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Serotonin transporter gene associated with lithium prophylaxis in mood disorders

Abstract

The aim of this study was to investigate the possible association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the prophylactic efficacy of lithium in mood disorders. Two hundred and one subjects affected by bipolar (n = 167) and major depressive (n = 34) disorder were followed prospectively for an average of 58.2 months and were typed for their 5-HTTLPR variant using polymerase chain reaction techniques. 5-HTTLPR variants were associated with lithium outcome (F = 5.35; df = 2,198; P = 0.005). Subjects with the s/s variant showed a worse response compared to both l/s and l/l variants. Consideration of possible stratification effects such as sex, polarity, age at onset, duration of lithium treatment and previous episodes did not influence the observed association. 5-HTTLPR variants may be a possible influencing factor for the prophylactic efficacy of lithium in mood disorders.

INTRODUCTION

Lithium is an effective prophylactic agent in mood disorders but not all patients equally respond to lithium therapy. Clinical predictors account for less than half of the variance1,2,3,4,5,6,7,8 and there is evidence suggesting that genetic factors play a substantial role. A positive family history of bipolar illness has repeatedly been associated with better outcome,9,10,11 and lithium responder probands proved to have a higher genetic loading when compared to non-responders.12,13,14 In light of this evidence, lithium response has been used as a tool to select homogeneous samples for association studies with genetic markers.15,16 Possible genetic predictors of lithium response have not, however, yet been evaluated.

The mode of action of lithium salts used in the prophylaxis of affective disorders is still unknown. Lithium activity may be mediated by second-messenger and nonspecific ionic flux effects.17 But a number of other complementary mechanisms have been proposed.18 Disturbances of the serotoninergic neurotransmitter system have been implicated in the pathogenesis of mood disorders19,20 and serotonin (5-HT) has also been repeatedly implicated in the mechanism of action of lithium. Animal studies evidenced that short and long-term lithium treatment enhanced 5-HT efflux in rat hippocampus21,22,23 and in the lateral hypothalamus.24 Chronic lithium administration enhances both electrophysiological and behavioral responses mediated by postsynaptic 5-HT1A receptors,25 with a significant reduction of 5-HT1 binding sites in the hippocampus.26 Moreover, the chronic administration of lithium increased the number of 5-HT transporters in cortical regions.27,28 Further evidence supports the view that lithium treatment acts through an enhancement of 5-HT function: lithium salts induced significant increases in plasma-free 5HT,29 and the prolactin response to tryptophan was significantly enhanced after short-term lithium treatment.30 The turnover of 5-HT in either frontal cortex or hippocampus was facilitated by lithium and lithium treatment causes the down-regulation of postsynaptic 5-HT1 and 5-HT2 receptors.31 However, this view is not unequivocally accepted because others have suggested that the effects of lithium on synaptic transmission and on neuronal excitability appeared independent from changes in endogenous 5-HT.32,33,34,35

Taken together, the previous studies show the effect of lithium on 5-HT function at the levels of precursor uptake, synthesis, storage, catabolism, release, receptors, and receptor-effector interactions. The weight of this evidence suggests that lithium primary actions on 5-HT may be presynaptic, with many secondary postsynaptic effects. Finally, studies in humans generally suggest that lithium has a net enhancing effect on 5-HT function.18 These actions of lithium may serve to correct 5-HT function abnormalities involved in the pathogenesis of mood disorders.36

The serotonin transporter is the major determinant of serotonin inactivation following release at synapses and it is the site of action of most antidepressants. The gene coding for it has been proposed as a possible candidate for involvement in the pathogenesis of major psychoses. A functional polymorphism in the upstream regulatory region of the gene has been associated with both major depressive and bipolar disorders,37,38,39 although subsequent studies did not replicate these results.40,41,42,43,44,45,46,47,48,49,50,51,52 The gene also proved to be associated or showed conflicting evidence with a number of other conditions, like anxiety-related traits in controls53,54,55,56,57,58,59 and in depressed patients,60 seasonal affective disorder,49,61 anxiety disorders,62 autism,63,64,65,66,67 severe alcoholism,68,69 suicidal behavior,70,71,72,73 psychotic symptomatology in neuroleptic-free schizophrenics,74 with schizophrenia75,76,77,78,79,80 but not with major psychoses symptomatology.81,82

The polymorphism in the upstream is a deletion/insertion (5-HTTLPR) located exactly at the 5′-flanking regulatory region of the serotonin transporter gene on chromosome 17q11.2. It consists of a 44-bp insertion or deletion involving repeat elements 6–8 (from bp −1212 to bp −1255).53 Heils83 found that in vitro the basal activity of the long (l) variant was more than twice that of the short (s) form of the 5-HTTLPR, suggesting that serotonin transporter gene transcription is modulated by variants of the 5-HTTLPR with the s allele corresponding to low serotonin uptake activity. The above mentioned evidence suggests that 5-HTTLPR is a potential candidate as a prediction of lithium response in mood disorders. We have therefore hypothesized that 5-HTTLPR variants could be involved in individual susceptibility to lithium prophylactic efficacy in mood disorders.

RESULTS

Of the 201 patients, 53 (26.4%) had no DSM-IV mood disorder episodes during follow up and 88 (43.8%) had a decrease in episode frequency, the remaining 60 (29.8%) had an increased episode frequency. The whole sample showed a significant reduction in episode frequency after lithium treatment (pre-lithium treatment recurrence index vs on-lithium treatment recurrence index: 8.35 vs 4.25; t = 5.63; df = 200, P < 0.0001). 5-HTTLPR genotypes were in Hardy–Weinberg equilibrium (χ2 = 0.01, df = 1, P = 0.91).

