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Improvement in hypersomnia with high frequency repetitive transcranial magnetic stimulation in depressed adolescents: Preliminary evidence from an open-label study
Journal Pre-proof Improvement in hypersomnia with high frequency repetitive transcranial magnetic stimulation in depressed adolescents: Preliminary evidence from an open-label study
A. Irem Sonmez, M. Utku Kucuker, Charles P. Lewis, Bhanu Prakash Kolla, Deniz Doruk Camsari, Jennifer L. Vande Voort, Kathryn M. Schak, Simon Kung, Paul E. Croarkin PII:
S0278-5846(19)30550-0
DOI:
https://doi.org/10.1016/j.pnpbp.2019.109763
Reference:
PNP 109763
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date:
5 July 2019
Revised date:
13 September 2019
Accepted date:
18 September 2019
Please cite this article as: A.I. Sonmez, M.U. Kucuker, C.P. Lewis, et al., Improvement in hypersomnia with high frequency repetitive transcranial magnetic stimulation in depressed adolescents: Preliminary evidence from an open-label study, Progress in Neuropsychopharmacology & Biological Psychiatry(2018), https://doi.org/10.1016/ j.pnpbp.2019.109763
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© 2018 Published by Elsevier.
Journal Pre-proof [Category: Original Article] Improvement in Hypersomnia with High Frequency Repetitive Transcranial Magnetic Stimulation in Depressed Adolescents: Preliminary Evidence from an Open-Label Study
A. Irem Sonmez, MD 1* M. Utku Kucuker, MD 1*
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Charles P. Lewis, MD 1
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Bhanu Prakash Kolla, MD, MRCPsych1,2
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Deniz Doruk Camsari, MD1 Jennifer L. Vande Voort, MD1
Simon Kung, MD1
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Author Affiliations:
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Paul E. Croarkin, DO, MSCS1†
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Kathryn M. Schak, MD1
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Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA Center for Sleep Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Authors contributed equally.
†
Reprints: Paul E. Croarkin, DO, MSCS, Department of Psychiatry and Psychology,
Mayo Clinic, 200 First St SW, Rochester, MN 55905 Email: [email protected] Telephone: (507) 293-2557 Fax: (507) 293-3933
Journal Pre-proof Abstract word count: 247 Brief Summary word count: 96 Text word count: 3,030
No. of tables: 2
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No. of figures: 2
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All authors have seen and approved the manuscript.
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Declarations for each author:
Financial support (presence or absence): Research reported in this publication was
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supported by the National Institutes of Health under award R01 MH113700 (Dr.
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Croarkin). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Neuronetics, Inc. provided equipment support for the study. Role of the Sponsor: The
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supporters had no role in the design, analysis, interpretation, or publication of the study. Conflict of interest: Dr. Croarkin has received research grant support from Pfizer, Inc.; equipment support from Neuronetics, Inc.; and received supplies and genotyping services from Assurex Health, Inc. for investigator-initiated studies. He is the primary investigator for a multicenter study funded by Neuronetics, Inc. and a site primary investigator for a study funded by NeoSync, Inc. Dr. Croarkin is a paid consultant for Procter & Gamble Company. Dr. Lewis receives research support from the Brain and Behavior Research Foundation and has served as a site co-investigator on multicenter
Journal Pre-proof trials funded by Neuronetics, Inc. and NeoSync, Inc. The other authors have no disclosures or potential conflicts of interest to declare.
Running title: Reduced hypersomnia with rTMS in depressed adolescents
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Clinical Trial Registry:
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Clinicaltrials.gov Identifiers: NCT00587639, NCT01502033, NCT01804270
Journal Pre-proof ABSTRACT
Study Objectives Sleep disruption is a significant symptom of major depressive disorder (MDD). To our knowledge, no prior work has examined the impact of repetitive transcranial magnetic stimulation (rTMS) on sleep disturbances in adolescents with MDD.
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Methods
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Seventeen adolescents with treatment-resistant depression received 30 daily sessions
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of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex (L-DLPFC). Clinical
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symptoms were assessed at baseline; after 10, 20, and 30 treatments; and at a 6-month follow-up visit. Insomnia was measured with a 3-item subscale of the Quick Inventory of
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Depressive Symptomatology – Adolescent (17 Item) – Self Report (QIDS-A17-SR).
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Hypersomnia was measured with a single QIDS-A17-SR item. Depression severity was rated with the Children’s Depression Rating Scale, Revised (CDRS-R). The effect of
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rTMS on sleep was examined via linear mixed model analyses, with fixed effects of time
Results
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(as a proxy of treatment), depression severity, age, and hypnotic medication use.
