We enrolled 22 depressed adolescents with BD and 24 HC. There were no medication-related Serious Adverse Events, psychiatric hospitalizations, suicide attempts or suicides in the BD group. As shown in FIGURE 3, the mean CDRS-R raw score at study entry for was 63.6 (SD=6.18). The mean CDRS-R score for BD participants completing 6 weeks of treatment with uridine was 32.3 (SD=6.30), a decrease of 49%.

Neuroimaging data was acquired on 14 BD and 24 HC. No intracranial abnormalities were detected on anatomical MRIs. There were no significant between-group differences between BD and HC in age, educational level, or handedness.

The BD participants included both unmedicated (n=8) & medicated (n=6) adolescents. Four unmedicated BD participants were medication-naïve; the remaining 4 unmedicated BD participants had a mean medication-free period of 70 + 47 weeks (range, 28-116 weeks) at study entry. 31P-MRSI: To assess for differences in mean cerebral metabolite concentrations between the 3 participant groups, ANOVA was performed on the baseline 31P-MRSI metabolite data (TABLE 1). Post-hoc Tukey-Kramer HSD pairwise comparisons were then performed on the frontal lobe phosphorus-31 metabolites that were significant using ANOVA (PCr and Pi).

In unnmedicated BD participants, we found decreased baseline Pi compared to both HC (p=0.035), and medicated BD (p=0.021).

1H-MRSI: Consistent with MRSI studies of adult BD (Yuksel and Ongur, 2010), our adolescent participants with bipolar depression demonstrated elevated Glx at baseline, compared with HC (Effect Size = 0.86) (data not shown).

TABLE 2 displays the 31P-MRSI data from the baseline (Week 0) and follow-up (Week 6) scans of HC and BD. Between-group differences in high-energy phosphate levels were noted in BD vs. HC: uridine-treated BD participants demonstrated changes in phosphocreatine (PCr) (p=0.01) and β-NTP (~ATP) (p=0.007) compared with untreated HC. (See FIGURE 4)

1.Based on these open-label results, further study of Uridine as a treatment for depressed adolescents with BD is warranted.

2.Our results support the view that frontal lobe mitochondrial function is altered in adolescent BD, and may have implications for the use of Pi and Glx as biomarkers.

3.Phosphorus-31 magnetic resonance spectroscopic imaging (31P-MRSI) has the potential to become a valuable translational research tool in child & adolescent psychiatry. This work was supported by a NARSAD Young Investigator Award to Dr. Kondo from the BRAIN & BEHAVIOR RESEARCH FOUNDATION’S Research Partners Program; by NIMH grant MH058681 to Dr. Renshaw; and by the Utah Science Technology and Research initiative (USTAR).

Gore et al. (2011) Global burden of disease in young people aged 10-24 years: a systematic analysis. Lancet 377(9783): 2093-2102. Kondo et al. (2011) Open-label uridine for treatment of depressed adolescents with bipolar disorder. J Child Adolesc Psychopharmacol 21(2):171-5. Patel et al. (2008) Neurochemical alterations in adolescent bipolar depression: a proton magnetic resonance spectroscopy pilot study of the prefrontal cortex. J Child Adolesc Psychopharmacol 18:623-627. Quiroz et al. (2008) Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 33:2551-2565. Sanacora et al. (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7:426-437. Vitiello, Correll et al. (2009) Antipsychotics in children and adolescents: increasing use, evidence for efficacy and safety concerns. Eur Neuropsychopharmacol 19:629-635. Yuksel & Ongur (2010) Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry 68:785-794. .

This study had three objectives: (1) to initiate testing of the nutritional supplement uridine as a treatment for depressed adolescents with bipolar disorder with an open-label study; (2) to measure the changes in participants’ neurochemistry associated with uridine treatment with proton (1H-MRSI) and phosphorus (31P-MRSI) magnetic resonance spectroscopic imaging; and (3) to compare the concentrations of specific brain chemicals measured with 1H-MRSI and 31P-MRSI between adolescents with bipolar depression and healthy controls. The World Health Organization ranks bipolar disorder (BD) as the 4th most disabling condition among persons 10-24 years of age (Gore et al. 2011). Adults with BD commonly report their symptoms and impairment began in adolescence. Experts including Husseini Manji have implicated both mitochondrial dysfunction (Quiroz et al., 2008), and the neurotransmitter glutamate (Sanacora et al., 2008), in the pathophysiology of BD.

Current pediatric BD drugs include mood stabilizers and 2nd generation antipsychotics (SGAs). Adherence is poor, and Vitiello and Correll have articulated the contrast between the rising number of SGA prescriptions to youth, and concerns regarding both efficacy and safety (2009).

Despite the fact that more than 50% of pediatric BD patients experience a major depressive episode, there are no FDA-approved treatments for bipolar depression in youth.

Uridine is an endogenous pyrimidine required for normal brain function. It is found in human mother’s milk, and is an ingredient in commercial infant formulas. Some patients with inborn errors have been treated with oral uridine for > 20 years. Triacetyluridine and cytidine are pyrimidines with positive studies in adult bipolar depression. Pyrimidines’ mechanism-of-action includes increased synthesis of monoamines, improved mitochondrial function, increased pH, decreased levels of Glutamate/Glutamine/γ-Aminobutyric acid (Glx) and improved phospholipid metabolism.

