebral n-3 polyunsaturated fatty acid peroxidation in humans. BMC Psychiatry, 8. doi:10.1016/j.nbd.2006.01.003
[24]	Puri, B.K., Ross, B.M. and Treasaden, I.H. (2008) Increased levels of ethane, a non-invasive, quantitative, direct marker of n-3 lipid peroxidation, in the breath of patients with schizophrenia. Progress in Neuropsychop- harmacology and Biological Psychiatry, 32, 858-862. doi:10.1016/j.pnpbp.2008.01.001
[25]	Ross, B.M., Maxwell, R. and Glen, I. (2011) Increased breath ethane levels in medicated patients with schizophrenia and bipolar disorder are unrelated to erythrocyte omega-3 fatty acid abundance. Progress in Neuropsy- chopharmacology and Biological Psychiatry, 35, 436-453.
[26]	Dillard, C.J., Dumelin, E.E. and Tappel, A.L. (1977) Eff- ect of dietary vitamin E on expiration of pentane and ethane by the rat. Lipids, 12, 109-114. doi:10.1007/BF02532981
[27]	Wade, C.R. and van Rij, A.M. (1985) In vivo lipid peroxidation in man as measured by the respiratory excretion of ethane, pentane, and other low-molecular-weight hydrocarbons. Analytical Biochemistry, 150, 1-7. doi:10.1016/0003-2697(85)90433-6
[28]	Ross, B.M., McKenzie, I., Glen, I. and Bennett, C.P. (2003) Increased levels of ethane, a non-invasive marker of n-3 fatty acid oxidation, in breath of children with attention deficit hyperactivity disorder. Nutritional Neuroscience, 6, 277-281. doi:10.1080/10284150310001612203
[29]	Amann, A., Span?l, P. and Smith, D. (2007) Breath analysis: The approach towards clinical applications. Mini Reviews in Medicinal Chemistry, 7, 115-129. doi:10.2174/138955707779802606
[30]	Bloor, R.N., Span?l, P. and Smith, D. (2006) Quantification of breath carbon disulphide and acetone following a single dose of disulfiram (antabuse) using selected ion flow tube mass spectrometry (SIFT-MS). Addiction Biology, 11, 163-169. doi:10.1111/j.1369-1600.2006.00015.x
[31]	Giacomuzzi, S.M., Riemer, Y., Pavlic, M., Schmid, A., Hinterhuber, H. and Amann, A. (2009) Applications of breath gas analysis in addiction medicine-preliminary results. Substance Use and Misuse, 44, 301-304. doi:10.1080/10826080802344864
[32]	Miljevic, C., Nikolic, M., Nikolic-Kokic, A., Jones, D.R., Niketic, V., Lecic-Tosevski, D. and Spasic, M.B. (2010) Lipid status, anti-oxidant enzyme defence and haemoglo- bin content in the blood of long-term clozapine-treated schizophrenic patients. Progress in Neuropsychopharm- acology and Biological Psychiatry, 34, 303-307. doi:10.1016/j.pnpbp.2009.11.024
[33]	Singh, O.P., Chakraborty, I., Dasgupta, A. and Datta, S. (2008) A comparative study of oxidative stress and interrelationship of important antioxidants in haloperidol and olanzapine treated patients suffering from schizophrenia. Indian Journal Psychiatry, 50, 171-176. doi:10.4103/0019-5545.43627
[34]	Walss-Bass, C., Weintraub, S.T., Hatch, J., Mintz, J. and Chaudhuri, A.R. (2008) Clozapine causes oxidation of proteins involved in energy metabolism: A possible mechanism for antipsychotic-induced metabolic alterations. International Journal of Neuropsychopharmacology, 11, 1097-1104. doi:10.1017/S1461145708008882
[35]	Martins, M.R., Petronilho, F.C., Gomes, K.M., Dal-Pizzol, F., Streck, E.L. and Quevedo, J. (2008) Antipsycho- tic-induced oxidative stress in rat brain. Neurotoxicolgy Research, 13, 63-69. doi:10.1007/BF03033368
[36]	American Psychiatric Association. (1994) Diagnostic and statistical manual of mental health disorders. 4th Edition, American Psychiatric Publishing, Washington, DC.
[37]	Smith, D., ?paněl, P., Enderby, B., Lenney, W., Turner, C. and Davies, S.J. (2010) Isoprene levels in the exhaled breath of 200 healthy pupils within the age range 7–18 years studied using SIFT-MS. Journal of Breath Research, 4, 017101.
