The serotonin transporter linked polymorphic region (5-HTTLPR) is an important genetic variation that has been studied in relation to both efficacy and adverse effects of serotonergic antidepressants. Before continuing to read this page, please read the basics on the following page: serotonin transporter linked polymorphic region (5-HTTLPR). For the association of 5-HTTLPR with overall burden of side effects, see this page: 5-HTTLPR and adverse effects of antidepressants
In persons with a history of antidepressant-induced mania, some of the studies have found a higher prevalence of the homozygous S allele and of the S/S genotype for 5-HTTLPR, while others have not.
The bottom line is that at this time, 5-HTTLPR polymorphisms cannot reliably predict who will or will not have antidepressant-induced mania.
Methodological problems
Bipolar I or bipolar II patients?
Rapid cycling present or excluded?
How long after starting the antidepressant?
Which antidepressant?
With a mood stabilizer or without?
Consideration of the L(G) allele as another low-expression allele? See serotonin transporter linked polymorphic region (5-HTTLPR)
Primary studies
Here are brief summaries of the published studies on the association between 5-HTTLPR polymorphisms and the risk of antidepressant-induced mania.
1. Mundo et al. (2001)
In this small study in persons with bipolar disorder who had a history of antidepressant-induced mania:
With a history of antidepressant-induced mania: 63% of the alleles were S, 37% of subjects were S/S, only 11% were L/L
Without a history of antidepressant-induced mania: 29% of the alleles were S, 7% of subjects were S/S, 48% were L/L.
Thus, persons with a history of antidepressant-induced mania were more likely to have the S allele than were those without such a history.
2. Rousseva et al. (2003)
In 305 patients with bipolar disorder, no association was found between the S allele and antidepressant-induced mania. However, an association was found with a lifetime history of rapid cycling.
3. Serretti et al. (2004)
In this study, 169 persons with bipolar I ( n=103) or bipolar II ( n=66) disorder were included. The subjects had had at least one sudden manic or hypomanic episode that occurred within three weeks after starting an antidepressant and without any interposed period of well being. These subjects were compared with a sex, age, and ethnicity-matched group of 247 subjects with bipolar disorder who had not had antidepressant-induced mania. No difference was found between the groups.
4. Masoliver et al. (2006)
I am waiting to obtain this paper.
5. Baumer et al. (2006)
No association between the S allele of 5-HTTLPR and antidepressant-induced mania was found.
6. Ferreira et al. (2009)
An association was found between the S allele of 5-HTTLPR and antidepressant-induced mania, but only in the subgroup of patients who were not also taking a mood stabilizer along with the antidepressant.
7. Frye et al. (2015)
Antidepressant-induced mania was defined as a manic or hypomanic episode within 60 days of starting an antidepressant or changing its dose.
Control subjects were those who had taken an antidepressant for at least sixty days but not had a manic or hypomanic episode during that period.
591 subjects exposed to an antidepressant were included of whom 205 had a history of antidepressant-induced mania and 386 did not.
No association between the S allele of 5-HTTLPR and antidepressant-induced mania was found.
Related Pages
Serotonin transporter linked polymorphic region (5-HTTLPR)
5-HTTLPR and adverse effects of antidepressants
Reviews
Biernacka JM, McElroy SL, Crow S, Sharp A, Benitez J, Veldic M, Kung S, Cunningham JM, Post RM, Mrazek D, Frye MA. Pharmacogenomics of antidepressant induced mania: a review and meta-analysis of the serotonin transporter gene (5HTTLPR) association. J Affect Disord. 2012 Jan;136(1-2):e21-9. PubMed PMID: 21680025.
Daray FM, Thommi SB, Ghaemi SN. The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis. Bipolar Disord. 2010 Nov;12(7):702-6. PubMed PMID: 21040287.
Primary studies
Baumer FM, Howe M, Gallelli K, Simeonova DI, Hallmayer J, Chang KD. A pilot study of antidepressant-induced mania in pediatric bipolar disorder: Characteristics, risk factors, and the serotonin transporter gene. Biol Psychiatry. 2006 Nov 1;60(9):1005-12. PubMed PMID: 16945343.
Ferreira Ade A, Neves FS, da Rocha FF, Silva GS, Romano-Silva MA, Miranda DM, De Marco L, Correa H. The role of 5-HTTLPR polymorphism in antidepressant-associated mania in bipolar disorder. J Affect Disord. 2009 Jan;112(1-3):267-72. PubMed PMID: 18534687.
Frye MA, McElroy SL, Prieto ML, Harper KL, Walker DL, Kung S, Chauhan M, Crow S, Sutor B, Galardy CW, Veldic M, Palmer BA, Geske JR, Fuentes M, Cuellar-Barboza AB, Seymour LR, Mori N, Biernacka JM. Clinical risk factors and serotonin transporter gene variants associated with antidepressant-induced mania. J Clin Psychiatry. 2015 Feb;76(2):174-80. PubMed PMID: 25611077.
Masoliver E, Menoyo A, Pérez V, Volpini V, Rio ED, Pérez J, Alvarez E, Baiget M. Serotonin transporter linked promoter (polymorphism) in the serotonin transporter gene may be associated with antidepressant-induced mania in bipolar disorder. Psychiatr Genet. 2006 Feb;16(1):25-9. PubMed PMID: 16395126.
Mundo E, Walker M, Cate T, Macciardi F, Kennedy JL. The role of serotonin transporter protein gene in antidepressant-induced mania in bipolar disorder: preliminary findings. Arch Gen Psychiatry. 2001 Jun;58(6):539-44. PubMed PMID: 11386982.
Rousseva A, Henry C, van den Bulke D, Fournier G, Laplanche JL, Leboyer M, Bellivier F, Aubry JM, Baud P, Boucherie M, Buresi C, Ferrero F, Malafosse A. Antidepressant-induced mania, rapid cycling and the serotonin transporter gene polymorphism. Pharmacogenomics J. 2003;3(2):101-4. PubMed PMID: 12746735.
Serretti A, Artioli P, Zanardi R, Lorenzi C, Rossini D, Cusin C, Arnoldi A, Catalano M. Genetic features of antidepressant induced mania and hypo-mania in bipolar disorder. Psychopharmacology (Berl). 2004 Aug;174(4):504-11. PubMed PMID: 15248044.
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