Variations in myo-inositol in fronto-limbic regions and clinical response to electroconvulsive therapy in major depression
Introduction
Electroconvulsive therapy (ECT) remains the most effective acute treatment for severe depression (Pagnin et al., 2004, Petrides et al., 2001) and is the modality of choice for patients failing standard therapeutic approaches (Janicak et al., 1985, Pagnin et al., 2004). However, the neurobiological events accounting for clinical response to ECT are still debated (Fosse and Read, 2013, Ishihara and Sasa, 1999). Renewed emphasis has been placed on the role of glial cells in antidepressant response as converging evidence suggests glia pathology and perturbations in glia number in depression. For instance, reductions in glia in major depressive disorder (MDD) are reported in post-mortem samples within regions widely implicated in depression such as the subgenual anterior cingulate (Öngür et al., 1998), dorsolateral prefrontal (Cotter et al., 2002) and orbitofrontal cortex (Rajkowska et al., 1999). Conversely, increased glial density has been reported in the hippocampus (Stockmeier et al., 2004).
Myo-inositol is a stereoisomer of inositol, a compound that is largely (though not solely) produced by the phosphoinositide second messenger signaling system (Moore et al., 2000). Although neurons contain measurable myo-inositol, the myo-inositol signal detected by 1H-MRS is considered to reflect glial myo-inositol where much higher concentrations are present (Brand et al., 1993). Reduced levels of myo-inositol, a putative glial marker (Hattingen et al., 2008), are indicated in the cerebral spinal fluid (CSF) and in the frontal cortex in post-mortem data of individuals with affective disorders (Barkai et al., 1978, Shimon et al., 1997). Further, several independent proton magnetic resonance spectroscopy (1H-MRS) studies report reduced resonance of myo-inositol in the prefrontal cortex (PFC) (Coupland et al., 2005), the anterior cingulate cortex (ACC) (Chen et al., 2014, Chiappelli et al., 2015, Frey et al., 1998) and hippocampus (Husarova et al., 2012) of depressed patients.
Oral supplementation of inositol has been tested in randomized controlled trials where at least two studies have shown reductions in depressive symptoms in association with inositol administration (Elizur et al., 1995, Levine, 1997). However, research addressing links between traditional antidepressant therapies and myo-inositol is sparse and conflicting. One 1H-MRS study reported significantly reduced ACC myo-inositol in patients taking different classes of antidepressants relative to unmediated patients (Frey et al., 1998). Conversely, a recent study indicated increased ACC myo-inositol concentration in depressed patients following administration of a selective serotonin reuptake inhibitor (Chen et al., 2014). Transcranial magnetic stimulation (TMS) has been shown to increase prefrontal myo-inositol in depressed adolescents (Zheng et al., 2010). One report also shows elevated myo-inositol in the ACC of depressed patients in remission (Taylor et al., 2009). In sharp contrast to standard pharmacotherapies that take weeks to months to elicit a full therapeutic response, ECT has a relatively rapid onset of action. Animal studies using electroconvulsive shock (ECS) as a model for ECT show increased markers of glial cells in regions important in depression such as the PFC (Jansson et al., 2009), hippocampus (Wennström et al., 2003, Wennström et al., 2006, Kaae et al., 2012), and amygdala (Wennström et al., 2004). However, whether changes in myo-inositol associate with response to ECT has not been addressed or documented.
Using single voxel 1H-MRS, we sampled myo-inositol levels from the dorsomedial ACC, right and left hippocampus to determine whether changes in myo-inositol occur in association with ECT and ECT-related clinical response. Patients with DSM-IV major depression scheduled to receive ECT were scanned at three time points: within 24 h prior to the first ECT treatment (T1), after the second and prior to the third ECT session (T2) and at the end of the ECT treatment index series (T3). To establish normative myo-inositol values and variance, demographically similar healthy controls were assessed at two time points (C1 and C2). Based on initial evidence from previous 1H-MRS studies that mostly suggest increased myo-inositol in association with other antidepressant therapies (Chen et al., 2014, Zheng et al., 2010), we hypothesized that myo-inositol values would increase in association with ECT and that patients would exhibit lower myo-inositol relative to controls at baseline.
Section snippets
Subjects
All study participants provided written informed consent as approved by the UCLA Institutional Review Board. The study was conducted in accordance with the latest version of the Declaration of Helsinki. Exclusion criteria for all participants included history of alcohol or substance abuse within the past 6 months and/or dependence within the past 12 months, any neurological disorder, and contraindication to MRI scanning. Demographic and clinical information for all subjects is provided in
Demographics
ECT patients and controls did not differ in sex, Χ2 (1,82) = 0.35, p = 0.55, or age, F(1, 82) = 2.19, p = 0.14.
Longitudinal analyses: effects of ECT
In patients, HAMD and MADRS rating improved significantly with ECT, F(2, 12.20) = 30.05 and F(2, 37.24) = 30.04, both p < 0.0001. The GLMM indicated a significant increase in dorsomedial ACC myo-inositol F(2, 32.34) = 3.497, p = 0.042 over the course of ECT treatment [Fig. 2]. Pairwise comparisons indicated significant differences in myo-inositol content between T1 and T3 (p = 0.021)
Discussion
Several lines of evidence suggest that glial pathology contributes to the pathophysiology of major depression and may play a role in the mechanisms of successful treatment (Rajkowska and Miguel-Hidalgo, 2007). Since myo-inositol is considered a 1H-MRS marker of glial cell integrity, the current study sought to determine whether changes in myo-inositol occur with ECT and relate to therapeutic response. Study results provide the first evidence of ECT-related increases in myo-inositol
Funding and disclosure
This study was supported by Award Numbers R01MH092301 and K24MH102743 from the National Institute of Mental Health and partially supported by the Office of the Director of the National Institutes of Health by Award Number S1OD011939. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health.
Conflict of interest
The authors declare no conflict of interest.
Contributors
There are no contributors to disclose.
Acknowledgements
The authors would like to acknowledge Drs. Aaron Hess, Andre van der Kouwe, Ernesta Meintjes, Jeffry Alger and Michele Zhang for their important contributions and/or consultation with regard to the development and implementation of the 1H-MRS acquisition sequences and their analysis.
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