Table 1 shows the sample divided according to 5-HTTLPR variants. Clinical and demographic variables were not significantly different among 5-HTTLPR variants except for a lower recurrency index for s/s subjects. Table 2 shows that 5-HTTLPR genotypes were associated with lithium efficacy as measured by the pre vs on lithium treatment recurrence index. In particular subjects with the s/s genotype were less responsive to lithium when compared to s/l subjects (P = 0.009). Consideration of possible stratification effects using ANCOVA such as sex, polarity, age at onset, duration of lithium treatment or pre-lithium episodes did not influence the observed association (P < 0.006 for all comparisons). We then separated depressive and manic episodes. Detailed information was available for 63 subjects. In this subsample no significant differences were observed for both manic (P = 0.24) and depressive episodes (P = 0.43).

Table 1 Clinical variables divided according to 5-HTTLPR variants
Table 2 -HTTLPR variants and lithium prophylactic efficacy

DISCUSSION

Homozygosity for the short variant of the functional polymorphism in the upstream regulatory region of the serotonin transporter gene showed a worse lithium outcome in our sample of mood disorder subjects. This was also true when known clinical and demographic risk factors, such as sex, polarity, onset, and duration of lithium administration were controlled for. To our knowledge, genetic liability factors for lithium response have not yet been studied except for our preliminary investigation of dopaminergic markers in the context of the BIOMED I project.84 In that analysis we evidenced a marginal association of the dopamine receptor D2 variants with lithium response. Our center is currently testing a number of possible candidate genes within both the dopaminergic and serotoninergic systems. We have recently reported that the A218C gene variant on the tryptophan hydroxylase gene was marginally associated with lithium efficacy85 and we excluded associations with other polymorphisms.86,87,88 Recently, the 5-HTTLPR polymorphism has been also associated with the antidepressant response to certain selective serotonin reuptake inhibitors, such as fluvoxamine89,90 and paroxetine.91,92 A possible common mechanism may therefore underlie SSRI and lithium efficacy even if the exact mechanism of action of lithium activity is largely unknown. Converging evidence suggests a focus on the second-messenger system, but also aminergic systems, like the serotoninergic one, could be implicated.36 It has been shown that the second-messenger mediated lithium activity depends on the activity of the first-messenger system: lithium activity is increased when first-messengers are hyperactive, while in normal conditions its activity is lower.18 This view is consistent with the clinical effectiveness of lithium in mood disturbances and with the lack of any detectable effect in controls.1 We may therefore provisionally hypothesize that the prophylactic efficacy of lithium may be regulated by the overall activity of the serotoninergic system, that is, in turn, influenced by 5-HTTLPR and TPH variants.

In the present study we observed that the 5-HTTLPR s/s variant differed both from s/l and l/l. This suggests more a recessive than a codominant effect; both the initial report and some authors suggested a dominant effect of the s allele,53,92,93,94 but others suggested a recessive effect.47,89,91,95 Conclusive findings are still lacking and will be achieved with larger samples and/or further basic and animal studies.

In our sample, 5-HTTLPR l and s allele frequencies were respectively 0.57 and 0.43, they are similar to those of previously published samples in Caucasians.39,53,61,96 On the other hand, Asian frequencies were different from all Caucasian samples.62,97

Genetic studies may be limited by sampling biases and by power issues. Ethnic origin is frequently a cause of stratification bias but our sample was composed of subjects with Italian antecedents for at least two generations and Italy is characterized by a substantial genetic homogeneity.98 It has been argued that most studies, like the present one, may be biased because the selection criteria limit the extent to which the sample is representative.99 Subjects for the present study were recruited in a specialized center and a bias toward a higher severity of mood disorder has been observed, with a lower DSM-IV Axis I comorbidity.100,101 But the purpose of this study was to enucleate predictive factors and this is more likely when confounding variables, like Axis I comorbidity or substance abuse, are minimized.

The power of our sample was enough to detect a standardized difference (effect size) up to d = 0.45 (depending on the frequency of the risk genotype, considering a power of 0.8 and alpha <0.05 two-tailed), that corresponds to a difference of 4.7 points on the lithium efficacy index. The difference in our sample was 5.37 points, therefore it is within the range of detectable differences. However, we may not rule out the possibility of a false positive finding. In terms of explained variance, 5-HTTLPR variants accounted for 4.8% of the whole variance (considering the values of Table 2, f = 0.226),102 this is in accordance with the current view of polygenic inheritance of complex traits.103,104

A limitation of the present study is that a number of clinical variables were not considered, such as number of days of hospitalization, the episodes’ sequence type (depression/mania),4 subthreshold symptomatology,105 life events or the time course of plasma lithium levels. With regard to this last point, lithium levels were maintained within range values in our setting and, though high-range serum levels have been associated with better outcome, there have been doubts raised as to their relevance.106,107 Lithium has been at times described as more effective with manic episodes, we were not able to test this issue, however an equal efficacy with manic and depressive episodes was frequently reported.108,109,110 Finally, while a very large number of variables intervene in modifying the time course of mood disorders, and of psychiatric disturbances in general, all variables could never be completely controlled.1 Replication using independent samples is therefore required.

