LETTERS TO THE EDITOR
DRD2-Related TaqIA Genotype Is Associated With Dopamine Release During a Gambling Task To the Editor:
T
he TaqIA [(rs1800497) singlenucleotide polymorphism (SNP) of the human ankyrin repeat and kinase domain containing 1 (ANKK1)] A1 allele has been linked to impulsivity and addiction disorders and has also been suggested to be overexpressed in patients with pathological gambling (PG) although the latter has been questioned in subsequent studies (Comings et al., 1996; Lobo et al., 2007, 2010; Lim et al., 2012). In vivo human positron emission tomography (PET) studies have confirmed that the TaqIA A1 allele (specifically the A1A2 genotype) is associated with reduced striatal D2 dopamine receptor availability (Pohjalainen et al.,
Received for publication December 20, 2013; accepted February 26, 2014. Supported by the Finnish Alcohol Research Foundation, the Finnish Medical Foundation, the Turku University Central Hospital (EVOfunds), the Turku University Foundation, and the Paulo Foundation. Dr Joutsa has received lecturer honoraria from BoehringerIngelheim and a research grant from Lundbeck. Dr Hirvonen works currently for Genzyme and has received a research grant from the Orion-Farmos Research Foundation. Dr Hietala has received speaker bureau honoraria and/or travel funds from Janssen, BristolMyers, Lilly, Astra-Zeneca, Pfizer and Lundbeck; served as a member of the advisory board of Servier and acts as a consultant for Orion-Pharma. Dr Kaasinen has received speaker honoraria and/or travel grants from Merck, Medtronic, Orion-Pharma, Abbvie, UCB, and Lundbeck; and has served as a member of the advisory board of UCB and as a consultant for Orion-Pharma and Lundbeck. The authors declare no conflicts of interest. Send correspondence and reprint requests to Juho Joutsa, MD, PhD, Turku PET Centre, P.O. Box 52, Turku University Hospital, 20521 Turku, Finland. E-mail: [email protected]. C 2014 American Society of Addiction Copyright Medicine ISSN: 1932-0620/14/0804-0294 DOI: 10.1097/ADM.0000000000000037
294
1998; J¨onsson et al., 1999). Moreover, previous PET studies have indicated a role for D2 (but also D3) receptors in PG (Clark et al., 2012; Boileau et al., 2013). We performed a genetic analysis of 24 Caucasian male subjects [12 PG patients and 12 healthy controls (HCs)] who had previously participated in a 11 C-raclopride PET study involving gambling with a slot machine (Joutsa et al., 2012). Dopamine release during high-reward and low-reward gambling was quantified in a region of 52 voxels (voxel size: 2 × 2 × 2 mm), where a statistically significant reduction in 11 C-raclopride binding potential was observed (repeated measures ANOVA condition effect, voxel-level family-wise error-corrected P < 0.05), as described previously (Joutsa et al., 2012). PCR-based sequencing methods were applied to determine the genotypes of the C957T (rs6277) and G1101A SNPs in the dopamine receptor D2 gene (DRD2) and the TaqIA polymorphism in the ANKK1 gene from venous blood samples, as described previously (Hirvonen et al., 2009). PET imaging data were not available for one HC and one low-reward scan of a PG patient. The study was approved by the local ethical committee and conducted in accordance with the Declaration of Helsinki. The genotype frequencies of ANKK1 TaqIA (A2A2–A2A1–A1A1) were 10–2–0 and 5–5–2 in HC and PG patients, respectively (Fisher exact test; P = 0.12), and the genotype frequencies of C957T (T/T–C/T–C/C) were 5– 6–1 and 3–2–7 (P = 0.07) in HC and PG patients, respectively. All subjects had the G1101A genotype G/G. As reported previously, there were no significant differences in gambling-related dopamine release between PG patients and HC during high-reward or lowreward gambling sessions (Joutsa et al., 2012). However, the striatal dopamine release differed according to the TaqIA genotype during high-reward gambling (Kruskal-Wallis test H = 6.80; df = 2; P = 0.033), and a similar trend was observed during low-reward gambling (H = 5.76; df = 2; P = 0.056) (Fig. 1). Post-hoc tests revealed that dopamine release during high-reward gambling
was greater in subjects with the A1A2 genotype than in subjects with the A2A2 genotype (post-hoc Mann-Whitney U test with Bonferroni correction U = 2.54; df = 21; P = 0.033). The C957T genotype did not have any significant effect on dopamine release (P > 0.16), and neither of the genotypes had an effect on baseline dopamine D2 receptor binding potential or mood ratings during the tasks (P > 0.11). Subjects with the A1A2 genotype released significantly more dopamine during gambling than subjects with the A2A2 genotype. This finding suggests that TaqIA polymorphisms have influence on brain dopaminergic processing of reward or reward-related stimuli during gambling. The results of this preliminary study need independent replication, and should be interpreted as hypothesis generating, as further studies are required to establish the role of the TaqIA genotype in dopamine neurotransmission and addiction disorders.
