Bcl-2 associated with severity of manic symptoms in bipolar patients in a manic phase
Introduction
The etiology of bipolar disorder remains unclear, but there is increasing evidence suggesting that it is associated with dysregulation of neurotrophic signaling cascades and apoptosis (Friedrich, 2005, Shaltiel et al., 2007, Uribe and Wix, 2012, Fries et al., 2014, Moutsatsou et al., 2014). The dysregulation of neurotrophic signaling cascades may be related to apoptosis and contribute to brain atrophy in bipolar disorder patients (Lyoo et al., 2004, Kim et al., 2010). B cell lymphoma protein-2 (Bcl-2) has been reported to be related to the pathology of bipolar disorder (Shaltiel et al., 2007, Machado-Vieira et al., 2011, Uemura et al., 2011, Soeiro-de-Souza et al., 2013). In addition, mood stabilizers have neuroprotective effects and can influence bcl-2 protein (Chuang, 2005, Wada et al., 2005, Hammonds and Shim, 2009, Soeiro-de-Souza et al., 2012, Leng et al., 2013).
Apoptosis is triggered through extrinsic and intrinsic (mitochondrial) pathways (Schulze-Osthoff et al., 1992, Wang et al., 2006, Uribe and Wix, 2012). Apoptosis pathways are related to many molecules such as Bcl-2, Bcl-2-associated death promoter (BAD), Bcl-2-associated X protein (BAX) caspase-3, caspase-9 and cytochrome c (Le Bras et al., 2006, Belizario et al., 2007, Guo et al., 2010, Grimm, 2012). The anti-apoptotic protein Bcl-2 prevents mitochondrial release of cytochrome c, which leads to apoptosis (Scorrano and Korsmeyer, 2003, Ohkubo et al., 2007). In addition, Bcl-2 may inhibit neuronal apoptosis and has a neuroprotective effect (Chen et al., 1997, Manji et al., 2000, Lei et al., 2012, Wei et al., 2013). Anti-apoptotic protein Bcl-2 may play a role in the pathophysiology of bipolar disorder (Benes et al., 2006, Kim et al., 2010).
Bcl-2 levels are significantly decreased in the prefrontal cortex of bipolar patients compared to healthy controls (Kim et al., 2010). Moutsatsou et al. (2014) reported increased BAX/Bcl-2 ratios in manic and depressed patients with bipolar disorder comparedto healthy controls. In addition, the Bcl-2 gene single nucleotide polymorphism (SNP) rs956572 was reported to be related to abnormal Bcl-2 gene expression in bipolar patients (Machado-Vieira et al., 2011). Our previous data revealed that there were no significant changes in Bcl-2 levels in schizophrenia patients who were in an acute phase and with 4-week treatment (Tsai et al., 2013). However, there is little data on the association between Bcl-2 level changes and manic episodes in bipolar patients.
The aims of this study were to investigate the serum levels of Bcl-2 in bipolar patients in a manic phase, and to determine the relationship between Bcl-2 levels and Young Mania Rating Scale (YMRS) scores in bipolar patients in a manic phase. In addition, we investigated the changes in Bcl-2 levels in patients after treatment. This was the first study to evaluate Bcl-2 serum levels in bipolar disorder patients.
Section snippets
Patients and study design
All patients with bipolar I disorder in a manic phase were enrolled from the inpatient ward of Kaohsiung Chang Gung Memorial Hospital, and all of them were diagnosed by the same psychiatrist using the Structured Clinical Interview (SCID) and DSM-IV criteria. The YMRS was administered by two board-certified psychiatrists at baseline and at the endpoint of the study to evaluate severity of disease. Data including age, sex, body mass index (BMI: kg/m2), and serum Bcl-2 levels was collected. All
Results
We consecutively enrolled 23 bipolar inpatients in a manic phase and 40 healthy subjects (20 men and 20 women). Three bipolar patients dropped out of the study, leaving 20 patients (12 men and 8 women) who were followed up. The 20 patients had mean hospitalization durations of 25.8±5.0 days. In addition, all the patients had at least YMRS=20 at baseline (Table 3). The serum Bcl-2 levels in the bipolar patients (0.65±0.48 ng/ml) in a manic phase were higher than those in the healthy subjects
Discussion
The most important finding in our study is that the serum Bcl-2 levels of bipolar patients in a manic phase were significantly negatively associated with YMRS scores.
Bcl-2 might have neuronal anti-apoptotic and neuroprotective effects (Manji et al., 2000, Lei et al., 2012, Wei et al., 2013). Oxidative stress causes brain damage in bipolar patients (Wang et al., 2009); therefore, Bcl-2 levels in bipolar patients in a manic phase might decrease. Our result suggested that Bcl-2 levels might be an
Acknowledgments
This work was supported by grants from Chang Gung Memorial Hospital in Taiwan (Research number: CMRPG8B0511) provided to Tsai MC. We did not obtain financial support from any drug company. In addition, Tsai MC and Huang TL conceptualized and designed the study, and formulated the hypotheses and analytical strategies. Chen WT and Tsai MC wrote the manuscript.
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