MATERIALS AND METHODS

Sample

Two hundred and one subjects consecutively admitted to the Lithium Clinic for Mood Disorders of S. Raffaele Hospital in Milan were included in this study (Table 1). Patients considered for this study were part of the sample collected in the context of the European Collaborative Project on Affective Disorders,84,111 124 subjects have been included in previous analysis with other polymorphisms.85,86,87,88

All patients were evaluated using the Schedule for Affective Disorders and Schizophrenia (SADS),112 and/or the Operational Criteria for Psychotic Illness checklist (OPCRIT).113 Lifetime diagnoses were assigned by two independent psychiatrists on the basis of interviews and medical records, according to DSM-IV criteria.114 Information about the illness before contact with our center was collected following the best estimate procedure, interviewing the subjects, family members, previous health professionals and obtaining records when possible.115 The presence of concomitant diagnoses of mental retardation, drug dependence, or other Axis I disorders, together with somatic or neurological illnesses that impaired psychiatric evaluation (eg hypothyroidism mimicking a depressive state) represented exclusion criteria as well as medication non-compliance as detected by persistently low lithium plasma levels. This allowed only a small part of our subjects to be included in the study. All enrolled patients received lithium as maintenance therapy with doses adjusted to obtain 12-h plasma levels within the standard therapeutic range. The mean values ranged between 0.4 and 0.7 mEq l−1 for plasma levels and between 0.2 and 0.4 mEq l−1 for red blood cell levels. Determination of lithium levels in each patient was performed every 3 months and, at the same time, the clinical condition of patients was evaluated using the Hamilton Rating Scale for Depression (21-HAMD),116 and Manic Rating Scale for Mania.117 Patients were evaluated weekly, or more often, during active phases of the illness and every 4 months during euthymia. If patients presented a major depressive (HAMD >18) or a manic (Young rating scale >20) episode after a euthymic period of at least 6 months, they were recognized as having a new recurrence118 and received additional care (hospitalization when needed) and treatment according to the judgment of their clinician. Subclinical episodes such as minor depressive episodes were not defined as new recurrences. All patients received our standard clinical management intervention, involving an explanation about the illness, lithium therapy to the patient and his/her relatives, and monitoring of the course of the illness.119 No formal cognitive, behavioral or other psychotherapy was administered. Informed consent was obtained from all probands after the procedure had been fully explained; probands were unrelated and of Italian descent with antecedents from all parts of the country. The study was carried out in accordance with the principles of the Declaration of Helsinki.120

Efficacy of lithium treatment is difficult to establish.1 The more straightforward method is to evaluate a complete absence of illness episodes after lithium treatment. But this happens only in a limited number of subjects, and the majority experience a decrease in number of illness episodes or in their severity.1 However, the raw number of episodes is dependent from the time of follow-up, and, on the other hand, measures weighted on the time of follow-up may vary considerably for very short observations. Therefore we reported both raw and weighted measurements and we excluded cases followed for less than 18 months. The recurrence rates before and during prophylaxis were evaluated by considering the occurring episodes of illness over the months from the onset to the beginning of lithium prophylaxis (pre-lithium treatment recurrence index = number of episodes/month duration of illness before lithium treatment × 100) and the occurring episodes from the beginning of prophylaxis to the moment of assessment (on-lithium treatment recurrence index = number of recurrences/month duration of lithium treatment × 100). The efficacy of prophylactic treatment was evaluated by calculating the difference between the pre-lithium treatment recurrence index and the on-lithium treatment recurrence index.121,122

DNA Analysis

Genomic DNA was extracted from leukocytes by NaCl precipitation.123 PCR forward primer 5′-GGCGTTGCCGCT CTGAATGC-3′ and reverse primer 5′-GAGGGACTGAGC TGGACAACCAC-3′ were employed. Thirty-five cycles of 1 min at 95°C, 1 min at 61°C and 1 min at 72°C were performed. The assay mix contained in a volume of 30 μl 50 ng genomic DNA, 2.5 mM dNTPs, 0.1 μg of sense and antisense primer, 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 5% DMSO and 1 U Taq Polymerase. PCR products were separated on 3% agarose gels supplemented with ethidium bromide allowing differentiation of the long (528 bp) and the short (484 bp) variant.

Statistical Analysis

The difference between the pre-treatment index and the ongoing-lithium treatment index (as defined in the Methods section) was used as the dependent variable, testing possible differences among TPH variants. Differences were assessed using Analysis of Variance (ANOVA) and post-hoc Newmann-Keuls tests. Analysis of Covariance (ANCOVA) was used to include possible confounders. Alpha levels were considered significant when less than 0.05. The power of our sample to detect differences amongst 5-HTTLPR variants was calculated considering an alpha value of 5% two-tailed. With these parameters in our sample we had a high power (0.80) to detect a medium effect size (d = 0.45, f = 0.22) that corresponded to a difference of approximately 4.7 points between the two major genotypes on the difference between pre-treatment index and the ongoing-lithium treatment index.102

DUALITY OF INTEREST

None declared.

References

  1. 1

    Goodwin F, Jamison K . Manic-Depressive Illness Oxford University Press: New York 1990

    Google Scholar 

  2. 2

    Schou M . Lithium Treatment of Manic Depressive Illness. A Practical Guide Karger: Basel 1989

    Google Scholar 

  3. 3

    Maj M, Arena F, Lovero N, Pirozzi R, Kemali D . Factors associated with response to lithium prophylaxis in DSM III major depression and bipolar disorder Pharmacopsychiatry 1985 18: 309–313

    CAS  PubMed  Google Scholar 

  4. 4

    Maj M, Pirozzi R, Starace F . Previous pattern of course of the illness as a predictor of response to lithium prophylaxis in bipolar patients J Affect Disord 1989 17: 237–241

    CAS  PubMed  Google Scholar 

  5. 5

    OConnell RA, Mayo JA, Flatow L, Cuthbertson BO, Brien BE . Outcome of bipolar disorder on long-term treatment with lithium Br J Psychiatry 1991 159: 123–129

    CAS  Google Scholar 

  6. 6

    Abou-Saleh MT . Who responds to prophylactic lithium therapy? Br J Psychiatry 1993 (suppl 21): 20–26

    Google Scholar 

  7. 7

    Franchini L, Zanardi R, Smeraldi E, Gasperini M . Early onset of lithium prophylaxis as a predictor of good long-term outcome Eur Arch Psychiatry Clin Neurosci 1999 249: 227–230

    CAS  PubMed  Google Scholar 

  8. 8

    Serretti A, Lattuada E, Franchini L, Smeraldi E . Melancholic features and response to lithium prophylaxis in mood disorders Depress Anxiety 2000 11: 73–79

