Clinical, Biological and Genetic Predictors of Lithium Treatment Response

Öz

Lithium was discovered by the Swedish Arfvedson at the beginning of the 1800s and began to be used in psychiatry for the past 1950s. Lithium, as a mood stabilizer, is the gold standard and first choice treatment agent for the treatment of bipolar disorders in adults. However, it is mostly difficult in clinical practice to predict which patient would respond to the treatment with lithium well due to the huge variation in patients’ characteristics. Clinicians seem to focus primarily on identifying a clinical phenotype to foresee lithium treatment response. In this article, researches on predictors of the lithium treatment response were reviewed and evaluated in four titles as clinical, biochemical, neuroimaging and genetic predictors.

Anahtar Kelimeler

• Lithium,treatment response,predictors

Lityuma Tedavi Yanıtının Klinik, Biyolojik ve Genetik Yordayıcıları

Öz

Lityum, 1800’lü yılların başında İ̇sveçli Arfvedson tarafından keşfedilmiş ve 1950’li yıllarda psikiyatri alanında kullanılmaya başlanmıştır. Yetişkinlerde bipolar tedavisinde ilk sırada gelen bir duygudurum düzenleyici ve altın standart bir tedavi ajanıdır. Ancak, klinik uygulamada bireyler arasında lityum tedavisine yanıt oranları hastaların farklı özellikleri nedeniyle oldukça değişken olup, hangi hastanın lityuma iyi yanıt vereceğini öngörmek çoğunlukla zordur. Lityum tedavi yanıtını öngörmede klinisyenler öncelikle klinik bir fenotipi tanımaya odaklanmış gibi durmaktadır. Bu yazıda lityum tedavi yanıtının yordayıcıları ile ilgili araştırmalar gözden geçirilerek; klinik, biyokimyasal, nörogörüntüleme ve genetik yordayıcılar olmak üzere dört başlık altında ele alınmıştır.

Anahtar Kelimeler

• Lityum,tedavi yanıtı,yordayıcı

Kaynakça

1. Alda, M., Turecki, G. X., Jaitovich-Groisman, I., de Lara, C. L., Duffy, A. C., Ruzickova, M., et al. (2006, August). Clinical and genetic heterogeneity of bipolar disorder. In Bıpolar Dısorders (vol. 8, pp. 60-60). 9600 Garsıngton rd, Oxford ox4 2dq, Oxon, England: Blackwell Publıshıng.
2. Altınbaş, K., Yeşilbaş, D., İnce, B., Cansız, A., Sılan, F., & Gülöksüz, S.(2017) İki Uçlu Bozukluk Hastalarında Lityuma Yanıt ile GSK-3β Polimorfizmi İlişkisinin Değerlendirilmesi.
3. Atack, J. R., Broughton, H. B., & Pollack, S. J. (1995). Inositol monophosphatase—a putative target for Li+ in the treatment of bipolar disorder. Trends in neurosciences, 18(8), 343-349.
4. Balance Investigators and Collaborators, Geddes JR, Goodwin GM, et al. (2010) Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): A randomised open-label trial. The Lancet 375(9712): 385–395.
5. Baldessarini, R. J., & Tondo, L. (2000). Does lithium treatment still work?: evidence of stable responses over three decades. Archives of General Psychiatry, 57(2), 187-190.
6. Baldessarini, R. J., & Tondo, L. (2008). Lithium and suicidal risk. Bipolar disorders, 10(1), 114-115.
7. Beckman, L., Perris, C., Strandman, E., & Wählby, L. (1978). HLA antigens and affective disorders. Human heredity, 28(2), 96-99.
8. Berridge, M. J. (1989). Inositol trisphosphate, calcium, lithium, and cell signaling. Jama, 262(13), 1834-1841.

9. Campbell, J., Crowe, R. R., Goeken, N., Pfohl, B., Pauls, D., & Palmer, D. (1984). Affective disorder not linked to HLA in a large bipolar kindred. Journal of affective disorders, 7(1), 45-51.
10. Can, A., Schulze, T. G., & Gould, T. D. (2014). Molecular actions and clinical pharmacogenetics of lithium therapy. Pharmacology Biochemistry and Behavior, 123, 3-16.
