Letters
1. Lane HY, Lin CH, Green MF, et al. Add-on treatment for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry. 2013;70(12):1267-1275. 2. Wibbertmann A, Kielhorn J, Koennecker G, Mangelsdorf I, Melber C; World Health Organization. Concise International Chemical Assessment Document 26: benzoic acid and sodium benzoate. 2005. http://www.who.int/ipcs /publications/cicad/cicad26_rev_1.pdf. Accessed March 21, 2014. 3. Food Standards Australia New Zealand. The 21st Australian Total Diet Study: a total diet study of sulphites, benzoates, and sorbates. 2005. http://www .foodstandards.gov.au/publications/documents/21st%20ATD%20Study %20report-Aug051.pdf. Accessed March 21, 2014. 4. Su AY-L. Factors influencing the consumption of sugar-sweetened beverages by Taiwanese hospitality students. J Hospital Marketing Management. 2012;21: 295-310. 5. Golbitz P. Soyfoods Consumption in the United States and Worldwide: A Statistical Analysis. Bar Harbor, ME: Soyatech Inc; 1991.
In Reply While commenting on our article published in JAMA Psychiatry,1 Glue et al raise the issue that “dietary benzoic acid intake may be a significant confounding variable that needs to be considered in interpreting the outcome of this study.” First, the double-blind placebo-controlled design confirmed that the add-on treatment of benzoate is much more efficacious than placebo in improving symptoms and cognition in schizophrenia. It is apparent that both groups had received benzoate from their daily intake of food and drink; however, the active treatment group received a 1000-mg sodium benzoate supplement a day, while the placebo group did not. Second, sodium benzoate is listed as a food preservative in the United States, European Union, Japan, Taiwan, and other countries. We had estimated that the benzoate in daily intake was not high enough to render therapeutic effects. As we pointed out, “concentration as a preservative is limited by the US Food and Drug Administration to 0.1% by weight. The World Health Organization suggests a provisional tolerable intake of 5 mg/kg daily.”1 In Taiwan, the allowance for sodium benzoate in drinks is 0.06% and 0.1% for soy product.2 With the estimated intake of drinks at approximately 2.5 L per week, the highest daily intake can potentially reach 214 mg. However, it is important not to interpret the daily limit of benzoate as the actual daily intake; the amount of benzoate in drinks varies and not all soft drinks contain benzoate as a preservative. Soy product is the other main source of benzoate intake. At yearly intake of 13 kg, the daily intake from soy product is 35.6 mg of benzoate. Taken together, we estimate the highest intake of benzoate from soft drinks and soy products in sum can reach 250 mg per day, while at the 0.035% limit of benzoate addition in soft drinks in Australia and New Zealand, where soy products are far less popular than in east Asian countries, the daily intake from soft drinks can potentially reach 125 mg. Our pilot dose-finding study showed that 250 mg daily is ineffective in improving the symptoms of schizophrenia1 and early dementia.3 In addition, our preliminary findings suggested that patients with refractory schizophrenia and treated with clozapine require 2 g or more of sodium benzoate daily to improve the symptoms, while 1 g is ineffective. Therefore, we concluded that the daily intake of benzoate, even with the highest allowance estimated, plays a negligible role in improving central nervous system disorders. However, we agree cautious strategy needs to be taken when benzoate treatment is
applied in populations that have special habits in diet and drinks, which may affect their daily intake of benzoate. For example, people binging on a brand of soft drink that contains a high amount of benzoate. In our study, we did not observe any participant who had behaviors like that. Guochuan E. Tsai, MD, PhD Author Affiliations: Department of Psychiatry, Harbor–UCLA Medical Center, Torrance, California; Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, California. Corresponding Author: Guochuan E. Tsai, MD, PhD, Harbor–UCLA Medical Center, 1000 W Carson St, Torrance, CA 90502 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Lane HY, Lin CH, Green MF, et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry. 2013;70(12):1267-1275. 2. National Environmental Health Research Center. http://nehrc.nhri.org.tw /toxic/news/1021202_2.pdf. Accessed September 17, 2014. 3. Lin CH, Chen PK, Chang YC, et al. Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry. 2014;75(9):678-685.