    CAS  PubMed  Google Scholar 

  9. 9

    Mendlewicz J, Fieve RR, Stallone F, Fleiss JL . Genetic history as a predictor of lithium response in manic-depressive illness Lancet 1972 1: 599–600

    CAS  PubMed  Google Scholar 

  10. 10

    Maj M, Del Vecchio M, Starace F, Pirozzi R, Kemali D . Prediction of affective psychoses response to lithium prophylaxis. The role of socio-demographic, clinical, psychological and biological variables Acta Psychiatr Scand 1984 69: 37–44

    CAS  PubMed  Google Scholar 

  11. 11

    Grof P, Alda M, Grof E, Zvolsky P, Walsh M . Lithium response and genetics of affective disorders J Affect Disord 1994 32: 85–95

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Morabito A, Gasperini M, Macciardi F, Smeraldi E . Possible relationship between outcome in primary affective disorders treated with lithium and family history Adv Biochem Psychopharmacol 1982 32: 157–163

    CAS  PubMed  Google Scholar 

  13. 13

    Smeraldi E, Petroccione A, Gasperini M, Macciardi F, Orsini A . The search for genetic homogeneity in affective disorders J Affect Disord 1984 7: 99–107

    CAS  PubMed  Google Scholar 

  14. 14

    Smeraldi E, Petroccione A, Gasperini M, Macciardi F, Orsini A, Kidd KK . Outcomes on lithium treatment as a tool for genetic studies in affective disorders J Affect Disord 1984 6: 139–151

    CAS  PubMed  Google Scholar 

  15. 15

    Cavazzoni P, Alda M, Turecki G, Rouleau G, Grof E, Gerlach JH et al . Lithium-responsive affective disorders: no association with the tyrosine hydroxylase gene Psychiatry Res 1996 64: 91–96

    CAS  PubMed  Google Scholar 

  16. 16

    Turecki G, Alda M, Grof P, Martin R, Cavazzoni PA, Gerlach JH et al . No association between chromosome-18 markers and lithium-responsive affective disorders Psychiatry Res 1996 63: 17–23

    CAS  Google Scholar 

  17. 17

    Belmaker RH, Bersudsky Y, Agam G, Levine J, Kofman O . How does lithium work on manic depression? Clinical and psychological correlates of the inositol theory Annu Rev Med 1996 47: 47–56

    CAS  PubMed  Google Scholar 

  18. 18

    El-Mallakh S . Lithum: Actions and Mechanisms American Psychiatric Press: Washington, DC 1996

    Google Scholar 

  19. 19

    Benkelfat C . Serotoninergic mechanisms in psychiatric disorders: new research tools, new ideas Int Clin Psychopharmacol 1993 8 suppl: 53–56

    Google Scholar 

  20. 20

    Jacobs BL, Fornal CA . Serotonin and behavior. A general hypothesis. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: The Fourth Generation of Progress Raven Press: New York 1995 pp 461–469

    Google Scholar 

  21. 21

    Pei Q, Leslie RA, Grahame-Smith DG, Zetterstrom TS . 5-HT efflux from rat hippocampus in vivo produced by 4-aminopyridine is increased by chronic lithium administration Neuroreport 1995 6: 716–720

    CAS  PubMed  Google Scholar 

  22. 22

    Sharp T, Bramwell SR, Lambert P, Grahame-Smith DG . Effect of short- and long-term administration of lithium on the release of endogenous 5-HT in the hippocampus of the rat in vivo and in vitro Neuropharmacology 1991 30: 977–984

    CAS  Google Scholar 

  23. 23

    Treiser SL, Cascio CS, O’Donohue TL, Thoa NB, Jacobowitz DM, Kellar KJ . Lithium increases serotonin release and decreases serotonin receptors in the hippocampus Science 1981 213: 1529–1531

    CAS  Google Scholar 

  24. 24

    Baptista TJ, Hernandez L, Burguera JL, Burguera M, Hoebel BG . Chronic lithium administration enhances serotonin release in the lateral hypothalamus but not in the hippocampus in rats. A microdialysis study J Neural Transm Gen Sect 1990 82: 31–41

    CAS  PubMed  Google Scholar 

  25. 25

    Goodwin GM . The effects of antidepressant treatments and lithium upon 5-HT1A receptor function Prog Neuropsychopharmacol Biol Psychiatry 1989 13: 445–451

    CAS  Google Scholar 

  26. 26

    Odagaki Y, Koyama T, Matsubara S, Matsubara R, Yamashita I . Effects of chronic lithium treatment on serotonin binding sites in rat brain J Psychiatr Res 1990 24: 271–277

    CAS  PubMed  Google Scholar 

  27. 27

    Carli M, Reader TA . Regulation of central serotonin transporters by chronic lithium: an autoradiographic study Synapse 1997 27: 83–89

    CAS  PubMed  Google Scholar 

  28. 28

    Carli M, Afkhami-Dastjerdian S, Reader TA . Effects of a chronic lithium treatment on cortical serotonin uptake sites and 5-HT1A receptors Neurochem Res 1997 22: 427–435

    CAS  Google Scholar 

  29. 29

    Artigas F, Sarrias MJ, Martinez E, Gelpi E, Alvarez E, Udina C . Increased plasma free serotonin but unchanged platelet serotonin in bipolar patients treated chronically with lithium Psychopharmacology 1989 99: 328–332

    CAS  PubMed  Google Scholar 

  30. 30

    Price LH, Charney DS, Delgado PL, Heninger GR . Lithium treatment and serotoninergic function. Neuroendocrine and behavioral responses to intravenous tryptophan in affective disorder Arch Gen Psychiatry 1989 46: 13–19