ACKNOWLEDGMENTS The authors are grateful for the staff of the Turku PET Centre for their skilled assistance during the PET investigations. Juho Joutsa, MD, PhD Turku PET Centre and Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland Mika M. Hirvonen, PhD Department of Pharmacology, Drug Development and Therapeutics University of Turku, Turku, Finland Eveliina Arponen, MSc Turku PET Centre, Turku University Hospital and University of Turku Turku, Finland Jarmo Hietala, MD, PhD Department of Psychiatry, Turku University Hospital and University of Turku, Turku, Finland Valtteri Kaasinen, MD, PhD Division of Clinical Neurosciences and Turku PET Centre, Turku University Hospital and University of Turku Turku, Finland
J Addict Med r Volume 8, Number 4, July/August 2014
Copyright © 2014 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
Letters to the Editor
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J Addict Med r Volume 8, Number 4, July/August 2014
FIGURE 1. Dopamine release (as indicated by reduction in 11 C-raclopride binding potential compared with the control task) during high-reward and low-reward slot machine gambling according to the TaqIA genotype. HC indicates healthy controls; PG, pathological gamblers.
REFERENCES Boileau I, Payer D, Chugani B, et al. The D2/3 dopamine receptor in pathological gambling: a positron emission tomography study with [11C]-(+)-propyl-hexahydronaptho-oxazin and [11C]raclopride. Addiction 2013;108:953–963. Clark L, Stokes PR, Wu K, et al. Striatal dopamine D2 /D3 receptor binding in pathological gambling is correlated with mood-related impulsivity. Neuroimage 2012;63:40–46. Comings DE, Rosenthal RJ, Lesieur HR, et al. A study of the dopamine D2 receptor gene in pathological gambling. Pharmacogenetics 1996;6:223–234. Hirvonen MM, Lumme V, Hirvonen J, et al. C957T polymorphism of the human dopamine D2 receptor gene predicts extrastriatal dopamine receptor availability in vivo. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:630–636. Joutsa J, Johansson J, Niemel¨a S, et al. Mesolimbic dopamine release is linked to symptom severity in pathological gambling. Neuroimage 2012;60:1992–1999. J¨onsson EG, N¨othen MM, Gr¨unhage F, et al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 1999;4:290–296. Lim S, Ha J, Choi SW, et al. Association study on pathological gambling and polymorphisms of dopamine D1, D2, D3, and D4 receptor genes in Korean population. J Gambl Stud 2012;28:481–491. Lobo DS, Vallada HP, Knight J, et al. Dopamine genes and pathological gambling in discordant sib-pairs. J Gambl Stud 2007;23:421– 433. Lobo DS, Souza RP, Tong RP, et al. Association of functional variants in the dopamine D2-like receptors with risk for gambling behaviour in healthy Caucasian subjects. Biol Psychol 2010;85:33–37. Pohjalainen T, Rinne JO, N˚agren K, et al. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 1998;3:256–260.