Attention Network Hypoconnectivity in Adults Diagnosed as Having Attention-Deficit/ Hyperactivity Disorder in Childhood To the Editor We thank Qi et al1 for their contribution to this important discussion about research in attention-deficit/ hyperactivity disorder (ADHD). We wish to use this opportunity to respond to the letter. We apologize for the typo in the Montreal Neurological Institute coordinate in the text of our article.2 The anterior cingulate cortex should be x = ±10, y = 35, and z = 2 rather than x = ±10, y = −35, and z = 2. However, the legend for Figure 1 is correct and may have been misunderstood by Qi et al1: left anterior cingulate cortex (ACC) and right ACC refer to the left and right seed region of the affective network. As noted in the legend, “participants with attention-deficit/hyperactivity disorder displayed greater resting-state functional connectivity between the [ACC] and superior parietal and cerebellar areas than did the control subjects. A, Left ACC (x = 18, y = −50, z = 64). B, Right ACC (x = 34, y = −76, z = −30).”2 We wish to respectfully disagree with the remaining comments raised by Qi et al.1 We were and are aware of the concerns posed by our sample’s size, treatment heterogeneity, and naturalistic longitudinal design. These concerns were outlined in the limitations section of our article2; thus Qi et al1 have not highlighted new issues here. Moreover, to our knowledge, we were the first to examine the affective, ventral, and dorsal attention networks in tandem with the cognitive control and default mode networks to determine the localization and specificity of ADHD-related resting-state functional connectivity differences in adults diagnosed as having ADHD in childhood. The strength of our study was the inclusion of a well-characterized sample of patients who were diagnosed as having ADHD as children. This is a considerable advantage because we overcame the serious issue of retrospective diagnoses of ADHD, which have been shown to be prone to recall bias during self-reports.3
jamapsychiatry.com
JAMA Psychiatry November 2014 Volume 71, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Tulane University User on 05/17/2015
1299
Letters
With regard to exposure to methylphenidate, 2 participants (13%) were treatment naive, 10 (63%) were drug free for a mean (SD) of 11.6 (4.2) years but had a history of methylphenidate drug treatment spanning a mean of 20.6 months, and 4 (25%) withheld their stimulant medication for 48 hours. We aimed to make our research as clinically relevant as possible; therefore, we posited that results from a drug-naive sample of participants would not be readily applicable to clinical practice because this would not reflect the natural treatment course of ADHD across the lifespan. Also, a drug-naive participant group with a childhood diagnosis of ADHD would be highly selective to those children and families identified with a diagnosis of ADHD who did not try a stimulant during their lifespan. With regards to the reference to Langleben et al,4 Qi et 1 al queried whether the inclusion of patients who withheld methylphenidate briefly might induce confused results. Within this study, the effect of methylphenidate withdrawal was highlighted as a potential confounding factor in obscuring the effects of ADHD in regional cerebral blood flow during a 36-hour withdrawal from methylphenidate compared with scans involving methylphenidate. 4 Although we applied a longer washout period than Langleben et al4 of 48 hours, we acknowledged that rebound effects from methylphenidate withdrawal are an inherent limitation of imaging studies examining participants who have been exposed to stimulant treatment. Also, Langleben et al4 clearly stated in their article that their results were for a group and no claims can be made about their predictive value in individuals. To understand the full impact of stimulant exposure on brain function, further work is clearly needed to examine potential rebound effects and possible tolerance levels to methylphenidate at varying washout points among participants with chronic stimulant exposure.
Parahippocampal Hypoactivation and Vulnerability to Schizophrenia
1. Qi R, Zhang LJ, Lu GM. Emphasize the effect of methylphenidate on brain function in attention-deficit/hyperactivity disorder research. JAMA Psychiatry. 2014;71(2):210.
To the Editor In JAMA Psychiatry, Rasetti et al1 presented a study of parahippocampal function during a declarative memory task in patients with schizophrenia and their healthy siblings. The authors found that during the encoding of visual scenes, both groups showed relatively reduced parahippocampal activation compared with healthy control individuals. In control participants, the degree of parahippocampal activation during encoding was positively correlated with their visual-memory scores. These findings suggest that parahippocampal hypoactivation during memory encoding may be an intermediate biological phenotype related to psychosis vulnerability. These results are similar to those from a functional magnetic resonance imaging study that we conducted in a different high-risk group, people at clinical high risk for psychosis. This group also showed parahippocampal hypoactivation during memory encoding, in this case, in the context of a verbal rather than visual-encoding task.2 Moreover, as in the Rasetti et al study,1 there was a direct correlation between memory performance and parahippocampal activation. Thus, our data are consistent with the suggestion by Rasetti et al 1 that an altered parahippocampal response during encoding is related to an increased vulnerability to psychosis. However, the increased risk in the participants in our study was related to their clinical features rather than a family history of psychosis. This raises the possibility that the findings may be a generic correlate of vulnerability as opposed to being specifically related to genetic factors. However, it is also possible that the increased vulnerability to psychosis in clinical high-risk individuals is related to genetic factors that are not manifest at the level of family history. At present, little is known about the genetic contribution to vulnerability in clinical high-risk samples but a number of multicenter studies in this population have been completed and may provide data that will clarify this issue. Although this was not examined in the study by Rasetti et al,1 we also assessed the relationship between parahippocampal responses and subcortical dopamine function using F-dopa positron emission tomography. This revealed that this relationship was significantly altered in the clinical high-risk group: in these individuals, the parahippocampal response was correlated with the level of striatal dopamine function, a relationship that was absent in control participants.3 These data suggest that changes in parahippocampal activity could influence subcortical dopamine function, in line with contemporary animal models of psychosis.4
2. McCarthy H, Skokauskas N, Mulligan A, et al. Attention network hypoconnectivity with default and affective network hyperconnectivity in adults diagnosed with attention-deficit/hyperactivity disorder in childhood. JAMA Psychiatry. 2013;70(12):1329-1337.
