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Decreased Anterior Cingulate Myo-Inositol/ Creatine Spectroscopy Resonance with Lithium Treatment in Children with Bipolar Disorder Pablo Davanzo, M.D., M

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Decreased Anterior Cingulate Myo-Inositol/ Creatine Spectroscopy Resonance with Lithium Treatment in Children with Bipolar Disorder Pablo Davanzo, M.D., M Decreased Anterior Cingulate Myo-inositol/ Creatine Spectroscopy Resonance with Lithium Treatment in Children with Bipolar Disorder Pablo Davanzo, M.D., M. Albert Thomas, Ph.D., Kenneth Yue, B.S., Thomas Oshiro, M.S., Thomas Belin, Ph.D., Michael Strober, Ph.D., and James McCracken, M.D. This project was designed to compare differences in brain normal controls, BPD subjects showed a trend towards a proton spectra between children and adolescents with higher myo-inositol/creatine during the manic phase. These bipolar disorder (BPD) and gender and age-matched normal preliminary data provide evidence that a significant controls, and to measure changes in myo-inositol levels reduction in anterior cingulate myo-inositol magnetic following lithium therapy, utilizing in vivo proton resonance may occur after lithium treatment, especially magnetic resonance spectroscopy (1H MRS). A single voxel among responders. Follow-up studies involving a larger (2x2x2 cm3) was placed in brain anterior cingulate cortex sample may allow us to confirm whether changes in myo- for acquisition of the 1H spectra at baseline and after acute inositol associated with acute lithium therapy persist in (~7 days) lithium administration in 11 children (mean age long-term clinical response of patients with and without 11.4 years) diagnosed with BPD, and in 11 normal lithium compliance. controls. Acute lithium treatment was associated with a [Neuropsychopharmacology 24:359–369, 2001] significant reduction in the myo-inositol/creatine ratio. © 2001 American College of Neuropsychopharmacology. This decrement was also significant in lithium-responders Published by Elsevier Science Inc. when analyzed separate from non-responders. Compared to KEY WORDS: Pre-adolescents; Mania; Hypomania; Lithium; though estimates vary widely (Costello et al. 1996). Magnetic resonance spectroscopy Given the increased frequency of lithium use among children and adolescents (Ryan et al. 1999) there is a Bipolar affective disorder (BPD) is a severe, recurrent, clear need to assess the effects of lithium in pediatric potentially life-threatening illness (Tondo et al. 1998). populations. Children may have greater lithium resis- Epidemiological data (Lewinsohn et al. 1995), suggest tance than adults (Himmelhoch and Garfinkel 1986; that the prevalence of juvenile-onset BPD may be as Hsu 1986), and it may take up to six weeks to deter- common as rates reported in adult populations, al- mine, based on clinical signs and symptoms, whether a child is responding to treatment. Biological markers of From the Department of Psychiatry and Behavioral Sciences (PD, MS, JM), Department of Radiological Sciences (MAT, KY, TO), treatment response would be extremely useful, particu- Department of Biostatistics (TB), School of Medicine, University of larly in these times of limited inpatient resources. The California, Los Angeles present study measured the magnetic resonance of Address correspondence to: Pablo Davanzo, M.D., Assistant Pro- 1 fessor, Dept. of Psychiatry, UCLA School of Medicine, Room 48- myo-inositol and other metabolites with H MRS in pe- 243C—UCLA Neuropsychiatric Institute, 760 Westwood Plaza, Los diatric subjects diagnosed with BPD, before and during Angeles, CA 90024. Tel.:310-825-0469, Fax: 310-206-4446, E-mail: lithium therapy, with baseline comparison to normal [email protected] Received April 13, 2000; revised August 25, 2000; accepted Sep- controls individually matched for age and gender. We tember 14, 2000. hypothesized that lithium would have an effect on the NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 4 © 2001 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(00)00207-4 360 P. Davanzo et al. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 4 magnetic resonance of myo-inositol in the anterior cin- BPD has been suggested by a reduction in cytosolic and gulate cortex in children with BPD, as measured by in membrane-associated PKC activities in platelets of lith- vivo proton magnetic resonance spectroscopy (1H MRS). ium-treated subjects with BPD (Friedman et al. 1993); Secondarily, we postulated that a decrease in myo-inos- and by elevated platelet membrane phosphatidylinosi- itol signal in response to lithium might be a predictor of tol-4,5-bisphosphate (PIP2) in medication-free patients treatment efficacy. with BPD during the manic phase (Brown et al. 1993). Lithium has traditionally been the preferred treat- Indirect in vivo measurement of brain inositol metab- ment of the manic phase of bipolar illness in adults, olism