C
Methadone Maintenance: “Interim Treatment” Compared to Waiting Lists To the Editor:
F
or more than 4 decades US regulations have demanded that a minimal level of psychosocial services accompany methadone treatment of opioid dependence, and required that programs deny admission to applicants when necessary to avoid excessive caseloads (Institute of Medicine, 1995). In 1993, these regulations were amended to permit “interim treatment” (IM) for a maximum of 120 days to be provided by some programs (there is an unexplained, across-the-board, exclusion of private and for-profit facilities), but few programs are both eligible and willing to offer this alternative (Federal Register, 1993; National Registry of Evidence-Based Programs and Practices, 2013). The result for the overwhelming majority of addicts who cannot be accommodated, and most of those without insurance who
Received for publication March 4, 2014; accepted April 3, 2014. The author declares no conflict of interest. C 2014 American Society of Addiction Copyright Medicine ISSN: 1932-0620/14/0804-0295 DOI: 10.1097/ADM.0000000000000046
are required to pay for all services or receive none, is therapeutic abandonment, continued illicit opioid misuse, high risk of morbidity and mortality, and enormous associated costs to the community. In a recent publication, Schwartz et al (2014) present a cost-benefit analysis of IM. They confirmed their earlier outcomes-oriented findings (Schwartz et al., 2012), including the similarity in retention. The retention rate of IM patients is especially remarkable since unlike standard methadone patients they “were not eligible for the motivational incentive of obtaining a takehome dose . . . after the first 90 days of treatment.” As for costs, they were very substantially higher for the “standard” treatment setting. This, of course, would be expected, but what is startling is the determination that the incremental cost to the program of offering IM was $3.50 per patient per week [sic!]! Surely this study should lead to an immediate radical change in governmental regulations and in self-imposed program policies as they relate to waiting lists. More generally, however, there should be open-minded reconsideration of imposing on both programs and patients a host of psychosocial services that in many instances neither can afford, and that both might believe are unnecessary. Robert G. Newman, MD, MPH Beth Israel Medical Center New York
2014 American Society of Addiction Medicine
Copyright © 2014 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
295
Letters to the Editor
REFERENCES Federal Register. Title 21. Codified at 58 CFR Sect/ 495, pt 291. 1993. Institute of Medicine. Rettig RA, Yarmolinsky A, eds. Federal Regulation of Methadone Treatment. Washington, DC: National Academies Press; 1995.
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J Addict Med r Volume 8, Number 4, July/August 2014
National Registry of Evidence-Based Programs and Practices (SAMHSA). 2013. http://nrepp. samhsa.gov/ViewIntervention.aspx?id=19. Accessed July 2, 2014. Schwartz RP, Kelly SM, O’Grady KE, Ghandi D, Jaffe JH. Randomized trial of standard methadone treatment compared to initiat-
ing methadone without counseling: 12-Month findings. Addiction 2012;107:943–952. Schwartz RP, Alexandre PK, Kelly SM, O’Grady KE, Gryczynski J, Jaffe JH. Interim versus standard methadone treatment: a benefit-cost analysis. J Subst Abuse Treat 2014;46:306– 314.
C
2014 American Society of Addiction Medicine
Copyright © 2014 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
DRD2-Related TaqIA Genotype Is Associated With Dopamine Release During a Gambling Task To the Editor:
T
he TaqIA [(rs1800497) singlenucleotide polymorphism (SNP) of the human ankyrin repeat and kinase domain containing 1 (ANKK1)] A1 allele has been linked to impulsivity and addiction disorders and has also been suggested to be overexpressed in patients with pathological gambling (PG) although the latter has been questioned in subsequent studies (Comings et al., 1996; Lobo et al., 2007, 2010; Lim et al., 2012). In vivo human positron emission tomography (PET) studies have confirmed that the TaqIA A1 allele (specifically the A1A2 genotype) is associated with reduced striatal D2 dopamine receptor availability (Pohjalainen et al.,