11. Cazzullo, C. L., Smeraldi, E., & Penati, G. (1974). The leucocyte antigenic system HL-A as a possible genetic marker of schizohprenia. The British Journal of Psychiatry.
12. Chen, C. H., Lee, C. S., Lee, M. T. M., Ouyang, W. C., Chen, C. C., Chong, M. Y., et al. (2014). Variant GADL1 and response to lithium therapy in bipolar I disorder. New England Journal of Medicine, 370(2), 119-128.
13. Cipriani A, Pretty H, Hawton K, et al. (2005) Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: A systematic review of randomized trials. The American Journal of Psychiatry 162: 1805–1819.
14. Collins PY, Patel V, Joestl SS, et al. (2011) Grand challenges in global mental health. Nature 475: 27–30.
15. Curran, G., & Ravindran, A. (2014). Lithium for bipolar disorder: a review of the recent literature. Expert review of neurotherapeutics, 14(9), 1079-1098.
16. Davanzo, P., Thomas, M. A., Yue, K., Oshiro, T., Belin, T., Strober, M., & McCracken, J. (2001). Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder. Neuropsychopharmacology, 24(4), 359-369.
17. Debnath, M., Busson, M., Jamain, S., Etain, B., Hamdani, N., Oliveira, J., ... & Bengoufa, D. (2013). The HLA-G low expressor genotype is associated with protection against bipolar disorder. Human immunology, 74(5), 593-597.
18. Del Vecchio, M., Farzati, B., Maj, M., Minucci, P., Guida, L., & Kemali, D. (1981). Cell membrane predictors of response to lithium prophylaxis of affective disorders. Neuropsychobiology, 7(5), 243-247.
19. Dubovsky, S. L., & Franks, R. D. (1983). Intracellular calcium ions in affective disorders: a review and an hypothesis. Biological psychiatry, 18(7), 781-797.
20. Emamghoreishi, M., Schlichter, L., Li, P. P., Parikh, S., Sen, J., Kamble, A., & Warsh, J. J. (1997). High intracellular calcium concentrations in transformed lymphoblasts from subjects with bipolar I disorder. American Journal of Psychiatry, 154(7), 976-982.
21. Foland, L. C., Altshuler, L. L., Sugar, C. A., Lee, A. D., Leow, A. D., Townsend, J., ... & Thompson, P. M. (2008). Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. Neuroreport, 19(2), 221.
22. Fountoulakis, K. N., Vieta, E., Young, A., Yatham, L., Grunze, H., Blier, P., ... & Kasper, S. (2017). The International College of Neuropsychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), part 4: Unmet needs in the treatment of bipolar disorder and recommendations for future research. International Journal of Neuropsychopharmacology, 20(2), 196-205.
23. Frazer, A., Mendels, J., Brunswick, D. A. V. I. D., London, J. A. C. K., Pring, M. A. R. T. I. N., Ramsey, T. A., & Rybakowski, J. (1978). Erythrocyte concentrations of the lithium ion: clinical correlates and mechanisms of action. Am J Psychiatry, 135(9), 1065-1069.
24. Friedman, S. D., Dager, S. R., Parow, A., Hirashima, F., Demopulos, C., Stoll, A. L., ... & Renshaw, P. F. (2004). Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder. Biological psychiatry, 56(5), 340-348.
25. Garnham, J., Munro, A., Slaney, C., MacDougall, M., Passmore, M., Duffy, A., et al. (2007). Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study. Journal of affective disorders, 104(1), 185-190.
26. Geddes, J. R., Burgess, S., Hawton, K., Jamison, K., & Goodwin, G. M. (2004). Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. American Journal of Psychiatry, 161(2), 217-222.
27. Goldin, L. R., Clerget-Darpoux, F., & Gershon, E. S. (1982). Relationship of HLA to major affective disorder not supported. Psychiatry research, 7(1), 29-45.
28. Goodwin FK, Fireman B, Simon GE, et al. (2003) Suicide risk in bipolar disorder during treatment with lithium and divalproex. Journal of American Medical Association 290: 1467–1473.
29. Goodwin, F. K., & Jamison, K. R. (2007). Manic-depressive illness: bipolar disorders and recurrent depression (Vol. 1). Oxford University Press.
