The authors report results of what we believe to be the first study of uridine as a treatment for depressed adolescents with bipolar disorder. Open-label uridine 500
mg twice daily for 6 weeks was associated with a mean decrease in CDRS-R raw score of 35.6, representing a reduction of 54% compared with baseline scores at study entry.
The benefit associated with uridine was not associated with switches to mania, treatment-emergent suicidal behavior, or serious adverse events. No clinically significant laboratory abnormalities were associated with uridine in our study. Although not measured systematically, improvement in psychosocial domains such as school performance, peer relations, and family function appeared to be associated with uridine treatment as well. Feedback from participants and parents suggests that uridine would score well on measures of patient acceptability and patient satisfaction.
Although uridine is a novel treatment for pediatric bipolar disorder, the history of uridine's use in medicine suggests that it may have few of the medically significant adverse events associated with mood stabilizers and second-generation antipsychotics. Reports of uridine treatment for the metabolic disorder Hereditary Orotic Aciduria began to appear in the 1960s (Becroft et al. 1969
). Some patients with this disease have been treated for over 20 years with oral uridine at doses up to 300
mg/kg per day, including two women who between them had six successful pregnancies, and one man who fathered a child. Six of the seven infants were normal; the seventh was born with congenital anomalies caused by a genetic mutation identified in the infant's mother and several maternal family members (Webster 1995
). Patients with Hereditary Orotic Aciduria report abdominal cramps and diarrhea as the only adverse events that appear to be related to uridine.
The collective evidence for mitochondrial dysfunction in bipolar disorder suggests a potential role for uridine in the treatment armamentarium. This evidence includes the co-morbidity of mood disorders with mitochondrial disorders (Kato 2006
), molecular genetic studies (Konradi et al. 2004
), neuroimaging (Stork and Renshaw 2005
), postmortem research (Andreazza et al. 2010
), and critical reviews (Quiroz et al. 2008
). Rational development of new treatments for bipolar disorder would include compounds designed to normalize the bioenergetic abnormalities associated with mitochondrial dysfunction (Kato 2007
). Other potential mechanisms of uridine in treating bipolar depression include change in phospholipid metabolism (Cansev 2006
; Wurtman et al. 2000
), catecholamine synthesis (Wang et al. 2005
), or synaptogenesis (Wurtman et al. 2009
Preclinical studies suggest that pyrimidines have antidepressant properties (Carlezon et al. 2002
). Studies of pyrimidines in adults with bipolar disorder have been promising as monotherapy (Repligen 2006
; Jensen et al. 2008
) and as an adjunct to valproate (Yoon et al. 2009
). Notably, participants treated with cytidine
valproate in the latter study experienced a rapid improvement in depressive symptoms in weeks 1–4, when compared with placebo
valproate patients. This phenomenon was echoed in our study, in which participants reported a decline in depressive symptoms within the first 2 weeks of treatment.
Given the lack of an exclusion criterion for current psychotropic medications, one notable aspect of the study sample is that just two of seven participants were on concomitant medications. Possible reasons for this include inadequate access to care, patient and family preference, and treatment adherence. The latter has been found to be poor in naturalistic studies of adolescent bipolar disorder (Coletti et al. 2005
; DelBello et al. 2007
) and in research settings (Drotar et al. 2007
). One study found that after hospital discharge on an atypical antipsychotic, 43% of adolescents had stopped the medication at the behest of a parent or physician (Pogge et al. 2005
). This underscores the need for treatments with improved patient, parent, and physician acceptability. As a substance known to be present in human mother's milk and commercial infant formula, if proven effective, uridine may be more acceptable than current drugs to the parents and physicians of adolescents with bipolar disorder.
The limitations of this pilot case series include its small sample size, the absence of a blinded placebo control group, and the heterogeneity of the population under study. Future work will be designed to address these limitations.