Magnetic Resonance Spectroscopic Imaging (MRSI) is a safe, non-invasive method for in vivo measurement of the brain chemicals that reflect both mitochondrial and glutamatergic function. MRSI has been used to discover differences in brain chemistry between pediatric bipolar depression and healthy controls, including N-acetyl aspartate (NAA), choline, and the creatine/phosphocreatine ratio (Patel et al., 2008).

We administered uridine, a supplement that may alter both the mitochondrial and glutamatergic systems, as an open-label treatment for adolescent bipolar depression. As shown in Figure 2, in addition to standardized clinical instruments, we used 1H-MRSI and 31P-MRSI to assess treatment response.

Clinical results, without neuroimaging findings, were previously reported for the first 7 participants (Kondo et al, 2011). We now report results for 23 depressed adolescents with BD and 25 healthy controls.

The University of Utah IRB approved the study. Written consent & assent were both obtained prior to study procedures. A Data Safety and Monitoring Board (DSMB) was established.

Inclusion criteria: females and males ages 13-18 with a primary diagnosis of BD I, II or NOS; and Children’s Depression Rating Scale-Revised raw score > 40. Medication-free and medicated adolescents were enrolled.

Exclusion criteria: primary Axis I diagnosis other than BD; Young Mania Rating Scale (YMRS) score > 10; psychotic symptoms; high risk for suicidal behavior; positive urine pregnancy test or drug screen; developmental disability; or unstable medical condition.

Lab studies including complete blood count, metabolic panel, lipid profile, TSH, and urinalysis were obtained at baseline, then repeated after 6 weeks, to prospectively identify abnormalities associated with uridine administration.

Healthy control (HC) adolescents were recruited for brain scans, to enable comparison with BD participants.

BD participants received Uridine 500mg by mouth twice daily for 6 weeks. Study visits included: CDRS-R; Clinical Global Impressions (S/I); Columbia-Suicide Severity Rating Scale (C-SSRS); and adverse events. Change in CDRS-R score was the primary outcome measure; magnetic resonance (MR) brain chemistry measurements were secondary outcomes.

A two-dimensional chemical shift imaging free induction decay (2D CSI FID) pulse sequence with an Fourier voxel resolution of 25×25×25mm3; Field of View=200x200x25mm3; TR/TE=3000/2.3ms; vector size=1024; bandwidth =2500Hz; data collection time=11.2 minutes; and number of averages=24 was implemented to collect 2D CSI FID data. The high-resolution localization images of CSI data were acquired with an inversion recovery magnetization prepared rapid gradient echo (MP-RAGE) pulse sequence with isotropic 1mm3 resolution. The imaging parameters were: TR/TE=2000/3.37ms, FOV = 256x192x144mm3; matrix size=256x192x144; total acquisition time=4.8 minutes. These data were analyzed using the jMRUI software package (JMRUI VERSION 4.0, EUROPEAN COMMUNITY). Nine voxels from a 25mm slice located at the corpus callosum, anterior commissure and posterior commissure were summed following 2D FFT. Each voxel FID was apodized with a 10 Hz exponential line broadening before zero filling and FFT. Zero-order and first-order phase correction was performed in all spectrums.

Signal amplitudes for individual proton-1 and phosphorus-31 metabolites were calculated with the Advanced Method for Accurate, Robust and Efficient Spectral fitting of MRS data (AMARES) algorithm in JMRUI.

Depressed Adolescents with Bipolar Disorder Treated with Open-Label Uridine: a Proton (1H-MRSI)

and Phosphorus (31P-MRSI) Magnetic Resonance Spectroscopic Imaging Study Douglas Kondo MD,1,2,3 Kristen K. Fiedler BS,1 Tracy L. Hellem RN,1 Xianfeng Shi PhD,1 Young-Hoon Sung MD,1,2 Rebekah S. Huber MS1 and Perry F. Renshaw MD, PhD, MBA1,2,3

The Brain Institute,1 Department of Psychiatry,2 VISN 19 Mental Illness Research, Education and Clinical Center (MIRECC),3 University of Utah School of Medicine, Salt Lake City, Utah

BACKGROUND

METHODS

CONCLUSIONS

OBJECTIVES

UtahBrain.org

FIGURE 1 Frontal Lobe Region of Interest

RESULTS: Clinical Measures

BASELINE NEUROIMAGING: 31P-MRSI & 1H-MRSI

FIGURE 2 Study Design Incorporating Neuroimaging Into

Treatment Studies of Pediatric Mood Disorders

ACKNOWLEDGEMENTS

REFERENCES

Dr. Kondo, Ms. Fiedler, Ms. Hellem, Dr. Shi, Dr. Sung and Ms. Huber report no real or potential conflict of interest, and did not receive travel support or honoraria from a commercial business to attend this meeting. Dr. Renshaw is an inventor on a patent application that describes the use of uridine as a treatment for bipolar disorder. This patent application is assigned to McLean Hospital, and is licensed to the Repligen Corporation. The University of Utah manages conflicts of interest related to intellectual property. As part of this management, Dr. Renshaw did not evaluate any study participant at any point in time.

FIGURE 3 CDRS-R Scores During 6 Weeks of Open-Label URIDINE

in Depressed Adolescents with Bipolar Disorder

*Start of treatment **End of treatment

REPEATED MEASURES NEUROIMAGING: 31P-MRSI

FIGURE 4

ΔPCr (LEFT PANEL) and

Δβ-NTP (RIGHT PANEL)

from repeated measures 31P-MRSI brain scans of BD

and HC, performed 6 weeks

apart. BD received Uridine

500mg twice daily; HC were

untreated.

- PCr Effect Size = 1.2

- β-NTP Effect Size = 1.0