SCHRES-06105; No of Pages 2 Schizophrenia Research xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Less is more Dear Editors, The recent trial of omega-3 fatty acids and the antioxidant alpha lipoic acid (ALA) for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia by (Emsley et al., 2014) was terminated early due to patient relapse. The authors discussed the possibility that their dosages may have been incorrect but dismissed it as unlikely as dosages were on the higher end of that normally prescribed. I disagree. The 300 mg ALA dose was too high. In (Seybolt, 2010) I proposed ALA be evaluated as an add-on therapy to antipsychotics and cautioned that the work of Altschule et al. (1959) and Giamattei (1957) suggested a low dose therapeutic window for ALA in the treatment of schizophrenia. Altschule et al. (1997) who had shown that injected glutathione (GSH) improved keto-acid metabolism and mental status in a female paranoid schizophrenic, decided to study the effects of ALA as a “vitamin concerned with the utilization of keto acids”. It is difficult to interpret the work of Altschule et al. (1959) because the dose and method of administration varied from patient to patient with no rationale provided for the discrepancies. Three patients were given intramuscular injections, daily doses ranging from 20 to 40 mg increased to 100 to 200 mg and three given oral doses starting at 100 mg increased to 100 mg two times a day. Initially, three improved, one remained unchanged and two became worse. When their dose was increased, two of the three improved patients deteriorated as did the patient who was at first unchanged. Clinical worsening was accompanied by impairment of keto-acid utilization, marked by increases in lactate and pyruvate. Interestingly, this seems to correlate with the deficiencies in pyruvate dehydrogenase and elevated levels of lactate found in the schizophrenic prefrontal cortex by Prabakaran et al. (2004). Within 10 days of discontinuation of ALA therapy all patients returned to their previous psychiatric status (Altschule et al, 1959). Giamattei, following a more rigorous protocol using smaller doses of ALA, 10 mg intravenous that equates to 30 mg oral and one tenth of that used in the Emsley study, had no such difficulties. Half of his patients improved, half remained unchanged. Theorizing that ALA as an antioxidant might improve liver function he selected ten of his hospitalized patients on the basis of poor liver test results. He administered 10 mg intravenous ALA per day over a period of 28 days. In all ten patients liver function was normalized. Unexpectedly, four of the ten patients' psychiatric symptoms improved as well. Encouraged by the results, he then tried the same regimen on a newly diagnosed patient who had been ill for only two months. On the 15th day when her improvement was most evident she was scheduled for ECT and was released shortly thereafter as improved (Giamattei, 1957). Prabakaran's metabolomic, proteonomic, genomic examination of cadaver brains found 50% of the differences between schizophrenia and control were related to mitochondrial dysfunction and oxidative stress (Prabakaran et al., 2004) making ALA a good candidate for
study. ALA and its reduced form dihydrolipoic acid (DHLA) are potent antioxidants and free radical scavengers (Packer et al., 1997). In addition, ALA supplementation raises GSH by stimulating the activation of the Nrf2/ARE/GCL gene pathway leading to a significant increase in GSH synthesis within 12 h (Suh et al., 2004). In the mitochondria, which lack catalase to remove toxic hydrogen peroxide (H2O2), GSH is used in the conversion of H2O2 to water. In the process GSH is oxidized to form glutathione disulfide (GSSG). A low GSH/GSSG ratio, an indicator of oxidative stress, is a characteristic of schizophrenia. DHLA helps maintain a favorable ratio by raising GSH through improved cysteine utilization (Han et al., 1997) and by converting GSSG back to GSH (Moini et al., 2002). ALA as lipoamide, functions as an essential cofactor in the pyruvate dehydrogenase complex in the conversion of pyruvate to Acetyl-CoA and within the mitochondria lipoamide is a cofactor in the alpha ketoglutarate and alpha keto-acid dehydrogenase complexes of the Krebs cycle. I consider the Emsley trial, a well-funded study conducted by respected investigators, as a missed opportunity. I commend the willingness of the authors to study nutritional alternatives but 300 mg ALA is more than the amount that gave Altschule problems and seems to support the concept of a low dose therapeutic window for ALA in the treatment of schizophrenia. Why are dosages within the boundary therapeutic for only half the patients but when given in excess cause symptom relapse in all? If Emsley had followed Altschule's lead and monitored keto-acid metabolism or lactate and pyruvate levels their study may have advanced our understanding of the pathological mechanisms underlying psychotic relapse in schizophrenia. It would be unfortunate if the Emsley setback discourages future investigation of low dose ALA in the treatment of schizophrenia. Contributors I declare I am the sole contributor to this manuscript.