Paul Allen, PhD Philip K. McGuire, MD, PhD
3. Mannuzza S, Castellanos FX, Roizen ER, Hutchison JA, Lashua EC, Klein RG. Impact of the impairment criterion in the diagnosis of adult ADHD: 33-year follow-up study of boys with ADHD. J Atten Disord. 2011;15(2):122-129.
Author Affiliations: Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, England.
Hazel McCarthy, MSc Norbert Skokauskas, MD, PhD Thomas Frodl, MD, MA Author Affiliations: Neuroimaging Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland (McCarthy, Skokauskas, Frodl); Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland (McCarthy, Frodl); Centre for Child and Youth Mental Health and Child Protection, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway (Skokauskas); Centre for Advanced Medical Imaging, St James’s Hospital, Dublin, Ireland (Frodl); Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany (Frodl). Corresponding Author: Thomas Frodl, MD, MA, Department of Psychiatry, University Dublin, Trinity College Dublin, College Green, Dublin 2, Ireland (frodlt @tcd.ie). Conflict of Interest Disclosures: None reported.
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4. Langleben DD, Acton PD, Austin G, et al. Effects of methylphenidate discontinuation on cerebral blood flow in prepubescent boys with attention deficit hyperactivity disorder. J Nucl Med. 2002;43(12):1624-1629.
JAMA Psychiatry November 2014 Volume 71, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Tulane University User on 05/17/2015
jamapsychiatry.com
1. Lane HY, Lin CH, Green MF, et al. Add-on treatment for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry. 2013;70(12):1267-1275. 2. Wibbertmann A, Kielhorn J, Koennecker G, Mangelsdorf I, Melber C; World Health Organization. Concise International Chemical Assessment Document 26: benzoic acid and sodium benzoate. 2005. http://www.who.int/ipcs /publications/cicad/cicad26_rev_1.pdf. Accessed March 21, 2014. 3. Food Standards Australia New Zealand. The 21st Australian Total Diet Study: a total diet study of sulphites, benzoates, and sorbates. 2005. http://www .foodstandards.gov.au/publications/documents/21st%20ATD%20Study %20report-Aug051.pdf. Accessed March 21, 2014. 4. Su AY-L. Factors influencing the consumption of sugar-sweetened beverages by Taiwanese hospitality students. J Hospital Marketing Management. 2012;21: 295-310. 5. Golbitz P. Soyfoods Consumption in the United States and Worldwide: A Statistical Analysis. Bar Harbor, ME: Soyatech Inc; 1991.