    CAS  PubMed  Google Scholar 

  31. 31

    Hotta I, Yamawaki S, Segawa T . Long-term lithium treatment causes serotonin receptor down-regulation via serotonergic presynapses in rat brain Neuropsychobiology 1986 16: 19–26

    CAS  Google Scholar 

  32. 32

    Cassidy F, Murry E, Carroll BJ . Tryptophan depletion in recently manic patients treated with lithium Biol Psychiatry 1998 43: 230–232

    CAS  Google Scholar 

  33. 33

    Chaouloff F, Gunn SH, Young JB . Serotonin does not mediate the adrenal catecholamine-releasing effect of acute lithium administration in rats Psychoneuroendocrinology 1992 17: 135–144

    CAS  PubMed  Google Scholar 

  34. 34

    Lacaille JC, Cloutier S, Reader TA . Lithium reduced synaptic transmission and increased neuronal excitability without altering endogenous serotonin, norepinephrine and dopamine in rat hippocampal slices in vitro Prog Neuropsychopharmacol Biol Psychiatry 1992 16: 397–412

    CAS  PubMed  Google Scholar 

  35. 35

    Manji HK, Hsiao JK, Risby ED, Oliver J, Rudorfer MV, Potter WZ . The mechanisms of action of lithium. I. Effects on serotoninergic and noradrenergic systems in normal subjects Arch Gen Psychiatry 1991 48: 505–512

    CAS  PubMed  Google Scholar 

  36. 36

    Price LH, Charney DS, Delgado PL, Heninger GR . Lithium and serotonin function: implications for the serotonin hypothesis of depression Psychopharmacology 1990 100: 3–12

    CAS  Google Scholar 

  37. 37

    Collier D, Stöber G, Li T, Heils A, Catalano M, Di Gerlach JH et al . A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders Mol Psychiatry 1996 1: 453–460

    CAS  PubMed  Google Scholar 

  38. 38

    Collier DA, Arranz MJ, Sham P, Battersby S, Vallada H, Gerlach JH et al . The serotonin transporter is a potential susceptibility factor for bipolar affective disorder Neuroreport 1996 7: 1675–1679

    CAS  PubMed  Google Scholar 

  39. 39

    Rees M, Norton N, Jones I, McCandless F, Scourfield J, Gerlach JH et al . Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT) Mol Psychiatry 1997 2: 398–402

    CAS  Google Scholar 

  40. 40

    Bellivier F, Laplanche JL, Leboyer M, Feingold J, Bottos C, Gerlach JH et al . Serotonin transporter gene and manic depressive illness: an association study Biol Psychiatry 1997 41: 750–752

    CAS  Google Scholar 

  41. 41

    Mendes de Oliveira JR, Otto PA, Vallada H, Lauriano V, Elkis H, Gerlach JH et al . Analysis of a novel functional polymorphism within the promoter region of the serotonin transporter gene (5-HTT) in Brazilian patients affected by bipolar disorder and schizophrenia Am J Med Gen 1998 81: 225–227

    CAS  Google Scholar 

  42. 42

    Furlong RA, Ho L, Walsh C, Rubinsztein JS, Jain S, Gerlach JH et al . Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders Am J Med Gen 1998 81: 58–63

    CAS  Google Scholar 

  43. 43

    Hoehe MR, Wendel B, Grunewald I, Chiaroni P, Levy N, Morris-Gerlach JH et al . Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders Am J Med Gen 1998 81: 1–3

    CAS  Google Scholar 

  44. 44

    Esterling LE, Yoshikawa T, Turner G, Badner JA, Bengel D, Gershon ES, Berrettini WH, Detera-Wadleigh SD . Serotonin transporter (5-HTT) gene and bipolar affective disorder Am J Med Gen 1998 81: 37–40

    CAS  Google Scholar 

  45. 45

    Gutierrez B, Arranz MJ, Collier DA, Valles V, Guillamat R, Gerlach JH et al . Serotonin transporter gene and risk for bipolar affective disorder—an association study in a Spanish population Biol Psychiatry 1998 43: 843–847

    CAS  Google Scholar 

  46. 46

    Oruc L, Verheyen GR, Furac I, Jakovljevic M, Ivezic S, Gerlach JH et al . Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder Am J Med Gen 1997 74: 504–506

    CAS  Google Scholar 

  47. 47

    Ewald H, Flint T, Degn B, Mors O, Kruse TA . A functional variant of the serotonin transporter gene in families with bipolar affective disorder J Affect Disord 1998 48: 135–144

    CAS  PubMed  Google Scholar 

  48. 48

    Kelsoe J, Remick R, Sadovnick A, Kristbjarnarson H, Flodman P, Gerlach JH et al . Genetic linkage study of bipolar disorder and the serotonin transporter Am J Med Gen 1996 67: 215–217

    CAS  Google Scholar 

  49. 49

    Lenzinger E, Neumeister A, Praschak-Rieder N, Fuchs K, Gerhard E, Gerlach JH et al . Behavioral effects of tryptophan depletion in seasonal affective disorder associated with the serotonin transporter gene? Psychiatry Res 1999 85: 241–246

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Mundo E, Walker M, Tims H, Macciardi F, Kennedy JL . Lack of linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and bipolar disorder Am J Med Genet 2000 96: 379–383

    CAS  Google Scholar 

  51. 51

    Ospina-Duque J, Duque C, Carvajal-Carmona L, Ortiz-Barrientos D, Soto I, Gerlach JH et al . An association study of bipolar mood disorder (type I) with the 5-HTTLPR serotonin transporter polymorphism in a human population isolate from Colombia Neurosci Lett 2000 292: 199–202

    CAS  Google Scholar 

  52. 52

    Saleem Q, Ganesh S, Vijaykumar M, Reddy YC, Brahmachari SK, Jain S . Association analysis of 5HT transporter gene in bipolar disorder in the Indian population Am J Med Genet 2000 96: 170–172