Conflict of interest I declare that there are no conflicts of interest.
Acknowledgements I would like to thank Dr. Peter J. Weiden for being the first to recognize the need for a pilot safety trial of alpha lipoic acid as adjunctive therapy in the treatment of schizophrenia and for his support in working toward that goal.
References Altschule, M.D., Goncz, R.M., Henneman, D.H., Holliday, P.D., 1957. Carbohydrate metabolism in brain disease. VII. The effect of glutathione on carbohydrate intermediary metabolism in schizophrenia and manic–depressive psychoses. AMA Arch. Intern. Med. 99, 22–27. Altschule, M.D., Goncz, R.M., Holliday, P.D., 1959. Carbohydrate metabolism in brain disease. XI. Effects of thioctic (alpha-lipoic) acid in chronic schizophrenia. AMA Arch. Intern. Med. 103, 726–729. Emsley, R., Chiliza, B., Asmal, L., du Plessis, S., Phahladira, L., van Niekerk, E., van Rensburg, S.J., Harvey, B.H., 2014. A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia. Schizophr. Res. http://dx.doi.org/10.1016/j.schres.2014.06.004. Giamattei, L., 1957. Thioctic acid in therapy of schizophrenia. Osp. Psichiatr. 25, 221–228.
http://dx.doi.org/10.1016/j.schres.2014.10.022 0920-9964/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Seybolt, S.E.J., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.10.022
2
Letter to the Editor
Han, D., Handelman, G., Marcocci, L., Sen, C.K., Roy, S., Kobuchi, H., Tritschler, H.J., Flohe, L., Packer, L., 1997. Lipoic acid improves de novo synthesis of glutathione by improving cystine utilization. Biofactors 6, 321–328. Moini, H., Packer, L., Saris, N.L., 2002. Antioxidant and prooxidant activities of alpha lipoic acid and dihydrolipoic acid. Toxicol. Appl. Pharmacol. 182, 84–90. Packer, L., Tritschler, H.J., Wessel, K., 1997. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic. Biol. Med. 22 (1–2), 359–378. Prabakaran, S., Swatton, J.E., Huffaker, S.J., Huang, J.T., Griffin, J.L., Wayland, M., Freeman, T., Dudbridge, F., Lilley, K.S., Karp, N.A., Hester, S., Tkachev, D., Mimmack, M.L., Yolken, R.H., Webster, M.J., Torrey, E.F., Bahn, S., 2004. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol. Psychiatry 9, 684–697. Seybolt, S.E., 2010. Is it time to reassess alpha lipoic acid and niacinamide therapy in schizophrenia? Med. Hypotheses 75 (6), 572–575. Suh, J.H., Shenvi, S.V., Dixon, B.M., Liu, H., Jaiswal, A.K., Liu, R.M., Hagen, T.M., 2004. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis,
which is reversible with lipoic acid. Proc. Natl. Acad. Sci. U. S. A. 101 (10), 3381–3386 (Epub 2004 Feb. 25).
Sheila E.J. Seybolt 7635 Jackson Blvd, Forest Park, IL 60130, USA Tel.: +1 708 366 0049; +1 708 985 5326. E-mail address: [email protected].