In Reply While commenting on our article published in JAMA Psychiatry,1 Glue et al raise the issue that “dietary benzoic acid intake may be a significant confounding variable that needs to be considered in interpreting the outcome of this study.” First, the double-blind placebo-controlled design confirmed that the add-on treatment of benzoate is much more efficacious than placebo in improving symptoms and cognition in schizophrenia. It is apparent that both groups had received benzoate from their daily intake of food and drink; however, the active treatment group received a 1000-mg sodium benzoate supplement a day, while the placebo group did not. Second, sodium benzoate is listed as a food preservative in the United States, European Union, Japan, Taiwan, and other countries. We had estimated that the benzoate in daily intake was not high enough to render therapeutic effects. As we pointed out, “concentration as a preservative is limited by the US Food and Drug Administration to 0.1% by weight. The World Health Organization suggests a provisional tolerable intake of 5 mg/kg daily.”1 In Taiwan, the allowance for sodium benzoate in drinks is 0.06% and 0.1% for soy product.2 With the estimated intake of drinks at approximately 2.5 L per week, the highest daily intake can potentially reach 214 mg. However, it is important not to interpret the daily limit of benzoate as the actual daily intake; the amount of benzoate in drinks varies and not all soft drinks contain benzoate as a preservative. Soy product is the other main source of benzoate intake. At yearly intake of 13 kg, the daily intake from soy product is 35.6 mg of benzoate. Taken together, we estimate the highest intake of benzoate from soft drinks and soy products in sum can reach 250 mg per day, while at the 0.035% limit of benzoate addition in soft drinks in Australia and New Zealand, where soy products are far less popular than in east Asian countries, the daily intake from soft drinks can potentially reach 125 mg. Our pilot dose-finding study showed that 250 mg daily is ineffective in improving the symptoms of schizophrenia1 and early dementia.3 In addition, our preliminary findings suggested that patients with refractory schizophrenia and treated with clozapine require 2 g or more of sodium benzoate daily to improve the symptoms, while 1 g is ineffective. Therefore, we concluded that the daily intake of benzoate, even with the highest allowance estimated, plays a negligible role in improving central nervous system disorders. However, we agree cautious strategy needs to be taken when benzoate treatment is
applied in populations that have special habits in diet and drinks, which may affect their daily intake of benzoate. For example, people binging on a brand of soft drink that contains a high amount of benzoate. In our study, we did not observe any participant who had behaviors like that. Guochuan E. Tsai, MD, PhD Author Affiliations: Department of Psychiatry, Harbor–UCLA Medical Center, Torrance, California; Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, California. Corresponding Author: Guochuan E. Tsai, MD, PhD, Harbor–UCLA Medical Center, 1000 W Carson St, Torrance, CA 90502 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Lane HY, Lin CH, Green MF, et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry. 2013;70(12):1267-1275. 2. National Environmental Health Research Center. http://nehrc.nhri.org.tw /toxic/news/1021202_2.pdf. Accessed September 17, 2014. 3. Lin CH, Chen PK, Chang YC, et al. Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry. 2014;75(9):678-685.
Attention Network Hypoconnectivity in Adults Diagnosed as Having Attention-Deficit/ Hyperactivity Disorder in Childhood To the Editor We thank Qi et al1 for their contribution to this important discussion about research in attention-deficit/ hyperactivity disorder (ADHD). We wish to use this opportunity to respond to the letter. We apologize for the typo in the Montreal Neurological Institute coordinate in the text of our article.2 The anterior cingulate cortex should be x = ±10, y = 35, and z = 2 rather than x = ±10, y = −35, and z = 2. However, the legend for Figure 1 is correct and may have been misunderstood by Qi et al1: left anterior cingulate cortex (ACC) and right ACC refer to the left and right seed region of the affective network. As noted in the legend, “participants with attention-deficit/hyperactivity disorder displayed greater resting-state functional connectivity between the [ACC] and superior parietal and cerebellar areas than did the control subjects. A, Left ACC (x = 18, y = −50, z = 64). B, Right ACC (x = 34, y = −76, z = −30).”2 We wish to respectfully disagree with the remaining comments raised by Qi et al.1 We were and are aware of the concerns posed by our sample’s size, treatment heterogeneity, and naturalistic longitudinal design. These concerns were outlined in the limitations section of our article2; thus Qi et al1 have not highlighted new issues here. Moreover, to our knowledge, we were the first to examine the affective, ventral, and dorsal attention networks in tandem with the cognitive control and default mode networks to determine the localization and specificity of ADHD-related resting-state functional connectivity differences in adults diagnosed as having ADHD in childhood. The strength of our study was the inclusion of a well-characterized sample of patients who were diagnosed as having ADHD as children. This is a considerable advantage because we overcame the serious issue of retrospective diagnoses of ADHD, which have been shown to be prone to recall bias during self-reports.3
jamapsychiatry.com
JAMA Psychiatry November 2014 Volume 71, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Tulane University User on 05/17/2015
1299
Letters
With regard to exposure to methylphenidate, 2 participants (13%) were treatment naive, 10 (63%) were drug free for a mean (SD) of 11.6 (4.2) years but had a history of methylphenidate drug treatment spanning a mean of 20.6 months, and 4 (25%) withheld their stimulant medication for 48 hours. We aimed to make our research as clinically relevant as possible; therefore, we posited that results from a drug-naive sample of participants would not be readily applicable to clinical practice because this would not reflect the natural treatment course of ADHD across the lifespan. Also, a drug-naive participant group with a childhood diagnosis of ADHD would be highly selective to those children and families identified with a diagnosis of ADHD who did not try a stimulant during their lifespan. With regards to the reference to Langleben et al,4 Qi et 1 al queried whether the inclusion of patients who withheld methylphenidate briefly might induce confused results. Within this study, the effect of methylphenidate withdrawal was highlighted as a potential confounding factor in obscuring the effects of ADHD in regional cerebral blood flow during a 36-hour withdrawal from methylphenidate compared with scans involving methylphenidate. 4 Although we applied a longer washout period than Langleben et al4 of 48 hours, we acknowledged that rebound effects from methylphenidate withdrawal are an inherent limitation of imaging studies examining participants who have been exposed to stimulant treatment. Also, Langleben et al4 clearly stated in their article that their results were for a group and no claims can be made about their predictive value in individuals. To understand the full impact of stimulant exposure on brain function, further work is clearly needed to examine potential rebound effects and possible tolerance levels to methylphenidate at varying washout points among participants with chronic stimulant exposure.