No significant main effect of time was observed on the insomnia subscale (F4,43.442 = 1.078, p = .379). However, there was a significant main effect of time on the QIDS-A17-SR hypersomnia score (F4,46.124 = 2.733, p = .040), with significant improvement from baseline to treatment 10 (padj = .019) and from baseline to 6-month follow-up (padj = .044). In exploratory sensitivity analyses, response/nonresponse to rTMS for overall depressive symptoms had no significant effect on sleep outcomes.
Journal Pre-proof Conclusions rTMS may have intrinsic effects on hypersomnia apart from its antidepressant effects in depressed adolescents. Future work should utilize sham controls and objective, quantitative measurements of sleep architecture to assess effects of rTMS in depressed
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adolescents.
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Keywords:
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Adolescent; depression; hypersomnia; insomnia; repetitive transcranial magnetic
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stimulation (rTMS).
Journal Pre-proof HIGHLIGHTS
1. Current Knowledge: Sleep disturbance is a common and incompletely understood symptom impacting the functioning of adolescents with depression. There are limited interventions that address sleep disturbances in depression, and often treatment (i.e., antidepressant medications) has an adverse effect on
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sleep architecture.
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2. Study Impact: Recent research has examined the safety and clinical effects of
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repetitive transcranial magnetic stimulation (rTMS) for depression in adolescents.
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This open-label, pilot study examined the potential impact of rTMS on insomnia and hypersomnia in a sample of adolescents with treatment-resistant depression
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and found that rTMS results in an improvement in hypersomnia.
Journal Pre-proof 1. INTRODUCTION
Insomnia, non-restorative sleep, and hypersomnia are common symptoms of major depressive disorder (MDD), with 80% of depressed patients reporting some form of sleep disruption.1 This may be a particularly important target for intervention for adolescents, who have increased sleep requirements.2 Sleep also plays an essential
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role in cognitive development.3 A recent meta-analysis of 19 studies in children aged 5-
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13 years found that longer sleep durations were associated with better cognitive
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functioning, including memory, attention, processing speed, and intelligence.4 Sleep in children has an important function in daytime performance and healthy cognitive
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development.5-7
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Sleep problems during childhood are likely a risk factor8 or initial symptom of
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depression among adolescents.9,10 Additionally, insomnia or hypersomnia may serve as early markers of depression relapse. Insufficient sleep may also be a risk factor for
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increased suicidal ideation in adolescents 11 as well as adults.12 Thus, sleep
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disturbances in the context of depression may have diagnostic, pathophysiological, and therapeutic significance.
Repetitive transcranial magnetic stimulation (rTMS) involves the stimulation of cortical neurons with magnetic pulses and is now widely available as a clinical treatment for adults. Current TMS treatments cleared by the U.S. Food and Drug Administration (FDA) typically involve 5 daily treatments per week, for 4 to 6 weeks, with 10-Hz, 120% motor threshold (MT) stimulation applied to the left dorsolateral prefrontal cortex (LDLPFC).13 rTMS is now an established FDA-approved treatment for MDD in adults14,15
Journal Pre-proof and a promising (but not FDA-approved) treatment for depression in youth,16 although its effects on sleep are largely unknown in this population. Preliminary studies have examined the impact of rTMS on sleep in adults.17 To our knowledge, no prior work has examined the impact of rTMS on sleep disturbances in adolescents with MDD. This exploratory post hoc analysis aimed to examine the impact of high frequency rTMS on sleep disturbances in a sample of 17 outpatient adolescents (ages
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13-19) with treatment-resistant MDD who were treated concurrently with antidepressant
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medication. We examined sleep as an outcome distinct from depression severity in
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view of both the clinical significance of sleep disturbance and the fact that sleep
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problems may not necessarily align with overall depression severity. We hypothesized that clinical measures of insomnia and hypersomnia would improve over the course of
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2. METHODS
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treatment with rTMS.
2.1 Overview Data for the present study were pooled from 3 protocols (NCT00587639, NCT01502033, NCT01804270) with consistent methodology in providing open-label, adjunctive rTMS for adolescents with treatment-resistant depression. The three trials utilized similar rTMS devices, coil localization procedures, and identical stimulation parameters. All participants were outpatients who were taking antidepressant
Journal Pre-proof medications concurrently. Results of antidepressant and neurocognitive outcomes from these trials have been published previously.18-20 All study procedures were approved by the local institutional review boards. Informed consent was provided by minor participants’ parents or guardians, with adolescents providing written assent, while adult participants age 18 or older provided written informed consent.