Please cite this article as: Seybolt, S.E.J., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.10.022
6 August 2014 Available online xxxx
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Less is more Dear Editors, The recent trial of omega-3 fatty acids and the antioxidant alpha lipoic acid (ALA) for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia by (Emsley et al., 2014) was terminated early due to patient relapse. The authors discussed the possibility that their dosages may have been incorrect but dismissed it as unlikely as dosages were on the higher end of that normally prescribed. I disagree. The 300 mg ALA dose was too high. In (Seybolt, 2010) I proposed ALA be evaluated as an add-on therapy to antipsychotics and cautioned that the work of Altschule et al. (1959) and Giamattei (1957) suggested a low dose therapeutic window for ALA in the treatment of schizophrenia. Altschule et al. (1997) who had shown that injected glutathione (GSH) improved keto-acid metabolism and mental status in a female paranoid schizophrenic, decided to study the effects of ALA as a “vitamin concerned with the utilization of keto acids”. It is difficult to interpret the work of Altschule et al. (1959) because the dose and method of administration varied from patient to patient with no rationale provided for the discrepancies. Three patients were given intramuscular injections, daily doses ranging from 20 to 40 mg increased to 100 to 200 mg and three given oral doses starting at 100 mg increased to 100 mg two times a day. Initially, three improved, one remained unchanged and two became worse. When their dose was increased, two of the three improved patients deteriorated as did the patient who was at first unchanged. Clinical worsening was accompanied by impairment of keto-acid utilization, marked by increases in lactate and pyruvate. Interestingly, this seems to correlate with the deficiencies in pyruvate dehydrogenase and elevated levels of lactate found in the schizophrenic prefrontal cortex by Prabakaran et al. (2004). Within 10 days of discontinuation of ALA therapy all patients returned to their previous psychiatric status (Altschule et al, 1959). Giamattei, following a more rigorous protocol using smaller doses of ALA, 10 mg intravenous that equates to 30 mg oral and one tenth of that used in the Emsley study, had no such difficulties. Half of his patients improved, half remained unchanged. Theorizing that ALA as an antioxidant might improve liver function he selected ten of his hospitalized patients on the basis of poor liver test results. He administered 10 mg intravenous ALA per day over a period of 28 days. In all ten patients liver function was normalized. Unexpectedly, four of the ten patients' psychiatric symptoms improved as well. Encouraged by the results, he then tried the same regimen on a newly diagnosed patient who had been ill for only two months. On the 15th day when her improvement was most evident she was scheduled for ECT and was released shortly thereafter as improved (Giamattei, 1957). Prabakaran's metabolomic, proteonomic, genomic examination of cadaver brains found 50% of the differences between schizophrenia and control were related to mitochondrial dysfunction and oxidative stress (Prabakaran et al., 2004) making ALA a good candidate for
study. ALA and its reduced form dihydrolipoic acid (DHLA) are potent antioxidants and free radical scavengers (Packer et al., 1997). In addition, ALA supplementation raises GSH by stimulating the activation of the Nrf2/ARE/GCL gene pathway leading to a significant increase in GSH synthesis within 12 h (Suh et al., 2004). In the mitochondria, which lack catalase to remove toxic hydrogen peroxide (H2O2), GSH is used in the conversion of H2O2 to water. In the process GSH is oxidized to form glutathione disulfide (GSSG). A low GSH/GSSG ratio, an indicator of oxidative stress, is a characteristic of schizophrenia. DHLA helps maintain a favorable ratio by raising GSH through improved cysteine utilization (Han et al., 1997) and by converting GSSG back to GSH (Moini et al., 2002). ALA as lipoamide, functions as an essential cofactor in the pyruvate dehydrogenase complex in the conversion of pyruvate to Acetyl-CoA and within the mitochondria lipoamide is a cofactor in the alpha ketoglutarate and alpha keto-acid dehydrogenase complexes of the Krebs cycle. I consider the Emsley trial, a well-funded study conducted by respected investigators, as a missed opportunity. I commend the willingness of the authors to study nutritional alternatives but 300 mg ALA is more than the amount that gave Altschule problems and seems to support the concept of a low dose therapeutic window for ALA in the treatment of schizophrenia. Why are dosages within the boundary therapeutic for only half the patients but when given in excess cause symptom relapse in all? If Emsley had followed Altschule's lead and monitored keto-acid metabolism or lactate and pyruvate levels their study may have advanced our understanding of the pathological mechanisms underlying psychotic relapse in schizophrenia. It would be unfortunate if the Emsley setback discourages future investigation of low dose ALA in the treatment of schizophrenia. Contributors I declare I am the sole contributor to this manuscript.