Received for publication December 20, 2013; accepted February 26, 2014. Supported by the Finnish Alcohol Research Foundation, the Finnish Medical Foundation, the Turku University Central Hospital (EVOfunds), the Turku University Foundation, and the Paulo Foundation. Dr Joutsa has received lecturer honoraria from BoehringerIngelheim and a research grant from Lundbeck. Dr Hirvonen works currently for Genzyme and has received a research grant from the Orion-Farmos Research Foundation. Dr Hietala has received speaker bureau honoraria and/or travel funds from Janssen, BristolMyers, Lilly, Astra-Zeneca, Pfizer and Lundbeck; served as a member of the advisory board of Servier and acts as a consultant for Orion-Pharma. Dr Kaasinen has received speaker honoraria and/or travel grants from Merck, Medtronic, Orion-Pharma, Abbvie, UCB, and Lundbeck; and has served as a member of the advisory board of UCB and as a consultant for Orion-Pharma and Lundbeck. The authors declare no conflicts of interest. Send correspondence and reprint requests to Juho Joutsa, MD, PhD, Turku PET Centre, P.O. Box 52, Turku University Hospital, 20521 Turku, Finland. E-mail: [email protected]. C 2014 American Society of Addiction Copyright Medicine ISSN: 1932-0620/14/0804-0294 DOI: 10.1097/ADM.0000000000000037
294
1998; J¨onsson et al., 1999). Moreover, previous PET studies have indicated a role for D2 (but also D3) receptors in PG (Clark et al., 2012; Boileau et al., 2013). We performed a genetic analysis of 24 Caucasian male subjects [12 PG patients and 12 healthy controls (HCs)] who had previously participated in a 11 C-raclopride PET study involving gambling with a slot machine (Joutsa et al., 2012). Dopamine release during high-reward and low-reward gambling was quantified in a region of 52 voxels (voxel size: 2 × 2 × 2 mm), where a statistically significant reduction in 11 C-raclopride binding potential was observed (repeated measures ANOVA condition effect, voxel-level family-wise error-corrected P < 0.05), as described previously (Joutsa et al., 2012). PCR-based sequencing methods were applied to determine the genotypes of the C957T (rs6277) and G1101A SNPs in the dopamine receptor D2 gene (DRD2) and the TaqIA polymorphism in the ANKK1 gene from venous blood samples, as described previously (Hirvonen et al., 2009). PET imaging data were not available for one HC and one low-reward scan of a PG patient. The study was approved by the local ethical committee and conducted in accordance with the Declaration of Helsinki. The genotype frequencies of ANKK1 TaqIA (A2A2–A2A1–A1A1) were 10–2–0 and 5–5–2 in HC and PG patients, respectively (Fisher exact test; P = 0.12), and the genotype frequencies of C957T (T/T–C/T–C/C) were 5– 6–1 and 3–2–7 (P = 0.07) in HC and PG patients, respectively. All subjects had the G1101A genotype G/G. As reported previously, there were no significant differences in gambling-related dopamine release between PG patients and HC during high-reward or lowreward gambling sessions (Joutsa et al., 2012). However, the striatal dopamine release differed according to the TaqIA genotype during high-reward gambling (Kruskal-Wallis test H = 6.80; df = 2; P = 0.033), and a similar trend was observed during low-reward gambling (H = 5.76; df = 2; P = 0.056) (Fig. 1). Post-hoc tests revealed that dopamine release during high-reward gambling
was greater in subjects with the A1A2 genotype than in subjects with the A2A2 genotype (post-hoc Mann-Whitney U test with Bonferroni correction U = 2.54; df = 21; P = 0.033). The C957T genotype did not have any significant effect on dopamine release (P > 0.16), and neither of the genotypes had an effect on baseline dopamine D2 receptor binding potential or mood ratings during the tasks (P > 0.11). Subjects with the A1A2 genotype released significantly more dopamine during gambling than subjects with the A2A2 genotype. This finding suggests that TaqIA polymorphisms have influence on brain dopaminergic processing of reward or reward-related stimuli during gambling. The results of this preliminary study need independent replication, and should be interpreted as hypothesis generating, as further studies are required to establish the role of the TaqIA genotype in dopamine neurotransmission and addiction disorders.
ACKNOWLEDGMENTS The authors are grateful for the staff of the Turku PET Centre for their skilled assistance during the PET investigations. Juho Joutsa, MD, PhD Turku PET Centre and Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland Mika M. Hirvonen, PhD Department of Pharmacology, Drug Development and Therapeutics University of Turku, Turku, Finland Eveliina Arponen, MSc Turku PET Centre, Turku University Hospital and University of Turku Turku, Finland Jarmo Hietala, MD, PhD Department of Psychiatry, Turku University Hospital and University of Turku, Turku, Finland Valtteri Kaasinen, MD, PhD Division of Clinical Neurosciences and Turku PET Centre, Turku University Hospital and University of Turku Turku, Finland
J Addict Med r Volume 8, Number 4, July/August 2014
Copyright © 2014 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
Letters to the Editor
(%)
(%)
J Addict Med r Volume 8, Number 4, July/August 2014
FIGURE 1. Dopamine release (as indicated by reduction in 11 C-raclopride binding potential compared with the control task) during high-reward and low-reward slot machine gambling according to the TaqIA genotype. HC indicates healthy controls; PG, pathological gamblers.