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2.2 Study Participants
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Participants were recruited from clinic and community referrals. Eligible
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participants were adolescents between the ages of 13 and 19 years with a current diagnosis of MDD according to Diagnostic and Statistical Manual of Mental Disorders,
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Fourth Edition, Text Revision (DSM-IV-TR) criteria,21 and with history of at least one
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failed antidepressant trial as defined by the Antidepressant Treatment History Form
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(ATHF).22 The Children’s Depression Rating Scale, Revised (CDRS-R),23 a 17-item clinician-rated scale incorporating reports from both parent and adolescent, was utilized
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to assess depressive symptom severity. For eligibility, participants required a score of
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40 or greater at study entry. Exclusion criteria consisted of diagnoses of schizophrenia, schizoaffective disorder, bipolar spectrum disorder, substance abuse or dependence, somatoform disorders, dissociative disorders, posttraumatic stress disorder, obsessivecompulsive disorder, eating disorders, mental retardation, seizure disorders, or other neurologic conditions. All participants received urine pregnancy and toxicology screens; negative toxicology results (and a negative pregnancy test for female participants) were necessary for enrollment. General TMS safety criteria, including but not limited to the
Journal Pre-proof absence of a seizure history and absence of metal objects around the head and neck area, were required for enrollment.
2.3 Clinical Assessments Participants were interviewed by a board-certified child and adolescent psychiatrist. The baseline assessments included comprehensive clinical evaluation and
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semi-structured diagnostic interview with the Schedule for Affective Disorders and
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Schizophrenia for School Aged Children – Present and Lifetime Version (K-SADS-PL).24
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Clinical symptoms were assessed at baseline, at 10, 20, and 30 treatments, and
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at a 6-month follow-up visit. Depression severity was rated with the CDRS-R.23 The summary raw score was used as the measure of depression severity. Clinical response
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was defined as a CDRS-R score less than 40 at the end of 30 treatments. Insomnia
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was measured with a 3-item subscale of the Quick Inventory of Depressive Symptomatology – Adolescent (17 Item) – Self Report (QIDS-A17-SR),25 a patient-
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completed questionnaire of depressive symptoms. The subscale included items
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assessing difficulty falling asleep, sleep restlessness and middle insomnia, and early awakening (see supplemental materials); each item is rated on an ordinal scale of 0 to 3, for an insomnia subscale with a potential range of 0 to 9. A separate QIDS-A17-SR item specifically assessing hypersomnia (ordinal scale, range 0 to 3; see supplemental materials) was treated as a separate outcome variable. QIDS-A17-SR sleep items were utilized to evaluate sleep outcomes instead of the single sleep item on the CDRS-R because of their capacity to capture greater dimensionality of sleep disturbances, particularly hypersomnia.
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2.4 Concurrent Treatments All participants continued to receive their established treatment regimens during the rTMS phase of the study. Psychotherapy was allowed if no change in therapist, type of therapy, or frequency of visits occurred in the 4 weeks prior to or during rTMS. All participants were on stable doses of antidepressant medications and/or previously
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prescribed hypnotics during the course of 30 rTMS treatments. Stimulants,
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antipsychotics, and anticonvulsant mood stabilizers were not allowed during the 6-week
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active treatment period. Participants could undergo changes to medications,
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2.5 rTMS Treatment Protocol
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psychotherapy, or both during the follow-up phase after rTMS treatment had concluded.
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High-frequency rTMS (10-Hz, 120% MT, 3000 stimuli/session in 40-pulse trains with a 26-second inter-train interval) was delivered to the left dorsolateral prefrontal
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cortex (L-DLPFC) in 30 sessions over 6-8 weeks. In trial 1, rTMS was delivered using
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the Neuronetics Model 2100 Therapy System (Neuronetics, Inc., Malvern, PA, USA); in trials 2 and 3, treatments were delivered using the NeuroStar®Therapy System (Neuronetics, Inc., Malvern, PA, USA). One study utilized the 5-cm L-DLPFC localization method (measurement from the area of motor cortex producing maximal abductor pollicis brevis contraction),19 while the other two employed neuroanatomical, magnetic resonance imaging-guided coil targeting of the L-DLPFC for TMS treatment.20 The MT was assessed with a visualization of movement technique. Repeat MT
Journal Pre-proof determinations occurred after every 10 treatments. Ear plugs were used during rTMS sessions to minimize the risk of auditory threshold changes and for participant comfort.