    CAS  PubMed  Google Scholar 

  53. 53

    Lesch K, Bengel D, Heils A, Sabol S, Greenberg B, Gerlach JH et al . Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region Science 1996 274: 1527–1530

    CAS  PubMed  Google Scholar 

  54. 54

    Jorm AF, Prior M, Sanson A, Smart D, Zhang Y, Easteal S . Association of a functional polymorphism of the serotonin transporter gene with anxiety-related temperament and behavior problems in children: a longitudinal study from infancy to the mid-teens Mol Psychiatry 2000 5: 542–547

    CAS  Google Scholar 

  55. 55

    Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Gerlach JH et al . Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample Am J Med Genet 2000 96: 202–216

    CAS  Google Scholar 

  56. 56

    Gustavsson JP, Nothen MM, Jonsson EG, Neidt H, Forslund K, Gerlach JH et al . No association between serotonin transporter gene polymorphisms and personality traits Am J Med Genet 1999 88: 430–436

    CAS  Google Scholar 

  57. 57

    Kumakiri C, Kodama K, Shimizu E, Yamanouchi N, Okada S, Gerlach JH et al . Study of the association between the serotonin transporter gene regulatory region polymorphism and personality traits in a Japanese population Neuroscience Lett 1999 263: 205–207

    CAS  Google Scholar 

  58. 58

    Katsuragi S, Kunugi H, Sano A, Tsutsumi T, Isogawa K, Gerlach JH et al . Association between serotonin transporter gene polymorphism and anxiety-related traits Biol Psychiatry 1999 45: 368–370

    CAS  PubMed  Google Scholar 

  59. 59

    Murakami F, Shimomura T, Kotani K, Ikawa S, Nanba E, Adachi K . Anxiety traits associated with a polymorphism in the serotonin transporter gene regulatory region in the Japanese J Hum Genet 1999 44: 15–17

    CAS  PubMed  Google Scholar 

  60. 60

    Serretti A, Cusin C, Lattuada E, Di Bella D, Catalano M, Smeraldi E . Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders Mol Psychiatry 1999 4: 280–283

    CAS  Google Scholar 

  61. 61

    Rosenthal N, Mazzanti C, Barnett R, Hardin T, Turner E, Gerlach JH et al . Role of serotonin transporter promoter repeat length polymorphism (5-HTTLPR) in seasonality and seasonal affective disorder Mol Psychiatry 1998 3: 175–177

    CAS  Google Scholar 

  62. 62

    Ohara K, Nagai M, Suzuki Y, Ochiai M . Association between anxiety disorders and a functional polymorphism in the serotonin transporter gene Psychiatry Res 1998 81: 277–279

    CAS  PubMed  Google Scholar 

  63. 63

    Klauck SM, Poustka F, Benner A, Lesch KP, Poustka A . Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 1997 6: 2233–2238

    CAS  Google Scholar 

  64. 64

    Cook EH Jr, Courchesne R, Lord C, Cox NJ, Yan S, Gerlach JH et al . Evidence of linkage between the serotonin transporter and autistic disorder Mol Psychiatry 1997 2: 247–250

    PubMed  Google Scholar 

  65. 65

    Persico AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Gerlach JH et al . Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples Am J Med Genet 2000 96: 123–127

    CAS  Google Scholar 

  66. 66

    Ohara K, Suzuki Y, Ochiai M, Tsukamoto T, Tani K . A variable-number-tandem-repeat of the serotonin transporter gene and anxiety disorders Prog Neuropsychopharmacol Biol Psychiatry 1999 23: 55–65

    CAS  PubMed  Google Scholar 

  67. 67

    Hamilton SP, Heiman GA, Haghighi F, Mick S, Klein DF, Gerlach JH et al . Lack of genetic linkage or association between a functional serotonin transporter polymorphism and panic disorder Psychiatr Genet 1999 9: 1–6

    CAS  PubMed  Google Scholar 

  68. 68

    Sander T, Harms H, Lesch KP, Dufeu P, Kuhn S, Gerlach JH et al . Association analysis of a regulatory variation of the serotonin transporter gene with severe alcohol dependence Alcohol Clin Exp Res 1997 21: 1356–1359

    CAS  PubMed  Google Scholar 

  69. 69

    Hammoumi S, Payen A, Favre JD, Balmes JL, Benard JY, Gerlach JH et al . Does the short variant of the serotonin transporter linked polymorphic region constitute a marker of alcohol dependence? Alcohol 1999 17: 107–112

    CAS  PubMed  Google Scholar 

  70. 70

    Bellivier F, Szoke A, Henry C, Lacoste J, Bottos C, Nosten-Gerlach JH et al . Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders Biol Psychiatry 2000 48: 319–322

    CAS  PubMed  Google Scholar 

  71. 71

    Gorwood P, Batel P, Ades J, Hamon M, Boni C . Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior Biol Psychiatry 2000 48: 259–264

    CAS  PubMed  Google Scholar 

  72. 72

    Geijer T, Frisch A, Persson ML, Wasserman D, Rockah R, Gerlach JH et al . Search for association between suicide attempt and serotonergic polymorphisms Psychiatr Genet 2000 10: 19–26

    CAS  PubMed  Google Scholar 

  73. 73

    Bligh-Glover W, Kolli TN, Shapiro-Kulnane L, Dilley GE, Friedman L, Gerlach JH et al . The serotonin transporter in the midbrain of suicide victims with major depression Biol Psychiatry 2000 47: 1015–1024

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Malhotra AK, Goldman D, Mazzanti C, Clifton A, Breier A, Pickar D . A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics Mol Psychiatry 1998 3: 328–332