30. Gould, T. D. (2006). Targeting glycogen synthase kinase-3 as an approach to develop novel mood-stabilising medications. Expert opinion on therapeutic targets, 10(3), 377-392.
31. Green, E. K., Raybould, R., Macgregor, S., Hyde, S., Young, A. H., O'donovan, M. C., et al. (2006). Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder. The British Journal of Psychiatry, 188(1), 21-25.
32. Grof, P., & Müller‐Oerlinghausen, B. (2009). A critical appraisal of lithium’s efficacy and effectiveness: the last 60 years. Bipolar disorders, 11(s2), 10-19.
33. Grof, P., Duffy, A., Cavazzoni, P., Grof, E., Garnham, J., MacDougall, M., et al. (2002). Is response to prophylactic lithium a familial trait?. The Journal of clinical psychiatry, 63(10), 942-947.
34. Hajek, T., Cullis, J., Novak, T., Kopecek, M., Blagdon, R., Propper, L., ... & Paus, T. (2013). Brain structural signature of familial predisposition for bipolar disorder: replicable evidence for involvement of the right inferior frontal gyrus. Biological psychiatry, 73(2), 144-152.
35. Hayes JF, Miles J, Walters K, et al. (2015) A systematic review and metaanalysis of premature mortality in bipolar affective disorder. Acta Psychiatrica Scandinavica 131: 417–425.
36. Ikeda, A., & Kato, T. (2003). Biological predictors of lithium response in bipolar disorder. Psychiatry and clinical neurosciences, 57(3), 243-250.
37. Jefferson JM, Greist JH. Lithium, In (2000) Sadock B, Sadock V(Eds) Comprehensive Textbook of Pschiatry Lippincott William Wilkins.
38. Johnson, G. F. S., Hunt, G. E., Robertson, S., & Doran, T. J. (1981). A linkage study of manic-depressive disorder with HLA antigens, blood groups, serum proteins and red cell enzymes. Journal of affective disorders, 3(1), 43-58.
39. Kato, T., Fujii, K., Kamiya, A., & Kato, N. (2000). White matter hyperintensity detected by magnetic resonance imaging and lithium response in bipolar disorder: a preliminary observation. Psychiatry and clinical neurosciences, 54(1), 117-120.
40. Kato, T., Inubushi, T., & Kato, N. (2000). Prediction of lithium response by 31P-MRS in bipolar disorder. International Journal of Neuropsychopharmacology, 3(1), 83-85.
41. Kato, T., Inubushi, T., & Takahashi, S. (1994). Relationship of Lithium Concentrations: in the Brain Measured by Lithium-7: Magnetic Resonance Spectroscopy to: Treatment Response in Mania.
42. Kato, T., Murashita, J., Kamiya, A., Shioiri, T., Kato, N., & Inubushi, T. (1998). Decreased brain intracellular pH measured by 31 P-MRS in bipolar disorder: a confirmation in drug-free patients and correlation with white matter hyperintensity. European archives of psychiatry and clinical neuroscience, 248(6), 301-306.
43. Kato, T., Shioiri, T., Inubushi, T., & Takahashi, S. (1993). Brain lithium concentrations measured with lithium-7 magnetic resonance spectroscopy in patients with affective disorders: relationship to erythrocyte and serum concentrations. Biological psychiatry, 33(3), 147-152.
44. Kato, T., Takahashi, S., & Inubushi, T. (1992). Brain lithium concentration by 7 li-and 1 h-magnetic resonance spectroscopy in bipolar disorder. Psychiatry Research: Neuroimaging, 45(1), 53-63.
45. Kessing, L. V., Hellmund, G., & Andersen, P. K. (2011). Predictors of excellent response to lithium: results from a nationwide register-based study. International clinical psychopharmacology, 26(6), 323-328.
46. Kessing, L. V., Vradi, E., & Andersen, P. K. (2014). Starting lithium prophylaxis early v. late in bipolar disorder. The British Journal of Psychiatry, 205(3), 214-220.
47. Kleindienst, N., Engel, R. R., & Greil, W. (2005). Which clinical factors predict response to prophylactic lithium? A systematic review for bipolar disorders. Bipolar disorders, 7(5), 404-417.
