Neurochemical Effects of Olanzapine in First-Hospitalization Manic Adolescents: A Proton Magnetic Resonance Spectroscopy Study

Abstract

We used proton magnetic resonance spectroscopy ( 1 H MRS) to compare the in vivo effects of olanzapine on prefrontal N-acetylaspartate (NAA) levels in treatment remitters and nonremitters. Secondary aims of this study were to identify neurochemical predictors of successful olanzapine treatment and other neurochemical effects of olanzapine. In all, 20 adolescents admitted for their first hospitalization for bipolar disorder, type I, manic or mixed and 10 demographically matched healthy subjects were recruited. Manic adolescents were treated with olanzapine monotherapy and scanned at three time points (N ¼ 19). Medial and left and right lateral ventral prefrontal NAA, choline, creatine/phosphocreatine, myo-inositol, and glutamate/glutamine were measured at baseline, prior to receiving medication, and on days 7 and 28 of treatment. Healthy subjects did not receive medication but underwent 1 H MRS scans at the same time points to assess for normal variability in metabolites over time. Although there was no overall increase in NAA in manic adolescents following 28 days of treatment with olanzapine, olanzapine remitters (N ¼ 11, 58%) exhibited a greater increase in medial ventral prefrontal NAA compared with nonremitters (N ¼ 8, 42%, p ¼ 0.006). Specifically, from baseline to end point, NAA levels decreased in nonremitters (p ¼ 0.03) and increased in remitters (p ¼ 0.05). Manic adolescents treated with olanzapine had an increase from baseline to day 7 in medial (p ¼ 0.002) and right lateral (p ¼ 0.02) ventral prefrontal choline. Baseline medial ventral prefrontal choline was greater in olanzapine remitters than in nonremitters (p ¼ 0.001). Successful treatment of mania with olanzapine may lead to increased ventral prefrontal neuronal viability and/or function as compared to unsuccessful treatment with olanzapine. Additionally, olanzapine-induced increases in choline may lead to alteration of abnormalities in cell membrane metabolism or second messenger pathways that are thought to be involved in the pathophysiology of bipolar disorder.

Large positive effect of lithium on prefrontal cortex N-acetylaspartate in patients with bipolar disorder: 2-centre study

“…This is in keeping with other studies that showed lower brain NAA levels relative to controls in groups of patients who were mostly treated with mood stabilizers other than Li 39,40 and with the lack of effect of valproate treatment on NAA in most clinical studies. 13,18,41 Similarly, no effect of atyp ical antipsychotics on NAA levels has been reported in a prospective study, 34 and lower levels of NAA have been found in patients treated with a combination of selective serotonin reuptake inhibitors and atypical antipsychotics. 42 A single study reported greater NAA levels in patients with bipolar disorder treated with valproate relative to medication-free patients.…”

Elevated Prefrontal Cortex γ-Aminobutyric Acid and Glutamate-Glutamine Levels in Schizophrenia Measured In Vivo With Proton Magnetic Resonance Spectroscopy

“…68 In bipolar disorder, MRS has shown lower GABA and glutamate levels in patients taking antipsychotic medications compared with patients not taking antipsychotics, 69 although another study of this disorder found no effects on Glx levels from these medications. 70 The variable MRS findings in medicated patients reported for both GABA [3][4][5][6] and the glutamate system, [7][8][9][10][11][12][13] and the suggestion from our data that these medications may lower GABA and Glx levels, emphasize the need for a within-subject medication vs no medication study design for more definitive assessment of the effect of treatment on these neurochemicals. Such a design would also address the question of a possible role of GABA or Glx changes in clinical improvement with antipsychotic medication.…”

Glutamine and Glutamate Levels in Children and Adolescents With Bipolar Disorder

“…Using MRI, Kaur et al (2005) measured reduced ACC volume in children and adolescents with BPD and Chang et al have used functional MRI to demonstrate altered corticolimbic activity, including abnormalities in the ACC, in children and adolescents with familial BPD . In addition, many magnetic resonance spectroscopy (MRS) studies have shown altered metabolite levels in the ACC of both adults and children with BPD (Cecil et al, 2002(Cecil et al, , 2003Davanzo et al, 2001Davanzo et al, , 2003DelBello et al, 2006;Moore et al, 2000;Moore and Galloway, 2002).…”

“…These alterations in the ACC in adult BPD also appear to be present in children and adolescents with the illness (Frazier et al, 2005 et al, 2004). In addition, many magnetic resonance spectroscopy (MRS) studies have shown altered metabolite levels in the ACC of both adults and children with BPD (Cecil et al, 2002(Cecil et al, , 2003Davanzo et al, 2001Davanzo et al, , 2003DelBello et al, 2006;Moore et al, 2000;Moore and Galloway, 2002).Postmortem studies in adults with BPD have demonstrated reductions in the total number of glia and increases in glial cell size in the prefrontal cortex and ACC in adults with BPD (Ongur et al, 1998;Rajkowska, 2002). Glia provide a pathway for neuronal glutamate synthesis and reuptake though the glutamate/glutamine cycle ( Fig.…”