    CAS  Google Scholar 

  75. 75

    Bonnet-Brilhault F, Laurent C, Thibaut F, Campion D, Chavand O, Gerlach JH et al . Serotonin transporter gene polymorphism and schizophrenia: an association study Biol Psychiatry 1997 42: 634–636

    CAS  Google Scholar 

  76. 76

    Stober G, Jatzke S, Heils A, Jungkunz G, Fuchs E, Gerlach JH et al . Susceptibility for schizophrenia is not influenced by a functional insertion/deletion variant in the promoter of the serotonin transporter gene Eur Arch Psychiatry Clin Neurosci 1998 248: 82–86

    CAS  Google Scholar 

  77. 77

    Naylor L, Dean B, Pereira A, Mackinnon A, Kouzmenko A, Copolov D . No association between the serotonin transporter-linked promoter region polymorphism and either schizophrenia or density of the serotonin transporter in human hippocampus Molec Med 1998 4: 671–674

    CAS  Google Scholar 

  78. 78

    Rao D, Jonsson E, Paus S, Ganguli R, Nothen M, Nimgaonkar V . Schizophrenia and the serotonin transporter gene Psychiatr Genet 1998 8: 207–212

    CAS  Google Scholar 

  79. 79

    Hranilovic D, Schwab SG, Jernej B, Knapp M, Lerer B, Gerlach JH et al . Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings Mol Psychiatry 2000 5: 91–95

    CAS  Google Scholar 

  80. 80

    Tsai SJ, Hong CJ, Yu YW, Lin CH, Song HL, Gerlach JH et al . Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response Schizophr Res 2000 44: 177–181

    CAS  PubMed  Google Scholar 

  81. 81

    Serretti A, Lattuada E, Catalano M, Smeraldi E . Serotonin transporter gene not associated with psychotic symptomatology of mood disorders Psychiatry Res 1999 86: 59–65

    CAS  Google Scholar 

  82. 82

    Serretti A, Catalano M, Smeraldi E . Serotonin transporter gene is not associated with symptomatology of schizophrenia Schizophr Res 1999 35: 33–39

    CAS  Google Scholar 

  83. 83

    Heils A, Teufel A, Petri S, Stöber G, Riederer P, Gerlach JH et al . Allelic variation of human serotonin transporter gene expression J Neurochem 1996 66: 2621–2624

    CAS  PubMed  Google Scholar 

  84. 84

    Lipp O, Mahieu B, Souery D, Serretti A, Cavallini C, Gerlach JH et al . Molecular genetics of bipolar disorders: implication for psychotropic drugs. Xth Congress of the European College of Neuropsychopharmacology 1997, Vienna, Austria

  85. 85

    Serretti A, Lilli R, Lorenzi C, Gasperini M, Smeraldi E . Tryptophan hydroxylase gene and response to lithium prophylaxis in mood disorders J Psychiatr Res 1999 33: 371–377

    CAS  PubMed  Google Scholar 

  86. 86

    Serretti A, Lilli R, Lorenzi C, Franchini L, DiBella D, Gerlach JH et al . Dopamine receptor D2, D4, GABAA alpha-1 subunit genes and response to lithium prophylaxis in mood disorders Psychiatry Res 1999 87: 7–19

    CAS  Google Scholar 

  87. 87

    Serretti A, Lilli R, Lorenzi C, Gasperini M, Smeraldi E . Dopamine receptor D3 gene and response to lithium prophylaxis in mood disorders Int J Neuropsychopharmacol 1998 1: 125–129

    PubMed  Google Scholar 

  88. 88

    Serretti A, Lorenzi C, Lilli R, Smeraldi E . Serotonin receptor 2A, 2C, 1A genes and response to lithium prophylaxis in mood disorders J Psychiatr Res 2000 34: 89–98

    CAS  PubMed  Google Scholar 

  89. 89

    Smeraldi E, Zanardi R, Benedetti F, Dibella D, Perez J, Catalano M . Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine Mol Psychiatry 1998 3: 508–511

    CAS  PubMed  Google Scholar 

  90. 90

    Zanardi R, Serretti A, Rossini D, Franchini L, Cusin C, Gerlach JH et al . Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression Biol Psychiatry (in press)

  91. 91

    Zanardi R, Benedetti F, DiBella D, Catalano M, Smeraldi E . Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of serotonin transporter gene J Clin Psychopharmacol 2000 20: 105–107

    CAS  PubMed  Google Scholar 

  92. 92

    Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Gerlach JH et al . Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression Neuropsychopharmacology 2000 23: 587–590

    CAS  Google Scholar 

  93. 93

    Benedetti F, Serretti A, Colombo C, Campori E, Barbini B, Di Gerlach JH et al . Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression Am J Psychiatry 1999 156: 1450–1452

    CAS  Google Scholar 

  94. 94

    Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL . Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets Am J Med Gen 1999 88: 83–87

    CAS  Google Scholar 

  95. 95

    Bellivier F, Henry C, Szoke A, Schurhoff F, Nosten-Bertrand M, Gerlach JH et al . Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression Neurosci Lett 1998 255: 143–146

    CAS  Google Scholar 

  96. 96

    Flory JD, Manuck SB, Ferrell RE, Dent KM, Peters DG, Muldoon MF . Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism Mol Psychiatry 1999 4: 93–96

    CAS  PubMed  Google Scholar 

  97. 97

    Matsushita S, Muramatsu T, Kimura M, Shirakawa O, Mita T, Gerlach JH et al . Serotonin transporter gene regulatory region polymorphism and panic disorder Mol Psychiatry 1997 2: 390–392

    CAS  Google Scholar 

  98. 98

    Fuciarelli M, Vienna A, Paba E, Bastianini A, Sansonetti B, Capucci E et l . PI, GC, HP, and TF serum protein polymorphisms in Siena, Tuscany, Italy, with a review of data for Italy Am J Hum Biol 1997 9: 629–646