2.6 Statistical Analyses For the primary aim, the effects of rTMS on insomnia and hypersomnia were examined via linear mixed model analyses. Two separate models were constructed
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(one with the QIDS-A17-SR insomnia subscale as dependent variable, the other with the
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QIDS-A17-SR hypersomnia item as dependent variable), each with fixed effects of time
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(representing treatment stage; five levels included baseline, 10 treatments, 20
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treatments, 30 treatments, and 6-month follow-up assessment), depression severity (CDRS-R score), age, and concurrent hypnotic medication use (dichotomized as
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present/absent). The two-tailed significance level was set at α = .05. For models with a
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significant main effect of time, post hoc pairwise comparison of estimated marginal means of sleep outcomes was conducted between baseline and each subsequent time
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point (for a total of four pairwise comparisons), adjusting for multiple comparisons using
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the Šidák correction. Exploratory analyses were conducted to examine the possible influence of rTMS response/nonresponse (for overall depressive symptoms) on sleep outcomes. Separate linear mixed models, with a repeated effect of time, were used to test the main effect of dichotomized response/nonresponse status on the QIDS-A17-SR insomnia and hypersomnia outcomes, again covarying for age and hypnotic medication status. All statistical analyses were performed using IBM SPSS Statistics, Version 25 (IBM Corp., Armonk, NY, USA).
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RESULTS
There were 21 participants enrolled in the three original studies. Four participants withdrew early after 1, 1, 5, and 17 treatment sessions due to difficulty with
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tolerability (3 participants) and emergent suicidal ideation (1 participant)18,20 and were
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not included in this analysis. Demographic and clinical characteristics of the 17
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adolescents who completed the course of rTMS treatment are shown in Table 1.
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Twelve female and 5 male participants with major depression between the ages of 13 and 19 years (mean ± standard deviation, 15.94 ± 1.35 years) were included. At
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baseline, depression severity was high (mean CDRS-R total score, 65.71 ± 8.16). All
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participants remained on antidepressant pharmacotherapy while receiving rTMS, and seven also took a hypnotic medication. Following the completion of rTMS, mean
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depression severity had improved (mean CDRS-R total score, 38.94 ± 13.61). Twelve
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participants were determined to have achieved clinical response (CDRS-R total score < 40) by the end of the rTMS course. Of the 14 participants who returned for the 6month evaluation, depressive symptoms remained lower than at baseline (mean CDRSR total score, 32.71 ± 11.50). Three participants who completed rTMS did not have 6month follow-up data. For sleep disturbance outcomes (QIDS-A17-SR insomnia and hypersomnia subscales), estimated marginal means and standard errors at each time point are reported in Table 2. In the linear mixed model analysis, there was no significant main
Journal Pre-proof effect of time (F4,43.442 = 1.078, p = .379), depression severity (F1,72.130 = 1.386, p = .243), age (F1,14.043 = 1.378, p = .260), or hypnotic medication (F1,13.789 = 0.003, p = .959) on QIDS-A17-SR insomnia subscale scores (Figure 1). However, in the linear mixed model examining the effect of rTMS on hypersomnia, time (treatment stage) had a significant main effect on QIDS-A17-SR hypersomnia scores (F4,46.124 = 2.733, p = .040; Figure 2). Depression severity (F1,71.369 = 0.292, p = .590), age (F1,14.186 = 0.728, p = .408), and
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hypnotic medications (F1,14.060 = 0.066, p = .801) did not have a significant main effect on
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QIDS-A17-SR hypersomnia scores. In pairwise comparisons between baseline and
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subsequent time points, there was a significant reduction in mean hypersomnia score
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between baseline and treatment 10 (padj = .019), and between baseline and 6-month follow-up (padj = .044), although not between baseline and treatment 20 (padj = .053) or
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baseline and treatment 30 (padj = .209).
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In the exploratory sensitivity analyses examining the effect of antidepressant response to rTMS on sleep outcomes, responder status did not have a significant main
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effect on either insomnia (F1,13.156 = 2.109, p = .170) or hypersomnia (F1,13.399 = 1.252,
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p = .283).
4. DISCUSSION
These preliminary data suggest that rTMS may have intrinsic sleep effects apart from its antidepressant effects in depressed adolescents. To our knowledge, this is the
Journal Pre-proof first study to suggest that hypersomnia improves over the course of 30 sessions of high frequency rTMS in adolescents with treatment-resistant depression. Although depressive symptom severity improved in this sample as well, this change appears unrelated to improvement in hypersomnia. Furthermore, improvements in hypersomnia were unrelated to concurrent hypnotic medications.
