Lithium response across generations

Mood Disorders Center of Ottawa, Ottawa, ON, Canada.
Acta Psychiatrica Scandinavica (Impact Factor: 5.61). 11/2009; 120(5):378-85. DOI: 10.1111/j.1600-0447.2009.01454.x
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To describe and integrate observations from bipolar patients responsive to lithium stabilization and their children.
Selected findings are described from the clinical and biological investigations of adults meeting research criteria for bipolar disorder and for responsiveness to lithium stabilization; and from prospective studies of the children of lithium responders and non-responders.
Response to prophylactic lithium identifies a valid subtype of bipolar disorder, however the search for biological markers of lithium response, while promising, has so far remained inconclusive. Adult responders to lithium stabilization exhibit definable clinical features which are also observable in their affected children. In prospective studies the children of bipolar parents develop symptoms earlier than reported previously, with marked differences between the offspring of lithium responders and non-responders. The illness evolves in predictable clinical stages, first from non-specific sleep and anxiety disorders to mood symptoms and then, often starting in adolescence, major depressive and later activated episodes.
Investigating and comparing unequivocal responders and non-responders to long-term lithium treatment and their offspring is a fertile research strategy for addressing a multitude of clinical and research questions.

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Available from: Martin Alda, Oct 04, 2015
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    • "In addition, the GM differences between patients with versus without Li treatment may reflect patient heterogeneity rather than effects of Li (Hajek et al. 2012c). The Li responders are likely to represent a distinct neurobiological category within BD (Grof et al. 2009). It is possible that it is only the patients who do not respond to Li who have a neuroprogressive nature of the illness and show brain structural changes. "
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    ABSTRACT: Background: Neuroimaging studies have demonstrated an association between lithium (Li) treatment and brain structure in human subjects. A crucial unresolved question is whether this association reflects direct neurochemical effects of Li or indirect effects secondary to treatment or prevention of episodes of bipolar disorder (BD). Method: To address this knowledge gap, we compared manually traced hippocampal volumes in 37 BD patients with at least 2 years of Li treatment (Li group), 19 BD patients with <3 months of lifetime Li exposure over 2 years ago (non-Li group) and 50 healthy controls. All BD participants were followed prospectively and had at least 10 years of illness and a minimum of five episodes. We established illness course and long-term treatment response to Li using National Institute of Mental Health (NIMH) life charts. Results: The non-Li group had smaller hippocampal volumes than the controls or the Li group (F 2,102 = 4.97, p = 0.009). However, the time spent in a mood episode on the current mood stabilizer was more than three times longer in the Li than in the non-Li group (t(51) = 2.00, p = 0.05). Even Li-treated patients with BD episodes while on Li had hippocampal volumes comparable to healthy controls and significantly larger than non-Li patients (t(43) = 2.62, corrected p = 0.02). Conclusions: Our findings support the neuroprotective effects of Li. The association between Li treatment and hippocampal volume seems to be independent of long-term treatment response and occurred even in subjects with episodes of BD while on Li. Consequently, these effects of Li on brain structure may generalize to patients with neuropsychiatric illnesses other than BD.
    Psychological Medicine 05/2013; 44(3):1-11. DOI:10.1017/S0033291713001165 · 5.94 Impact Factor
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    • "In this context, research has focused on the identification of predictors of lithium response in BD. Clinical studies have shown that lithium responders have distinct clinical features compared to nonresponders , such as an episodic clinical course, family history of BD and absence of rapid cycling [10]. Moreover, response to lithium appears to be familial, [11] suggesting that genetic predisposition may constitute a key factor. "
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    ABSTRACT: Bipolar disorder (BD) is a debilitating psychiatric disease characterized by alternating episodes of mania and depression. Among mood stabilizers, lithium is the mainstay for the treatment of BD, with approximately one-third of patients showing remission from episode recurrence. While there is evidence suggesting genetic load for lithium response in BD, its molecular underpinnings are still not completely understood. To identify genes potentially involved in (or correlated with) lithium response, we carried out a genome-wide expression analysis on lymphoblastoid cell lines (LCLs) from 10 BD patients responders (R) and 10 non-responders (NR) to lithium. We compared expression levels of the two groups and tested whether in vitro lithium treatment had different effects in LCLs of R compared to NR. At basal, 2060 genes were differentially expressed between R and NR while no genes were differentially regulated by lithium in the two groups. After pathway analysis based on the 2060 genes, 9 genes were selected for validation with qRT-PCR. Eight genes were validated in the same sample of LCLs while only Insulin-like Growth Factor 1 (IGF-1) was significantly over-expressed in R compared to NR in the same sample as well as in an independent sample comprised of 6 R and 6 NR (sample 1, fold change=1.94; p=0.005; sample 2, fold change=2.21; p=0.005). IGF-1 was also significantly over-expressed in R but not in NR when compared to a sample of non-psychiatric controls. Our findings suggest that IGF-1 may be involved in lithium response, supporting further investigation on its potential as a biomarker.
    Pharmacological Research 04/2013; DOI:10.1016/j.phrs.2013.04.004 · 4.41 Impact Factor
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    ABSTRACT: Bipolar disorder is a severe recurrent psychiatric illness that often manifests in adolescence, a time of marked neurobiological change. The current model is one of multiple susceptibility genes interacting with other risk factors leading to alterations in the normal maturational trajectory of the CNS. Longitudinal studies of children of affected parents has enabled mapping of the early natural history of bipolar disorder. Convergent evidence from longitudinal high-risk studies suggest that bipolar disorder evolves in a series of clinical stages from nonspecific childhood disorders to depressive disorders in early adolescence and bipolar spectrum disorders in later adolescence and adulthood. At present, genetic studies and research into specific biological markers in bipolar patients and their family members are underway. Advances in understanding the neurobiological underpinnings of bipolar disorder will require addressing etiological heterogeneity of bipolar disorder and refining the phenotypic definition. In the latter case, the staging model may be a helpful organizing framework.
    Future Neurology 03/2010; 5(2):317-323. DOI:10.2217/fnl.10.3
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