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
Source: PubMed


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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    • "With longer prospective study, it became evident that these earlier varied presentations in high-risk offspring were signaling vulnerability for mood disorders. Specifically, there is now convergent evidence that high-risk offspring who manifest childhood anxiety and sleep disorders have a significantly elevated risk of developing major mood disorders (ie, depression, BD, schizoaffective-BD) in adolescence and early adulthood (Grof et al., 2009; Duffy et al., 2010; Nurnberger, 2011; Ritter et al., 2012). This raises several questions, including: (1) are these childhood risk syndromes an indicator of specific risk for mood disorder in an immature brain or an indicator of nonspecific vulnerability? "
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    ABSTRACT: Background Psychiatric illnesses like bipolar disorder (BD) are increasingly understood to be neurodevelopmental disorders with clinical, psychological and biological indicators recognizable long before the emergence of the full-blown syndromes.Methods This paper is a selective review of findings from studies of high-risk children of affected parents that inform knowledge of illness risk and development markers of BD. We specifically focus on candidate clinical, biological and psychological risk indicators that could serve as targets for future early intervention and prevention studies.ResultsThere is convergent evidence from prospective studies that BD typically debuts as depressive episodes after puberty. In some high-risk children, sleep and anxiety disorders precede mood disorders by several years and reflect an increased vulnerability. An association between early exposure to adversity (e.g. exposure to parental illness, neglect from mother) and increased risk of psychopathology may be mediated through increased stress reactivity evident at both behavioural and biological levels. Inter-related psychological processes including reward sensitivity, unstable self-esteem, rumination and positive self-appraisal are risk factors for mood disorders. Disturbances in circadian rhythm and immune dysfunction are associated with mood disorders and may be vulnerability markers influenced by these other risk factors.Conclusions There is accruing evidence of a number of measurable and potentially modifiable markers of vulnerability and developing illness in youth at familial risk for BD. Longitudinal studies of multiple biological and psychological risk processes in high-risk offspring, both individually and together, will improve our understanding of illness onset and lead to the development of specific early interventions. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 06/2015; DOI:10.1093/ijnp/pyv071 · 4.01 Impact Factor
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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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