in adult patients treated with lithium has been at- children (Geller and Luby 1997), and adolescents tempted through measuring phosphomonoester peaks (Strober et al. 1995) with BPD. Open-label (Hsu 1986; with phosphorus (31P) magnetic resonance spectros- Carlson et al. 1992; Strober et al. 1995), and one double- copy (MRS) (Kato et al. 1995), proton (1H) MRS (Kato et blind placebo-controlled study of adolescents with sub- al. 1996; Silverstone et al. 1996) and lithium MRS stance abuse and mania (Geller et al. 1998) suggest that (Gonzalez et al. 1993; Kato et al. 1993; Sachs et al. 1995) juveniles with BPD may have somewhat reduced bene- (involving a lithium-sensitive coil). In vivo 1H MRS is a fit from acute lithium therapy compared with adults. non-invasive technique for measuring metabolite con- Nevertheless, lithium continues to be widely prescribed centrations in living tissue (Renshaw et al. 1995). The among children and adolescents with BPD (Geller and major compounds observed in 1H MRS spectra of the Luby 1997) as well as for young patients presenting brain are myo-inositol (mI), choline moieties (Cho), cre- with excessive irritability (Fava 1997) and extreme af- atine (Cr), and N-acetyl-aspartate (NAA) (Miller 1991). fective dysregulation (Vitiello and Stoff 1997). Sharma and colleagues (Sharma et al. 1992) reported an The precise neurobiological mechanisms whereby elevation of the inositol/Cr ratios in the basal ganglia of lithium reduces acute manic excitement and protects adult patients treated with lithium, a finding that ap- against recurrence of illness remain uncertain. It is pears to contradict in vitro findings showing a decre- apparent that lithium exerts an effect on intracellular ment of inositol with lithium treatment in animals second-messenger systems in which activated receptor- (Manji et al. 1996). Likewise, Silverstone and colleagues ligand complexes stimulate the turnover of inositol- (Silverstone et al. 1996) reported that chronic lithium containing phospholipids (del Rio et al. 1998; Feldman did not alter human myo-inositol/Cr peak ratios as et al. 1997; Murray and Greenberg 1997; Soares et al. measured by 1H MRS, in a study of seven volunteer 1999). Lithium’s inhibitory action on receptor-mediated subjects receiving lithium compared to four volunteers signal-transduction pathways has been demonstrated receiving placebo over seven days. These studies ap- in vitro (Atack et al. 1995) showing that it reduces myo- pear to contradict the hypothesis that lithium signifi- inositol levels by non-competitively inhibiting the en- cantly affects brain concentrations of myo-inositol or zyme inositol monophosphate, a catalyst for converting phosphomonoesters. However, the possibility cannot inositol monophosphate hydroxyls to myo-inositol be discounted that these earlier failures to detect (Manji et al. 1996). Since the phosphoinositide cycle (PI) changes in brain metabolism (ie. myo-inositol and regulates a wide variety of neuronal functions, includ- phosphomonoester concentrations) were due to small ing intracellular calcium mobilization and protein ki- samples, or studying patients who were on lithium at nase C (PKC) activity (Feldman et al. 1997), lithium- serum levels in the lower end of the therapeutic range induced modification of the PI cycle has been proposed (Sachs et al. 1995). as a potential therapeutic mechanism underlying its Recently, Moore and colleagues (Moore et al. 1999) mood-stabilizing effect (Berridge et al. 1982; del Rio et used 1H MRS to study lithium’s effects on in vivo brain al. 1998; Murray and Greenberg 1997; Soares et al. inositol and choline levels in adult depressed patients 1999). Although brain tissue can synthesize myo-inositol with BPD. Brain myo-inositol and choline levels were de novo, the ability of neurons to maintain a steady-state measured at three time points: at baseline, after 5-7 supply of cytosolic myo-inositol appears to be crucial to days of acute lithium treatment and 3-4 weeks of initia- the resynthesis of phosphoinositides, and, conceivably, tion of lithium. Significant decreases, averaging 30%, to the membrane receptor response to stimulation and were observed in levels of myo-inositol in the right neuronal homeostasis. Dampening of PI-mediated sig- frontal lobe following acute lithium administration, nal transduction in excitatory neurons would therefore, which persisted through one month of treatment. Re- result in antimanic effect (Feldman et al. 1997). duction in myo-inositol resonance was observed prior However, clinical findings bearing on PI signal to onset of observed clinical improvement, suggesting a transduction activity in BPD are inconsistent (Feldman marker for the beginning of a cascade of neuronal et al. 1997). Most information about PI metabolism in changes involving PKC regulation, and gene expression BPD derives from studies using tissues other than CNS
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