48. Komoroski, R. A., Newton, J. E. O., Walker, E., Cardwell, D., Jagannathan, N. R., Ramaprasad, S., & Sprig, J. (1990). In Vivo NMR spectroscopy of lithium‐7 in humans. Magnetic resonance in medicine, 15(3), 347-356.
49. Kulhara, P., Basu, D., Mattoo, S. K., Sharan, P., & Chopra, R. (1999). Lithium prophylaxis of recurrent bipolar affective disorder: long-term outcome and its psychosocial correlates. Journal of affective disorders, 54(1), 87-96.
50. Kusumi, I., Koyama, T., & Yamashita, I. (1994). Serotonin-induced platelet intracellular calcium mobilization in depressed patients. Psychopharmacology, 113(3), 322-327.
51. Kusumi, I., Suzuki, K., Sasaki, Y., Kameda, K., & Koyama, T. (2000). Treatment response in depressed patients with enhanced Ca mobilization stimulated by serotonin. Neuropsychopharmacology, 23(6), 690-696.
52. Licht, R. W., Vestergaard, P., & Brodersen, A. (2008). Long‐term outcome of patients with bipolar disorder commenced on lithium prophylaxis during hospitalization: a complete 15‐year register‐based follow‐up. Bipolar disorders, 10(1), 79-86.
53. Lopez AD and Murray CC (1998) The global burden of disease, 1990– 2020. Nature Medicine 4: 1241–1243.
54. Luca, A., Calandra, C., & Luca, M. (2016). Gsk3 Signalling and Redox Status in Bipolar Disorder: Evidence from Lithium Efficacy. Oxidative medicine and cellular longevity, 2016.
55. Maj, M., Arena, F., Lovero, N., Pirozzi, R., & Kemali, D. (1985). Factors associated with response to lithium prophylaxis in DSM III major depression and bipolar disorder. Pharmacopsychiatry, 18(05), 309-313.
56. Maj, M., Vecchio, M., Starace, F., Pirozzi, R., & Kemali, D. (1984). Prediction of affective psychoses response to lithium prophylaxis. Acta Psychiatrica Scandinavica, 69(1), 37-44.
57. Malhi, G. S., & Outhred, T. (2016). Therapeutic mechanisms of lithium in bipolar disorder: recent advances and current understanding. CNS drugs, 30(10), 931-949.
58. Manchia, M., Adli, M., Akula, N., Ardau, R., Aubry, J. M., Backlund, L., et al. (2013). Assessment of response to lithium maintenance treatment in bipolar disorder: a Consortium on Lithium Genetics (ConLiGen) report. PloS one, 8(6), e65636.
59. Masui, T., Hashimoto, R., Kusumi, I., Suzuki, K., Tanaka, T., Nakagawa, S., et al. (2006). A possible association between the− 116C/G single nucleotide polymorphism of the XBP1 gene and lithium prophylaxis in bipolar disorder. The The International Journal of Neuropsychopharmacology, 9(1), 83-88.
60. Masui, T., Hashimoto, R., Kusumi, I., Suzuki, K., Tanaka, T., Nakagawa, S., et al. (2006). Lithium response and Val66Met polymorphism of the brain-derived neurotrophic factor gene in Japanese patients with bipolar disorder. Psychiatric genetics, 16(2), 49-50.
61. McCarthy, M. J., Leckband, S. G., & Kelsoe, J. R. (2010). Pharmacogenetics of lithium response in bipolar disorder. Pharmacogenomics, 11(10), 1439-1465.
62. Meltzer, H. L. (1986). Lithium mechanisms in bipolar illness and altered intracellular calcium functions. Biological psychiatry, 21(5), 492-510.
63. Mendels, J., & Frazer, A. (1973). Intracellular lithium concentration and clinical response: towards a membrane theory of depression. Journal of Psychiatric Research, 10(1), 9-18.
64. Mimi, J. (1995). T2 hyperintensities in bipolar disorder: magnetic resonance imaging comparison and literature meta-analysis. Am J Psychiatry, 1, 52.
