Schizophrenia Research 160 (2014) 224–225
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Re: Less is more
Dear Editors We thank Dr Seybolt for her interest in our study. Her comments address the important and difficult task of selecting the most appropriate dose of a compound for clinical trials where there is scant empirical evidence to guide these decisions. She suggests that the 300 mg/d dose of alpha lipoic acid (ALA) we chose is too high — that a therapeutic window for ALA exists, and that a lower dose would have had a better chance of success. She bases her suggestion on two studies conducted in the 1950s. In the first study mental status improvements were reported in 4 of 10 patients with unspecified liver dysfunction who were treated with ALA 10 mg intravenously per day for 28 days (Giamattei, 1957). In the second study 6 patients with chronic schizophrenia received varying doses of ALA and most seemed to deteriorate when the dose was increased (Altschule et al., 1959). Given the methodological shortcomings of older studies such as small samples, lack of validated assessment instruments and lack of randomization, blinding and an active control group, we don't believe that this constitutes sufficient justification to select doses within this range. It could be equally argued that the dose we selected was too low. Two more recent studies investigating the effects of ALA on weight and metabolic profile in patients with schizophrenia used doses of 1200 mg/d. In these studies the ALA was well tolerated and there was no change in clinical status (Kim et al., 2008; Ratliff et al., 2013). Further, ALA has been used in randomized, controlled trials in doses of 1800 mg/d for 6 months in the treatment of diabetic neuropathy (Ziegler et al., 1999) and 800 mg/d for 4 months for cardiac neuropathy (Ziegler et al., 1997), with no increase in adverse events versus placebo. Trying to predict therapeutic effects of antioxidants is complex. For example, in an animal study (Harvey et al., 2008) we noted that the antioxidant N-acetyl cysteine (NAC) dose-dependently worsened redox status in healthy animals while improving redox status and reversing pathology in “sick” animals. Thus, an antioxidant such as ALA (or others such as NAC) may perform differently depending on the cellular milieu. It may act either as an anti-oxidant or as a pro-oxidant depending on the redox status of the organism (Tylicki et al, 2003; Flora, 2009), which likely relates to illness severity. Within this already complex cellular environment it may be that the applied dose of the antioxidant, compounded by illness state/severity, also has a role in determining the clinical outcome. This can only be predicted once we fully understand the ephemeral nature of antioxidant response within the context of disease. Also, to extrapolate these findings to human studies may not be straight forward. Finally, our study did not investigate the effects of ALA as monotherapy — rather as an adjunct to omega-3 fatty acids. We should also point out that we don't agree with the suggestion by Dr Seybolt that the “excessive” doses of ALA given in our study “caused relapse in all” — rather, as relapse rates were similar to those in the placebo arm, the combination of omega-3 fatty acids and ALA failed to show efficacy in preventing relapse. While Dr Seybolt is concerned
http://dx.doi.org/10.1016/j.schres.2014.10.014 0920-9964/© 2014 Elsevier B.V. All rights reserved.
that our paper may deter further work on ALA in schizophrenia, we hope that it will do exactly the opposite — that it will encourage further interest in searching for a therapeutic effect for anti-oxidants and other nutritional supplements in schizophrenia. Contributors All of the authors met International Council of Medical Journal Editors criteria and all those who fulfilled those criteria are listed as authors. All authors provided direction and comments on the manuscript. They provided intellectual contributions and approved the final draft submission to the journal. Conflicts of interest Dr Emsley has participated in speakers/advisory boards and received honoraria from AstraZeneca, Janssen, Lilly, Lundbeck, Pfizer, Servier, and Otsuka. He has received research funding from Janssen, Lundbeck and AstraZeneca. Dr Chiliza has received honoraria from Sandoz and Janssen for speaking at educational meetings. Brian Harvey has participated in advisory boards and received honoraria from Organon, Pfizer and Servier, and has received research funding from Lundbeck. Drs Asmal, du Plessis. Phahladira, van Rensburg and van Niekerk have no conflicts of interest to declare. Acknowledgment This study was funded by the Stanley Medical Research Institute (Grant #09T-1281).