REFERENCES Boileau I, Payer D, Chugani B, et al. The D2/3 dopamine receptor in pathological gambling: a positron emission tomography study with [11C]-(+)-propyl-hexahydronaptho-oxazin and [11C]raclopride. Addiction 2013;108:953–963. Clark L, Stokes PR, Wu K, et al. Striatal dopamine D2 /D3 receptor binding in pathological gambling is correlated with mood-related impulsivity. Neuroimage 2012;63:40–46. Comings DE, Rosenthal RJ, Lesieur HR, et al. A study of the dopamine D2 receptor gene in pathological gambling. Pharmacogenetics 1996;6:223–234. Hirvonen MM, Lumme V, Hirvonen J, et al. C957T polymorphism of the human dopamine D2 receptor gene predicts extrastriatal dopamine receptor availability in vivo. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:630–636. Joutsa J, Johansson J, Niemel¨a S, et al. Mesolimbic dopamine release is linked to symptom severity in pathological gambling. Neuroimage 2012;60:1992–1999. J¨onsson EG, N¨othen MM, Gr¨unhage F, et al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 1999;4:290–296. Lim S, Ha J, Choi SW, et al. Association study on pathological gambling and polymorphisms of dopamine D1, D2, D3, and D4 receptor genes in Korean population. J Gambl Stud 2012;28:481–491. Lobo DS, Vallada HP, Knight J, et al. Dopamine genes and pathological gambling in discordant sib-pairs. J Gambl Stud 2007;23:421– 433. Lobo DS, Souza RP, Tong RP, et al. Association of functional variants in the dopamine D2-like receptors with risk for gambling behaviour in healthy Caucasian subjects. Biol Psychol 2010;85:33–37. Pohjalainen T, Rinne JO, N˚agren K, et al. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 1998;3:256–260.
C
Methadone Maintenance: “Interim Treatment” Compared to Waiting Lists To the Editor:
F
or more than 4 decades US regulations have demanded that a minimal level of psychosocial services accompany methadone treatment of opioid dependence, and required that programs deny admission to applicants when necessary to avoid excessive caseloads (Institute of Medicine, 1995). In 1993, these regulations were amended to permit “interim treatment” (IM) for a maximum of 120 days to be provided by some programs (there is an unexplained, across-the-board, exclusion of private and for-profit facilities), but few programs are both eligible and willing to offer this alternative (Federal Register, 1993; National Registry of Evidence-Based Programs and Practices, 2013). The result for the overwhelming majority of addicts who cannot be accommodated, and most of those without insurance who
Received for publication March 4, 2014; accepted April 3, 2014. The author declares no conflict of interest. C 2014 American Society of Addiction Copyright Medicine ISSN: 1932-0620/14/0804-0295 DOI: 10.1097/ADM.0000000000000046
are required to pay for all services or receive none, is therapeutic abandonment, continued illicit opioid misuse, high risk of morbidity and mortality, and enormous associated costs to the community. In a recent publication, Schwartz et al (2014) present a cost-benefit analysis of IM. They confirmed their earlier outcomes-oriented findings (Schwartz et al., 2012), including the similarity in retention. The retention rate of IM patients is especially remarkable since unlike standard methadone patients they “were not eligible for the motivational incentive of obtaining a takehome dose . . . after the first 90 days of treatment.” As for costs, they were very substantially higher for the “standard” treatment setting. This, of course, would be expected, but what is startling is the determination that the incremental cost to the program of offering IM was $3.50 per patient per week [sic!]! Surely this study should lead to an immediate radical change in governmental regulations and in self-imposed program policies as they relate to waiting lists. More generally, however, there should be open-minded reconsideration of imposing on both programs and patients a host of psychosocial services that in many instances neither can afford, and that both might believe are unnecessary. Robert G. Newman, MD, MPH Beth Israel Medical Center New York
2014 American Society of Addiction Medicine
Copyright © 2014 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
295
Letters to the Editor
REFERENCES Federal Register. Title 21. Codified at 58 CFR Sect/ 495, pt 291. 1993. Institute of Medicine. Rettig RA, Yarmolinsky A, eds. Federal Regulation of Methadone Treatment. Washington, DC: National Academies Press; 1995.
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J Addict Med r Volume 8, Number 4, July/August 2014
National Registry of Evidence-Based Programs and Practices (SAMHSA). 2013. http://nrepp. samhsa.gov/ViewIntervention.aspx?id=19. Accessed July 2, 2014. Schwartz RP, Kelly SM, O’Grady KE, Ghandi D, Jaffe JH. Randomized trial of standard methadone treatment compared to initiat-
ing methadone without counseling: 12-Month findings. Addiction 2012;107:943–952. Schwartz RP, Alexandre PK, Kelly SM, O’Grady KE, Gryczynski J, Jaffe JH. Interim versus standard methadone treatment: a benefit-cost analysis. J Subst Abuse Treat 2014;46:306– 314.
C
2014 American Society of Addiction Medicine
Copyright © 2014 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