65. Moore, C. M., Breeze, J. L., Gruber, S. A., Babb, S. M., deB Frederick, B., Villafuerte, R. A., ... & Renshaw, P. F. (2000). Choline, myo‐inositol and mood in bipolar disorder: a proton magnetic resonance spectroscopic imaging study of the anterior cingulate cortex. Bipolar disorders, 2(3p2), 207-216.
66. Moore, G. J., Bebchuk, J. M., Wilds, I. B., Chen, G., & Menji, H. K. (2000). Lithium-induced increase in human brain grey matter. The Lancet, 356(9237), 1241-1242.
67. Murashita, J., Kato, T., Shioiri, T., Inubushi, T., & Kato, N. (2000). Altered brain energy metabolism in lithium-resistant bipolar disorder detected by photic stimulated 31 P-MR spectroscopy. Psychological Medicine, 30(1), 107-115.
68. Müller-Oerlinghausen, B., Müser-Causemann, B., & Volk, J. (1992). Suicides and parasuicides in a high-risk patient group on and off lithium long-term medication. Journal of Affective Disorders, 25(4), 261-269.
69. National Institute for Health and Care Excellence (NICE) (2014) The assessment and management of bipolar disorder in adults, children and young people in primary and secondary care, updated edition. London.
70. Nemanov, L., Ebstein, R. P., Belmaker, R. H., Osher, Y., & Agam, G. (1999). Effect of bipolar disorder on lymphocyte inositol monophosphatase mRNA levels. The The International Journal of Neuropsychopharmacology, 2(1), 25-29.
71. Noworolski, S. M., Nelson, S. J., Henry, R. G., Day, M. R., Wald, L. L., Star‐Lack, J., & Vigneron, D. B. (1999). High spatial resolution 1H‐MRSI and segmented MRI of cortical gray matter and subcortical white matter in three regions of the human brain. Magnetic resonance in medicine, 41(1), 21-29.
72. Perlis, R. H., Smoller, J. W., Ferreira, M. A., McQuillin, A., Bass, N., Lawrence, J., et al. (2009). A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. American Journal of Psychiatry, 166(6), 718-725.
73. Perris, C., Strandman, E., & Wählby, L. (1979). HL-A antigens and the response to prophylactic lithium. Neuropsychobiology, 5(2), 114-118.
74. Pfennig, A., Alda, M., Young, T., MacQueen, G., Rybakowski, J., Suwalska, A., ... & Wittekind, D. (2014). Prophylactic lithium treatment and cognitive performance in patients with a long history of bipolar illness: no simple answers in complex disease-treatment interplay. International journal of bipolar disorders, 2(1), 16.
75. Pfennig, A., Schlattmann, P., Alda, M., Grof, P., Glenn, T., Müller‐Oerlinghausen, B., ... & Berghöfer, A. (2010). Influence of atypical features on the quality of prophylactic effectiveness of long‐term lithium treatment in bipolar disorders. Bipolar disorders, 12(4), 390-396.
76. Renshaw, P. F., & Wicklund, S. (1988). In vivo measurement of lithium in humans by nuclear magnetic resonance spectroscopy. Biological psychiatry, 23(5), 465-475.
77. Rohayema, J., Bayléb, J. F., & Richaa, S. (2008). Prédicteurs de réponse prophylactique au lithium Predictors of prophylactic response to lithium. L’Encéphale, 34, 394-399.
78. Rybakowski, J. K., Chlopocka‐Wozniak, M., & Suwalska, A. (2001). The prophylactic effect of long‐term lithium administration in bipolar patients entering treatment in the 1970s and 1980s. Bipolar disorders, 3(2), 63-67.
79. Rybakowski, J. K., Dmitrzak-Weglarz, M., Dembinska-Krajewska, D., Hauser, J., Akiskal, K. K., & Akiskal, H. H. (2014). Polymorphism of circadian clock genes and temperamental dimensions of the TEMPS-A in bipolar disorder. Journal of affective disorders, 159, 80-84.
80. Rybakowski, J. K., Suwalska, A., Czerski, P. M., Dmitrzak-Weglarz, M., Leszczynska-Rodziewicz, A., & Hauser, J. (2005). Prophylactic effect of lithium in bipolar affective illness may be related to serotonin transporter genotype. Pharmacol Rep, 57(1), 124-127.