    PubMed  Google Scholar 

  99. 99

    Maj M, Pirozzi R, Magliano L, Bartoli L . Long-term outcome of lithium prophylaxis in bipolar disorder: a 5-year prospective study of 402 patients at a lithium clinic Am J Psychiatry 1998 155: 30–35

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Lattuada E, Serretti A, Cusin C, Gasperini M, Macciardi F, Smeraldi E . Symptomatologic analysis of psychotic and non-psychotic depression J Affect Disord 1999 54: 183–187

    CAS  PubMed  Google Scholar 

  101. 101

    Serretti A, Lattuada E, Cusin C, Gasperini M, Smeraldi E . Clinical and demographical features of psychotic and nonpsychotic depression Compr Psychiatry 1999 40: 358–362

    CAS  PubMed  Google Scholar 

  102. 102

    Cohen J . Statistical Power Analysis for the Behavioral Sciences Lawrence Erlbaum Associates: Hillsdale, New Jersey 1988

    Google Scholar 

  103. 103

    Risch N, Botstein D . A manic depressive history Nat Genet 1996 12: 351–353

    CAS  Google Scholar 

  104. 104

    Tsuang M, Faraone S . The Genetics of Mood Disorders The Johns Hopkins University Press: Baltimore 1990

    Google Scholar 

  105. 105

    Muller-Oerlinghausen B . Does effective lithium prophylaxis result in a symptom-free state of manic-depressive illness? Some thoughts on the fine-tuning of mood stabilization Compr Psychiatry 2000 41: 26–31

    CAS  PubMed  Google Scholar 

  106. 106

    Page C, Benaim S, Lappin F . A long-term retrospective follow-up study of patients treated with prophylactic lithium carbonate Br J Psychiatry 1987 150: 175–179

    CAS  PubMed  Google Scholar 

  107. 107

    Vestergaard P, Licht RW, Brodersen A, Rasmussen NA, Christensen H, Gerlach JH et al . Outcome of lithium prophylaxis—a prospective follow-up of affective disorder patients assigned to high and low serum lithium levels Acta Psychiatr Scand 1998 98: 310–315

    CAS  PubMed  Google Scholar 

  108. 108

    Kulhara P, Basu D, Mattoo SK, Sharan P, Chopra R . Lithium prophylaxis of recurrent bipolar affective disorder: long-term outcome and its psychosocial correlates J Affect Disord 1999 54: 87–96

    CAS  PubMed  Google Scholar 

  109. 109

    Tondo L, Baldessarini RJ, Hennen J, Floris G . Lithium maintenance treatment of depression and mania in bipolar I and bipolar II disorders Am J Psychiatry 1998 155: 638–645

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Baldessarini RJ, Tondo L . Does lithium treatment still work? Evidence of stable responses over three decades Arch Gen Psychiatry 2000 57: 187–190

    CAS  PubMed  Google Scholar 

  111. 111

    Souery D, Lipp O, Serretti A, Mahieu B, Rivelli SK, Gerlach JH et al . European Collaborative Project on Affective Disorders: Interactions between genetic and psychosocial vulnerability factors Psychiatr Genet 1998 8: 197–205

    CAS  Google Scholar 

  112. 112

    Endicott J, Spitzer R . A diagnostic interview: the schedule for affective disorders and schizophrenia Arch Gen Psychiatry 1978 35: 837–844

    CAS  PubMed  Google Scholar 

  113. 113

    McGuffin P, Farmer A, Harvey I . A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system Arch Gen Psychiatry 1991 48: 764–770

    CAS  PubMed  Google Scholar 

  114. 114

    American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders, 4th edn American Psychiatric Association: Washington DC 1994

    Google Scholar 

  115. 115

    Leckman JF, Sholomskas D, Thompson WD, Belanger A, Weissman MM . Best estimate of lifetime psychiatric diagnosis: a methodological study Arch Gen Psychiatry 1982 39: 879–883

    CAS  PubMed  Google Scholar 

  116. 116

    Hamilton M . Development of a rating scale for primary depressive illness Br J Soc Clin Psychol 1967 6: 278–296

    CAS  Google Scholar 

  117. 117

    Young R, Biggs J, Ziegler V, Meyer D . A rating scale for mania: reliability, validity and sensitivity Br J Psychiatry 1978 133: 429–435

    CAS  Google Scholar 

  118. 118

    Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Gerlach JH et al . Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence Arch Gen Psychiatry 1991 48: 851–855

    CAS  Google Scholar 

  119. 119

    American Psychiatric Association . Practice guideline for the treatment of patients with bipolar disorder Am J Psychiatry 1994 151: 1–36

    Google Scholar 

  120. 120

    WMA . World Medical Association declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects JAMA 1997 277: 925–926

    Google Scholar 

  121. 121

    Gasperini M, Scherillo P, Manfredonia M, Franchini L, Smeraldi E . A study of relapses in subjects with mood disorder on lithium treatment Eur Neuropsychopharmacol 1993 3: 103–110

    CAS  PubMed  Google Scholar 

  122. 122

    Franchini L, Gasperini M, Smeraldi E . A 24-month follow-up study of unipolar subjects: a comparison between lithium and fluvoxamine J Affect Disord 1994 32: 225–231

    CAS  PubMed  Google Scholar 

  123. 123

    Lahiri DK, Nurnberger JIJ . A rapid non-enzimatic method for the preparation of HMW DNA from blood for RFLP studies Nucleic Acid Res 1991 19: 5444

    CAS  Google Scholar 

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Serretti, A., Lilli, R., Mandelli, L. et al. Serotonin transporter gene associated with lithium prophylaxis in mood disorders. Pharmacogenomics J 1, 71–77 (2001). https://doi.org/10.1038/sj.tpj.6500006

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Keywords

  • lithium
  • bipolar disorder
  • follow-up studies
  • pharmacogenetics

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