Abstract
ContextRapid cycling is a severe form of bipolar disorder with an increased rate of episodes that is particularly treatment-responsive to chronotherapy and stable sleep-wake cycles. We hypothesized that the P2RX7 gene would be affected by sleep deprivation and be implicated in rapid cycling.ObjectivesTo assess whether P2RX7 expression is affected by total sleep deprivation and if variation in P2RX7 is associated with rapid cycling in bipolar patients.DesignGene expression analysis in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and case-case and case-control SNP/haplotype association analyses in patients.ParticipantsHealthy volunteers at the sleep research center, University of California, Irvine Medical Center (UCIMC), USA (n = 8) and Swedish outpatients recruited from specialized psychiatric clinics for bipolar disorder, diagnosed with bipolar disorder type 1 (n = 569; rapid cycling: n = 121) and anonymous blood donor controls (n = 1,044).Results P2RX7 RNA levels were significantly increased during sleep deprivation in PBMCs from healthy volunteers (p = 2.3*10−9). The P2RX7 rs2230912 _A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 (rs1718119 to rs1621388) containing the protective rs2230912_G allele (OR = 0.45–0.49, p = 0.003–0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls.ConclusionsSleep deprivation increased P2RX7 expression in healthy persons and the putatively low-activity P2RX7 rs2230912 allele A variant was associated with rapid cycling in bipolar disorder. This supports earlier findings of P2RX7 associations to affective disorder and is in agreement with that particularly rapid cycling patients have a more vulnerable diurnal system.
Highlights
Rapid cycling (RC) is a severe form of bipolar disorder, characterized by four or more disease episodes within one year (DSM-IV) [1,2]
P2RX7 RNA levels were significantly increased during sleep deprivation in peripheral blood mononuclear cells (PBMCs) from healthy volunteers (p = 2.3*1029)
The P2RX7 rs2230912 _A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 containing the protective rs2230912_G allele (OR = 0.45–0.49, p = 0.003–0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls
Summary
Rapid cycling (RC) is a severe form of bipolar disorder, characterized by four or more disease episodes within one year (DSM-IV) [1,2]. A RC course occurs in 12–24% of bipolar disorder patients [3]. In addition to more frequent episodes, RC implies greater functional impairment, increased risk of suicide attempts and a higher rate of alcohol abuse [1,4,5,6]. Due to the clinical severity of RC, clinicians try to prevent its development by early active symptom treatment. Antidepressants are often necessary to treat bipolar depression, despite the possible risk for mood switches in vulnerable patients [7,8,9,10]. Methods to identify patients at risk for RC would be of great clinical value
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