81. Rybakowski, J. K., Suwalska, A., Skibinska, M., Dmitrzak‐Weglarz, M., Leszczynska‐Rodziewicz, A., & Hauser, J. (2007). Response to lithium prophylaxis: interaction between serotonin transporter and BDNF genes. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 144(6), 820-823.
82. Rybakowski, J. K., Suwalska, A., Skibinska, M., Szczepankiewicz, A., Leszczynska-Rodziewicz, A., Permoda, A., et al. (2005). Prophylactic lithium response and polymorphism of the brain-derived neurotrophic factor gene. Pharmacopsychiatry, 38(04), 166-170.
83. Ryder, L. P., Nielsen, L. S., & Svejgaard, A. (1974). Associations between HL-A histocompatibility antigens and non-malignant diseases. Human Genetics, 25(4), 251-264.
84. Sachs, G. S., Renshaw, P. F., Lafer, B., Stoll, A. L., Guimarães, A. R., Rosenbaum, J. F., & Gonzalez, R. G. (1995). Variability of brain lithium levels during maintenance treatment: a magnetic resonance spectroscopy study. Biological psychiatry, 38(7), 422-428.
85. Schou, M. (2001). Lithium treatment at 52. Journal of affective disorders, 67(1), 21-32.
86. Schulze, T. G., Alda, M., Adli, M., Akula, N., Ardau, R., Bui, E. T., ... & Detera-Wadleigh, S. D. (2010). The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment. Neuropsychobiology, 62(1), 72-78.
87. Serretti, A., Lilli, R., Mandelli, L., Lorenzi, C., & Smeraldi, E. (2001). Serotonin transporter gene associated with lithium prophylaxis in mood disorders. The pharmacogenomics journal, 1(1), 71-77.
88. Serretti, A., Lorenzi, C., Lilli, R., & Smeraldi, E. (2000). Serotonin receptor 2A, 2C, 1A genes and response to lithium prophylaxis in mood disorders. Journal of psychiatric research, 34(2), 89-98.
89. Serretti, A., Lorenzi, C., Lilli, R., Mandelli, L., Pirovano, A., & Smeraldi, E. (2002). Pharmacogenetics of lithium prophylaxis in mood disorders: Analysis of COMT, MAO‐A, and Gβ3 variants. American Journal of Medical Genetics Part A, 114(4), 370-379.
90. Severus, E., Taylor, M. J., Sauer, C., Pfennig, A., Ritter, P., Bauer, M., & Geddes, J. R. (2014). Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. International journal of bipolar disorders, 2(1), 15.
91. Shaldubina, A., Agam, G., & Belmaker, R. H. (2001). The mechanism of lithium action: state of the art, ten years later. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 25(4), 855-866.
92. Shapiro, R. W., Bock, E., Rafaelsen, O. J., Ryder, L. P., & Svejgaard, A. (1976). Histocompatibility antigens and manic-depressive disorders. Archives of general psychiatry, 33(7), 823-825.
93. Shapiro, R. W., Ryder, L. P., Svejgaard, A., & Rafaelsen, O. J. (1977). HLA antigens and manic-depressive disorders: further evidence of an association. Psychological medicine, 7(3), 387-396.
94. Silverstone, P. H., Wu, R. H., O'donnell, T., Ulrich, M., Asghar, S. J., & Hanstock, C. C. (2003). Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients. International clinical psychopharmacology, 18(2), 73-79.
95. Sklar, P., Gabriel, S. B., McInnis, M. G., Bennet, P., Lim, Y. M., Tsan, G. et al. (2002). Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Molecular psychiatry, 7(6).
96. Soares, J. C., Krishnan, K. R. R., & Keshavan, M. S. (1996). Nuclear magnetic resonance spectroscopy: new insights into the pathophysiology of mood disorders. Depression, 4(1), 14-30.
97. Sportiche, S., Geoffroy, P. A., Brichant-Petitjean, C., Gard, S., Khan, J. P., Azorin, J. M., ... & Bellivier, F. (2017). Clinical factors associated with lithium response in bipolar disorders. Australian & New Zealand Journal of Psychiatry, 51(5), 524-530.
