Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents
Introduction
Major depressive disorder (MDD) frequently presents in adolescence and is often recalcitrant to treatment (Brent, 2009) which leads to substantial morbidity, mortality, and a societal financial burden (Blazer et al., 1994, Greenberg et al., 2015). Suicide is a leading cause of death in adolescents and a stark reminder that the current mechanistic understanding of depression is underdeveloped (Vitiello et al., 2011). Unfortunately, antidepressant medications, cognitive-behavioral therapy, and combined treatment are either ineffective or have minimal durability for most depressed adolescents (March et al., 2009).
Noninvasive brain stimulation technologies such as repetitive transcranial magnetic stimulation (rTMS) may have promise as enduring therapeutic interventions in young people (Donaldson et al., 2014). Prior research has shown that rTMS applied to the left dorsolateral prefrontal cortex (L-DLPFC) is a safe and effective treatment for MDD in adults who fail to benefit from antidepressant medications (O'Reardon et al., 2007, George et al., 2010). Initial open-label studies of rTMS for MDD in adolescents suggest that it may be effective and well-tolerated in younger people, as well (Donaldson et al., 2014). Although rTMS treatment has US Food and Drug Administration clearance for adults, little is known about its mechanism of action and target engagement, especially in adolescents. Further research focused on understanding the underlying pathophysiology of MDD and how rTMS changes a patient's underlying neurophysiology would facilitate precision medicine approaches to brain stimulation treatments.
Glutamate (Glu) is the primary excitatory neurotransmitter, with roles in neurogenesis, synaptogenesis, neuronal migration, cognition, learning, and memory. Following release into the synaptic cleft, Glu is taken up by adjacent astrocytes and converted to glutamine (Gln) which is then transported back to the neuron. The glutamate–glutamine neurotransmitter recycling system is essential for normal neurotransmission (Yuksel and Ongur, 2010) and drives a large fraction of cerebral oxidative metabolism.
Prior research implicates dysregulated glutamatergic neurotransmission in mood disorders (Krystal et al., 2002, Sanacora et al., 2012) and suggests that rTMS may modulate glutamatergic circuitry (Michael et al., 2003). Initial preclinical (Yue et al., 2009) and clinical work (Michael et al., 2003) suggests that multiple sessions of rTMS increase cortical Glu concentrations in the brain.
Many previous proton magnetic resonance spectroscopy (1H-MRS) studies have examined Glu+Gln (so-called Glx) levels in psychiatric disorders, while contemporary studies at higher field strength (3 T and above) have been able to separately measure Glu and Gln. While it is relatively easy to quantify brain Glu (in part due to its higher concentration of approximately 10 mM), accurate measurement of brain Gln remains difficult due to its relatively low brain concentration (estimated at 2–4 mM) and large spectral overlap with other brain metabolites (Hancu and Port, 2011). To mitigate this measurement difficulty and improve sensitivity for detecting glutamate-glutamine cycle dysfunction, recently investigators have used the Gln/Glu ratio (Brennan et al., 2010, Ongur et al., 2011) or the Glu/Gln ratio (Hermann et al., 2012) for detecting neurotransmission abnormalities in patients with psychiatric disorders.
In this study, we assumed that depressed adolescents have glutamate–glutamine cycle dysfunction. The study objective was to examine changes in Gln/Glu ratios in the anterior cingulate cortex and left dorsolateral prefrontal cortex of depressed adolescents receiving high-frequency rTMS. We hypothesized that the Gln/Glu ratio would increase over time as Gln levels would increase and Glu levels would stay the same or decrease following treatment (Yuksel and Ongur, 2010). We also hypothesized that this change would relate to symptom improvement.
Section snippets
Participants
Participants were recruited and enrolled from the Mayo Clinic Mood Disorders Clinic for this prospective, open-label study of rTMS. The patient group consisted of 10 adolescents aged 13–17 years with treatment-refractory MDD. Parents provided informed consent and adolescents provided informed assent. Adolescents were evaluated and monitored by a child and adolescent psychiatrist for the duration of the study. Baseline assessments to determine eligibility included a semistructured diagnostic
Participant characteristics
The demographics of the study cohort are shown in Table 1. The mean number of rTMS sessions completed was 23.2 (11.4) (range, 1–30); 6 patients completed all 30 sessions, and 1 each completed 29, 17, 5, and 1 sessions. Of note, CDRS-R scores in the cohort declined considerably following rTMS therapy, and this decline decreased even further by the 6-month followup time point compatible with a durable response. As specified by the protocol participants were on a stable dose of an antidepressant
Discussion
In 10 adolescents with treatment-refractory depression, up to 30 sessions of high-frequency rTMS produced increases in the Gln/Glu ratio in the ACC and DLPFC over 6-months’ follow-up, as assessed with 2 different 1H-MRS sequences, but only reached statistical significance in the ACC with a PRESS sequence. Furthermore, throughout the 6-month follow-up, depression symptom severity assessed with the CDRS-R had an inverse relationship with Gln/Glu ratios, which suggests that Gln/Glu ratios
Contributions
Author contributions: All authors contributed to the conception and design of the study. Drs. Croarkin, Wall, Murphy, and Port collected and assembled the data. Drs. Croarkin, Nakonezny, Frye and Port analyzed and interpreted the data. All authors contributed to writing the manuscript and gave final approval of the manuscript. Dr. Croarkin had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Conflicts of interest financial disclosures
Financial disclosure: Dr. Croarkin reports research grant support from Pfizer, National Institute of Mental Health (K23 MH100266), Brain and Behavior Research Foundation, and Mayo Foundation. He has served as a site subprincipal or principal investigator (without additional compensation) for Eli Lilly and Co, Indianapolis, Indiana; Forest Laboratories, Inc, New York, New York; Merck and Co, Inc, Whitehouse Station, New Jersey; and Pfizer Inc. Dr. Croarkin has received in kind support for
Acknowledgments
This study was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number K23MH100266 (Dr Croarkin) and by a 2011 Klingenstein Third Generation Foundation Fellowship (Dr Wall). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Neuronetics provided equipment for the study (disposable Senstar shields) but had no involvement in the protocol design,
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