Conflict of interest I declare that there are no conflicts of interest.
Acknowledgements I would like to thank Dr. Peter J. Weiden for being the first to recognize the need for a pilot safety trial of alpha lipoic acid as adjunctive therapy in the treatment of schizophrenia and for his support in working toward that goal.
References Altschule, M.D., Goncz, R.M., Henneman, D.H., Holliday, P.D., 1957. Carbohydrate metabolism in brain disease. VII. The effect of glutathione on carbohydrate intermediary metabolism in schizophrenia and manic–depressive psychoses. AMA Arch. Intern. Med. 99, 22–27. Altschule, M.D., Goncz, R.M., Holliday, P.D., 1959. Carbohydrate metabolism in brain disease. XI. Effects of thioctic (alpha-lipoic) acid in chronic schizophrenia. AMA Arch. Intern. Med. 103, 726–729. Emsley, R., Chiliza, B., Asmal, L., du Plessis, S., Phahladira, L., van Niekerk, E., van Rensburg, S.J., Harvey, B.H., 2014. A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia. Schizophr. Res. http://dx.doi.org/10.1016/j.schres.2014.06.004. Giamattei, L., 1957. Thioctic acid in therapy of schizophrenia. Osp. Psichiatr. 25, 221–228.
http://dx.doi.org/10.1016/j.schres.2014.10.022 0920-9964/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Seybolt, S.E.J., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.10.022
2
Letter to the Editor
Han, D., Handelman, G., Marcocci, L., Sen, C.K., Roy, S., Kobuchi, H., Tritschler, H.J., Flohe, L., Packer, L., 1997. Lipoic acid improves de novo synthesis of glutathione by improving cystine utilization. Biofactors 6, 321–328. Moini, H., Packer, L., Saris, N.L., 2002. Antioxidant and prooxidant activities of alpha lipoic acid and dihydrolipoic acid. Toxicol. Appl. Pharmacol. 182, 84–90. Packer, L., Tritschler, H.J., Wessel, K., 1997. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic. Biol. Med. 22 (1–2), 359–378. Prabakaran, S., Swatton, J.E., Huffaker, S.J., Huang, J.T., Griffin, J.L., Wayland, M., Freeman, T., Dudbridge, F., Lilley, K.S., Karp, N.A., Hester, S., Tkachev, D., Mimmack, M.L., Yolken, R.H., Webster, M.J., Torrey, E.F., Bahn, S., 2004. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol. Psychiatry 9, 684–697. Seybolt, S.E., 2010. Is it time to reassess alpha lipoic acid and niacinamide therapy in schizophrenia? Med. Hypotheses 75 (6), 572–575. Suh, J.H., Shenvi, S.V., Dixon, B.M., Liu, H., Jaiswal, A.K., Liu, R.M., Hagen, T.M., 2004. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis,
which is reversible with lipoic acid. Proc. Natl. Acad. Sci. U. S. A. 101 (10), 3381–3386 (Epub 2004 Feb. 25).
Sheila E.J. Seybolt 7635 Jackson Blvd, Forest Park, IL 60130, USA Tel.: +1 708 366 0049; +1 708 985 5326. E-mail address: [email protected].
Please cite this article as: Seybolt, S.E.J., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.10.022
6 August 2014 Available online xxxx