98. Steeir, V. M., Løvlie, R., Osher, Y., Belmaker, R. H., Berle, J. Ø., & Gulbrandsen, A. K. (1998). The polymorphic inositol polyphosphate 1-phosphatase gene as a candidate for pharmacogenetic prediction of lithium-responsive manic-depressive illness. Pharmacogenetics and Genomics, 8(3), 259-268.
99. Suzuki, K., Kusumi, I., Sasaki, Y., & Koyama, T. (2001). Serotonin-induced platelet intracellular calcium mobilization in various psychiatric disorders: is it specific to bipolar disorder?. Journal of affective disorders, 64(2), 291-296.
100. Swayze, V. W., Andreasen, N. C., Alliger, R. J., Ehrhardt, J. C., & Yuh, W. T. (1990). Structural brain abnormalities in bipolar affective disorder: ventricular enlargement and focal signal hyperintensities. Archives of general psychiatry, 47(11), 1054-1059.
101. Targum, S. D., Gershon, E. S., Van Eerdewegh, M., & Rogentine, N. (1979). Human leukocyte antigen system not closely linked to or associated with bipolar manic-depressive illness. Biological psychiatry.
102. Tighe, S. K., Mahon, P. B., & Potash, J. B. (2011). Predictors of lithium response in bipolar disorder. Therapeutic advances in chronic disease, 2(3), 209-226.
103. Tobe, B. T., Crain, A. M., Winquist, A. M., Calabrese, B., Makihara, H., Zhao, W. N.,et al. (2017). Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis. Proceedings of the National Academy of Sciences, 114(22), E4462-E4471.
104. Tondo, L., Baldessarini, R. J., & Floris, G. (2001). Long-term clinical effectiveness of lithium maintenance treatment in types I and II bipolar disorders. The British Journal of Psychiatry, 178(41), s184-s190.
105. Usher, J., Menzel, P., Schneider‐Axmann, T., Kemmer, C., Reith, W., Falkai, P., ... & Scherk, H. (2010). Increased right amygdala volume in lithium‐treated patients with bipolar I disorder. Acta Psychiatrica Scandinavica, 121(2), 119-124.
106. Ünal, A., Çöpoğlu, Ü. S., Bülbül, F., Vırıt, O., & Savaş, H. A. (2013). Lityumun kırk yıldır sorunsuz kullanımı: Olgu sunumu. Journal of Mood Disorders, 3(2), 70-73.
107. Ventura, T., Lobo, A., & Marco, J. C. (1990). HLA antigens in bipolar affective patients. Actas luso-espanolas de neurologia, psiquiatria y ciencias afines, 18(5), 339-343.
108. Washizuka, S., Ikeda, A., Kato, N., & Kato, T. (2003). Possible relationship between mitochondrial DNA polymorphisms and lithium response in bipolar disorder. International Journal of Neuropsychopharmacology, 6(4), 421-424.
109. Yamawaki, S., Kagaya, A., Tawara, Y., & Inagaki, M. (1998). Intracellular calcium signaling systems in the pathophysiology of affective disorders. Life sciences, 62(17), 1665-1670.
110. Yatham LN, Fountoulakis KN, Rahman Z, et al. (2013) Efficacy of aripiprazole versus placebo as adjuncts to lithium or valproate in relapse prevention of manic or mixed episodes in bipolar I patients stratified by index manic or mixed episode. Journal of Affective Disorders 147: 365–372.
111. Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Beaulieu, S., Alda, M., ... & Ravindran, A. (2013). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar disorders, 15(1), 1-44.
112. Yoon, I. S., Li, P. P., Siu, K. P., Kennedy, J. L., Cooke, R. G., Parikh, S. V., & Warsh, J. J. (2001). Altered IMPA2 gene expression and calcium homeostasis in bipolar disorder. Molecular psychiatry, 6(6), 678-683.
113. Young, A. H., & Hammond, J. M. (2007). Lithium in mood disorders: increasing evidence base, declining use?. The British Journal of Psychiatry, 191(6), 474-476.
114. Yucel, K., McKinnon, M. C., Taylor, V. H., Macdonald, K., Alda, M., Young, L. T., & MacQueen, G. M. (2007). Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology, 195(3), 357-367.