Parahippocampal Hypoactivation and Vulnerability to Schizophrenia
1. Qi R, Zhang LJ, Lu GM. Emphasize the effect of methylphenidate on brain function in attention-deficit/hyperactivity disorder research. JAMA Psychiatry. 2014;71(2):210.
To the Editor In JAMA Psychiatry, Rasetti et al1 presented a study of parahippocampal function during a declarative memory task in patients with schizophrenia and their healthy siblings. The authors found that during the encoding of visual scenes, both groups showed relatively reduced parahippocampal activation compared with healthy control individuals. In control participants, the degree of parahippocampal activation during encoding was positively correlated with their visual-memory scores. These findings suggest that parahippocampal hypoactivation during memory encoding may be an intermediate biological phenotype related to psychosis vulnerability. These results are similar to those from a functional magnetic resonance imaging study that we conducted in a different high-risk group, people at clinical high risk for psychosis. This group also showed parahippocampal hypoactivation during memory encoding, in this case, in the context of a verbal rather than visual-encoding task.2 Moreover, as in the Rasetti et al study,1 there was a direct correlation between memory performance and parahippocampal activation. Thus, our data are consistent with the suggestion by Rasetti et al 1 that an altered parahippocampal response during encoding is related to an increased vulnerability to psychosis. However, the increased risk in the participants in our study was related to their clinical features rather than a family history of psychosis. This raises the possibility that the findings may be a generic correlate of vulnerability as opposed to being specifically related to genetic factors. However, it is also possible that the increased vulnerability to psychosis in clinical high-risk individuals is related to genetic factors that are not manifest at the level of family history. At present, little is known about the genetic contribution to vulnerability in clinical high-risk samples but a number of multicenter studies in this population have been completed and may provide data that will clarify this issue. Although this was not examined in the study by Rasetti et al,1 we also assessed the relationship between parahippocampal responses and subcortical dopamine function using F-dopa positron emission tomography. This revealed that this relationship was significantly altered in the clinical high-risk group: in these individuals, the parahippocampal response was correlated with the level of striatal dopamine function, a relationship that was absent in control participants.3 These data suggest that changes in parahippocampal activity could influence subcortical dopamine function, in line with contemporary animal models of psychosis.4
2. McCarthy H, Skokauskas N, Mulligan A, et al. Attention network hypoconnectivity with default and affective network hyperconnectivity in adults diagnosed with attention-deficit/hyperactivity disorder in childhood. JAMA Psychiatry. 2013;70(12):1329-1337.
Paul Allen, PhD Philip K. McGuire, MD, PhD
3. Mannuzza S, Castellanos FX, Roizen ER, Hutchison JA, Lashua EC, Klein RG. Impact of the impairment criterion in the diagnosis of adult ADHD: 33-year follow-up study of boys with ADHD. J Atten Disord. 2011;15(2):122-129.
Author Affiliations: Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, England.
Hazel McCarthy, MSc Norbert Skokauskas, MD, PhD Thomas Frodl, MD, MA Author Affiliations: Neuroimaging Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland (McCarthy, Skokauskas, Frodl); Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland (McCarthy, Frodl); Centre for Child and Youth Mental Health and Child Protection, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway (Skokauskas); Centre for Advanced Medical Imaging, St James’s Hospital, Dublin, Ireland (Frodl); Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany (Frodl). Corresponding Author: Thomas Frodl, MD, MA, Department of Psychiatry, University Dublin, Trinity College Dublin, College Green, Dublin 2, Ireland (frodlt @tcd.ie). Conflict of Interest Disclosures: None reported.
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4. Langleben DD, Acton PD, Austin G, et al. Effects of methylphenidate discontinuation on cerebral blood flow in prepubescent boys with attention deficit hyperactivity disorder. J Nucl Med. 2002;43(12):1624-1629.
JAMA Psychiatry November 2014 Volume 71, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Tulane University User on 05/17/2015
jamapsychiatry.com