References 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. Flora, S.J., 2009. Structural, chemical and biological aspects of antioxidants for strategies against metal and metalloid exposure. Oxid. Med. Cell. Longev. 2 (4), 191–206. Giamattei, L., 1957. Thioctic acid in therapy of schizophrenia. Osp. Psichiatr. 25, 221–228. Harvey, B.H., Joubert, C., Du Preez, J.L., Berk, M., 2008. Effect of chronic N-acetyl cysteine administration on oxidative status in the presence and absence of induced oxidative stress in rat striatum. Neurochem. Res. 33 (3), 508–517. Kim, E., Park, D.W., Choi, S.H., Kim, J.J., Cho, H.S., 2008. A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug-induced weight gain in patients with schizophrenia. J. Clin. Psychopharmacol. 28 (2), 138–146. Ratliff, J.C., Palmese, L.B., Reutenauer, E.L., Tek, C., 2013. An open-label pilot trial of alphalipoic acid for weight loss in patients with schizophrenia without diabetes. Clin. Schizophr. Relat. Psychoses 7, 1–13. Tylicki, L., Rutkowski, B., Hörl, W.H., 2003. Antioxidants: a possible role in kidney protection. Kidney Blood Press. Res. 26 (5–6), 303–314. Ziegler, D., Schatz, H., Conrad, F., Gries, F.A., Ulrich, H., Reichel, G., 1997. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial. Diabetes Care 20 (3), 369–373. Ziegler, D., Hanefeld, M., Ruhnau, K.J., Hasche, H., Lobisch, M., Schütte, K., Kerum, G., Malessa, R., 1999. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III study group. Alpha-lipoic acid in diabetic neuropathy. Diabetes Care 22 (8), 1296–1301.
Robin Emsley Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa Bonginkosi Chiliza Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
Letter to the Editor
225
Laila Asmal Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
Susan J. van Rensburg Division of Chemical Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
Stefan du Plessis Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
Brian H. Harvey Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North West University, South Africa
Lebogang Phahladira Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
11 September 2014
Evette van Niekerk Division of Human Nutrition, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Re: Less is more
Dear Editors We thank Dr Seybolt for her interest in our study. Her comments address the important and difficult task of selecting the most appropriate dose of a compound for clinical trials where there is scant empirical evidence to guide these decisions. She suggests that the 300 mg/d dose of alpha lipoic acid (ALA) we chose is too high — that a therapeutic window for ALA exists, and that a lower dose would have had a better chance of success. She bases her suggestion on two studies conducted in the 1950s. In the first study mental status improvements were reported in 4 of 10 patients with unspecified liver dysfunction who were treated with ALA 10 mg intravenously per day for 28 days (Giamattei, 1957). In the second study 6 patients with chronic schizophrenia received varying doses of ALA and most seemed to deteriorate when the dose was increased (Altschule et al., 1959). Given the methodological shortcomings of older studies such as small samples, lack of validated assessment instruments and lack of randomization, blinding and an active control group, we don't believe that this constitutes sufficient justification to select doses within this range. It could be equally argued that the dose we selected was too low. Two more recent studies investigating the effects of ALA on weight and metabolic profile in patients with schizophrenia used doses of 1200 mg/d. In these studies the ALA was well tolerated and there was no change in clinical status (Kim et al., 2008; Ratliff et al., 2013). Further, ALA has been used in randomized, controlled trials in doses of 1800 mg/d for 6 months in the treatment of diabetic neuropathy (Ziegler et al., 1999) and 800 mg/d for 4 months for cardiac neuropathy (Ziegler et al., 1997), with no increase in adverse events versus placebo. Trying to predict therapeutic effects of antioxidants is complex. For example, in an animal study (Harvey et al., 2008) we noted that the antioxidant N-acetyl cysteine (NAC) dose-dependently worsened redox status in healthy animals while improving redox status and reversing pathology in “sick” animals. Thus, an antioxidant such as ALA (or others such as NAC) may perform differently depending on the cellular milieu. It may act either as an anti-oxidant or as a pro-oxidant depending on the redox status of the organism (Tylicki et al, 2003; Flora, 2009), which likely relates to illness severity. Within this already complex cellular environment it may be that the applied dose of the antioxidant, compounded by illness state/severity, also has a role in determining the clinical outcome. This can only be predicted once we fully understand the ephemeral nature of antioxidant response within the context of disease. Also, to extrapolate these findings to human studies may not be straight forward. Finally, our study did not investigate the effects of ALA as monotherapy — rather as an adjunct to omega-3 fatty acids. We should also point out that we don't agree with the suggestion by Dr Seybolt that the “excessive” doses of ALA given in our study “caused relapse in all” — rather, as relapse rates were similar to those in the placebo arm, the combination of omega-3 fatty acids and ALA failed to show efficacy in preventing relapse. While Dr Seybolt is concerned
http://dx.doi.org/10.1016/j.schres.2014.10.014 0920-9964/© 2014 Elsevier B.V. All rights reserved.