[38]	Smith, D., Turner, C. and Spaněl, P. (2007) Volatile metabolites in the exhaled breath of healthy volunteers: Their levels and distributions. Journal of Breath Research, 1, 014004. 2007doi:10.1088/1752-7155/1/1/014004
[39]	Abela, J.E., Skeldon, K.D., Stuart, R.C. and Padgett, M.J. (2009) Exhaled ethane concentration in patients with cancer of the upper gastrointestinal tract - A proof of concept study. Bioscience Trends, 3, 110-114. Reddy, R.D., Keshavan, M.S. and Yao, J.K. (2004) Reduced red blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neuroleptic-naive baseline. Schizophrenia Bulletin, 30, 901-911.
[40]	Peet, M., Shah, S., Selvam, K. and Ramchand, C.N. (2004) Polyunsaturated fatty acid levels in red cell membranes of unmedicated schizophrenic patients. World Journal of Biological Psychiatry, 5, 92-99. doi:10.1080/15622970410029917
[41]	Raffa, M., Mechri, A., Othman, L.B., Fendri, C., Gaha, L. and Kerkeni, A. (2009) Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Progress in Neuropsychophar- macology and Biological Psychiatry, 33, 1178-1183. doi:10.1016/j.pnpbp.2009.06.018
[42]	Clemens, M.R., Remmer, H. and Waller, H.D. (1984) Phenylhydrazine-induced lipid peroxidation of red blood cells in vitro and in vivo: Monitoring by the production of volatile hydrocarbons. Biochemical Pharmacology, 33, 1715-1718. doi:10.1016/0006-2952(84)90338-1
[43]	Clemens, M.R. and Remmer, H. (1982) Volatile alkanes produced by erythrocytes: An assay for in vitro studies on lipid peroxidation. Blut, 45, 329-335. doi:10.1007/BF00319527
[44]	Einsele, H., Clemens, M.R. and Remmer, H. (1987) In vitro aging of red blood cells and lipid peroxidation. Archives of Toxicology, 60, 163-166. doi:10.1007/BF00296972
[45]	Fowler, D., Coyle, M. and Anderson, R. (1997) Ozone in the United Kingdom. The Fourth Report of the Oxidants Review Group. Department of the Environment, Transport and the Regions, London, UK.
[46]	Srinivasan, T.N. and Thara, R. (2002) Smoking in schiz- ophrenia - All is not biological. Schizophrenia Research, 56, 67-74. doi:10.1016/S0920-9964(01)00187-6
[47]	Puri, B.K., Treasaden, I.H., Cocchi, M., Tsaluchidu, S., Tonello, L. and Ross, B.M. (2008) A comparison of oxidative stress in smokers and non-smokers: An in vivo human quantitative study of n-3 lipid peroxidation. MC Psychiatry, 8, Suppl 1:S4. doi:10.1186/1471-244X-8-S1-S4
[48]	Habib, M.P., Clements, N.C. and Garewal, H.S. (1995) Cigarette smoking and ethane exhalation in humans. American Journal of Respiratory and Critical Care Medicine, 151, 1368-1372.
[49]	McCreadie, R.G. (2003) Diet, smoking and cardiovascular risk in people with schizophrenia. British Journal of Psychiatry, 183, 534-539. doi:10.1192/bjp.183.6.534
[50]	Wei, W., Liu, Q., Tan, Y., Liu, L., Li, X. and Cai, L. Oxidative stress, diabetes, and diabetic complications. Hem- oglobin, 33, 370-377. doi:10.3109/03630260903212175
[51]	Bruckdorfer, K.R. (2008) Antioxidants and CVD. Proceedings of the Nutrition Society, 67, 214-222. doi:10.1017/S0029665108007052
[52]	Visconti, R. and Grieco, D. (2009) New insights on oxidative stress in cancer. Current Opinions in Drug Discovery Development, 12, 240-245.
[53]	Bushe, C.J., Bradley, A.J., Wildgust, H.J. and Hodgson, R.E. (2009) Schizophrenia and breast cancer incidence: A systematic review of clinical studies. Schizophrenia Research, 114, 6-16. doi:10.1016/j.schres.2009.07.012
[54]	Koponen, H., Alar?is?nen, A., Saari, K., Pelkonen, O., Huikuri, H., Raatikainen, M.J., Savolainen, M. and Isohanni, M. (2008) Schizophrenia and sudden cardiac death: A review. Nordic Journal of Psychiatry, 62, 342-345. doi:10.1080/08039480801959323
[55]	Suvisaari, J., Per?l?, J., Saarni, S.I., H?rk?nen, T., Pirkola, T., Joukamaa, M., Koskinen, S., L?nnqvist, J. and Reunanen, A. (2008) Type 2 diabetes among persons with schizophrenia and other psychotic disorders in a general population survey. European Archives of Psychiatry and Clinical Neuroscience, 258, 129-136.