Genetic studies of bipolar disorder in patients selected by their treatment response

Abigail Ortiz-Domínguez; Martin Alda

2008, Number 6

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Salud Mental 2008; 31 (6)

Genetic studies of bipolar disorder in patients selected by their treatment response

Ortiz-Domínguez A, Alda M

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Language: English
References: 227
Page: 431-440
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ABSTRACT

Bipolar disorder (BD) is a major mood disorder with several genes of moderate or small effect contributing to the genetic susceptibility. It is also likely heterogeneous, which stimulated efforts to refine its clinical phenotype, studies investigating the link between BD susceptibility and response to a specific mood stabilizer appear to be one of the promising directions. In particular, excellent response to lithium prophylaxis has been described as a clinical marker of a more homogeneous subgroup of BD, characterized by an episodic course, low rates of co-morbid conditions, absence of rapid cycling, and a strong genetic loading. These results also suggest that lithium response clusters in families (independent of the increased familial loading for affective disorders), likely on a genetic basis. For almost 40 years, clinical studies have pointed to differences between lithium responders (LR) and non-responders (LNR). For instance, there is a higher frequency of BD in LR families. As well, investigations in offspring of LR and LNR probands show that the offspring of LR tend to manifest a higher frequency of affective disorders, less co-morbidity and an episodic course of the disorder, compared with the offspring of LNR, who had a broad range of psychopathology, a higher rate of co-morbidity and a chronic course of the disorder. A number of candidate genes have been studied in patients treated with lithium; of these, several showed an association in at least one study: cAMP responsive element binding protein (CREB), Xbox binding protein 1 (XBP-1), inositol polyphosphate-1-phosphatase (INNP1), serotonin transporter gene (5-HTT), brain-derived neurotrophic factor (BDNF), phospholipase γ-1(PLCγ-1), dopamine receptors (D2 and D4), polyglutamine tracts, tyrosine hydroxylase, inositol monophosphatase (IMPA), mitochondrial DNA, and breakpoint cluster region (BCR) gene. Clinical studies have shown as well that the treatment response and outcome appear to be specific for the different types of mood stabilizers. Patie ts who respond to lithium exhibit qualitative differences from patients responding to other medications, such as valproate, carbamazepine or lamotrigine. Responders to carbamazepine had atypical clinical features, such as moodincongruent psychosis, an age at onset of illness below 30 years old, and a negative family history of mood disorders. Similarly, in a study comparing the phenotypic spectra in responders to lithium versus lamotrigine the probands differed with respect to clinical course (with rapid cycling and non-episodic course in the lamotrigine group) and co-morbidity, with the lamotrigine-responder group showing a higher frequency of panic attacks and substance abuse. In conclusion, pharmacogenetic studies may provide important clues to the nature of bipolar disorder and the response to long term treatment.

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Grof P, Alda M, Grof E, Zvolsky P, Walsh M. Lithium response and genetics of affective disorders. J Affective Disorders 1994;32:85-95.
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Grof P, Duffy A, Cavazzoni P et al. Is response to prophylactic lithium a familial trait? J Clinical Psychiatry 2002;63(10):942-947.
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Engstrom C, Astrom M, Nordqvist K, Adolfsson R, Nylander P. Relationship between prophylactic effect of lithium therapy and family history of affective disorders. Biological Psychiatry 1997;42:425-433.
Misra PC, Burns BH. «Lithium non-responders» in a lithium clinic. Acta Psychiatr Scand 1977;55(1):32-40.
Alda M, Grof P, Zvolsky P. Genetic factors and response to lithium treatment.Ref Type: Serial (Book,Monograph) 2008.
Grof P, Alda M. Discrepancies in the efficacy of lithium. Archives General Psychiatry 2000;57:191.
McKnew DH, Cytryn L, Buchsbaum MS et al. Lithium in children of lithium-responding parents. Psychiatry Res 1981;4(2):171-180.
Duffy A, Alda M, Kutcher S, Fusee C, Grof P. Psychiatric symptoms and syndromes among adolescent children of parents with lithium-responsive or lithium-nonresponsive bipolar disorder. American J Psychiatry 1998;155(3):431-433.
Duffy A, Alda M, Kutcher S et al. A prospective study of the offspring of bipolar parents responsive and nonresponsive to lithium treatment. J Clinical Psychiatry 2002;63(12):1171-1178.
Duffy A, Alda M, Milin R, Grof P. A consecutive series of treated affected offspring of parents with bipolar disorder: is response associated with the clinical profile? Canadian J Psychiatry 2007;52(6):369-376.
Alda M. Pharmacogenetics of lithium response in bipolar disorder. J Psychiatry Neuroscience 1999;24(2):154-158.
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