that our paper may deter further work on ALA in schizophrenia, we hope that it will do exactly the opposite — that it will encourage further interest in searching for a therapeutic effect for anti-oxidants and other nutritional supplements in schizophrenia. Contributors All of the authors met International Council of Medical Journal Editors criteria and all those who fulfilled those criteria are listed as authors. All authors provided direction and comments on the manuscript. They provided intellectual contributions and approved the final draft submission to the journal. Conflicts of interest Dr Emsley has participated in speakers/advisory boards and received honoraria from AstraZeneca, Janssen, Lilly, Lundbeck, Pfizer, Servier, and Otsuka. He has received research funding from Janssen, Lundbeck and AstraZeneca. Dr Chiliza has received honoraria from Sandoz and Janssen for speaking at educational meetings. Brian Harvey has participated in advisory boards and received honoraria from Organon, Pfizer and Servier, and has received research funding from Lundbeck. Drs Asmal, du Plessis. Phahladira, van Rensburg and van Niekerk have no conflicts of interest to declare. Acknowledgment This study was funded by the Stanley Medical Research Institute (Grant #09T-1281).
References 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. Flora, S.J., 2009. Structural, chemical and biological aspects of antioxidants for strategies against metal and metalloid exposure. Oxid. Med. Cell. Longev. 2 (4), 191–206. Giamattei, L., 1957. Thioctic acid in therapy of schizophrenia. Osp. Psichiatr. 25, 221–228. Harvey, B.H., Joubert, C., Du Preez, J.L., Berk, M., 2008. Effect of chronic N-acetyl cysteine administration on oxidative status in the presence and absence of induced oxidative stress in rat striatum. Neurochem. Res. 33 (3), 508–517. Kim, E., Park, D.W., Choi, S.H., Kim, J.J., Cho, H.S., 2008. A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug-induced weight gain in patients with schizophrenia. J. Clin. Psychopharmacol. 28 (2), 138–146. Ratliff, J.C., Palmese, L.B., Reutenauer, E.L., Tek, C., 2013. An open-label pilot trial of alphalipoic acid for weight loss in patients with schizophrenia without diabetes. Clin. Schizophr. Relat. Psychoses 7, 1–13. Tylicki, L., Rutkowski, B., Hörl, W.H., 2003. Antioxidants: a possible role in kidney protection. Kidney Blood Press. Res. 26 (5–6), 303–314. Ziegler, D., Schatz, H., Conrad, F., Gries, F.A., Ulrich, H., Reichel, G., 1997. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial. Diabetes Care 20 (3), 369–373. Ziegler, D., Hanefeld, M., Ruhnau, K.J., Hasche, H., Lobisch, M., Schütte, K., Kerum, G., Malessa, R., 1999. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III study group. Alpha-lipoic acid in diabetic neuropathy. Diabetes Care 22 (8), 1296–1301.
Robin Emsley Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa Bonginkosi Chiliza Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
Letter to the Editor
225
Laila Asmal Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
Susan J. van Rensburg Division of Chemical Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
Stefan du Plessis Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
Brian H. Harvey Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North West University, South Africa
Lebogang Phahladira Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
11 September 2014
Evette van Niekerk Division of Human Nutrition, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa