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4.1 Mechanisms of Insomnia and Hypersomnia in Depression
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Sleep problems are common in depression, and a bidirectional causal
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relationship may exist. Adolescents with insomnia are at increased risk of depression,
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while adolescents with depression have higher rates of sleep problems.26 Sleep disturbances also have been found to be associated with depression severity and
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suicide risk.27 Sleep problems also predict treatment outcomes, as shown by higher
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rates of insomnia in study groups with persistent MDD after treatment. 9,28 The pathophysiology of sleep problems, especially insomnia, in the context of depression
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has been a focus of prior research, but definitive explanations remain elusive.
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Alterations in slow wave activity (SWA) and timing of sleep point to disruption in homeostatic mechanisms. By contrast, changes in sleep structure in depressed individuals, such as REM latency, increase in stage 1 sleep, and early waking, suggest alterations in circadian rhythm as potential mechanisms. The positive effect of sleep deprivation on mood implies that both of these mechanisms could be involved. 29 Involvement of the limbic system and brain stem-thalamic nuclei pathways in both depression and sleep disorders points to a potential shared pathophysiology originating from these neural circuits.30
Journal Pre-proof Depression with hypersomnia is also relatively common and could represent a distinct subtype of MDD.9 Patients with comorbid hypersomnia and MDD have been reported to have greater symptom burden and functional impairment.31 Hypersomnia could represent an important treatment target in patients with MDD and could be an indicator of differential treatment response. One hypothesized explanation for hypersomnia is that as depressed patients have decreased slow wave sleep,
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hypersomnia may compensate for this by extending sleep duration.30 rTMS also might
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improve hypersomnia by increasing SWA,32 thus decreasing need for compensatory
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sleep. Another explanation for the effects of rTMS on sleep is related to neuronal excitability.33 One case report and another case series showed an association between
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improvement in hypersomnia symptoms and increased neuronal excitability.34,35 As
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high frequency rTMS has been shown to increase neuronal excitation,36 significant
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improvement in hypersomnia might be caused by the excitability-enhancing effects of
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high frequency rTMS used in our study.
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4.2 Current Evidence about the Clinical Effects of rTMS on Sleep The clinical utility of rTMS treatment on circadian rhythm and sleep disturbances in MDD in adults is still debated. Evidence on the effects of rTMS on sleep remains equivocal, with rTMS being linked to improved overall sleep37-39 or changes in sleep physiology40 in some studies, as well as having no effect on sleep in others.17,41-44 One recent open-label trial of depressed young adults found that rTMS treatment had no significant effect on sleep as measured by actigraphy.43 To our knowledge, no prior studies have examined the impact of rTMS on sleep in adolescents with depression.
Journal Pre-proof In a study that examined the effect of bilateral low frequency (1-Hz) rTMS over the DLPFC in primary insomnia patients, marked reduction was seen in Pittsburgh Sleep Quality Index (PSQI) scores compared to pre-treatment.33 Another study examined the effect of low frequency (1-Hz) rTMS over the right parietal lobe in patients with comorbid generalized anxiety disorder and insomnia, finding a significant improvement in insomnia symptoms as measured by a reduction in PSQI scores.45 In a
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population of 24 patients with focal epilepsy, low frequency (1-Hz) rTMS application
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over epileptic foci resulted in a significant increase in sleep efficiency and in total sleep
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time.46 This study also showed a significant decrease in sleep latency and number of
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awakenings as measured by polysomnography (PSG).46 5-Hz rTMS application over bilateral parietal cortices in Parkinson’s disease patients resulted in significant
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improvement in sleep fragmentation and sleep efficiency, along with a significant
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decrease in the average duration of nocturnal awakenings. This change was not related to changes in mood or motor symptoms.47
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By contrast, a double-blind
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randomized controlled study examining the effect of 10-Hz, 3000 pulses/session rTMS
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to the L-DLPFC for depression found no significant difference between sham and active TMS groups in sleep factors on the Hamilton Depression Rating Scale (HDRS) at 10, 20, and 30 treatments.14 Another randomized controlled study that examined the effect of high frequency rTMS (10-Hz, 3000 pulses/session, L-DLPFC) on MDD found no significant difference between sham and active TMS groups in sleep factors on the HDRS and Inventory of Depressive Symptomology-Self Rated (IDS-SR) scales at any point during the treatment.17
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4.3 Possible Mechanisms for the Effects of rTMS on Sleep The exact mechanisms involved in the impact of rTMS on sleep are unknown. Several hypotheses examine the potential roles of neuroplasticity, neuroendocrinological systems, neurotransmitters, neural circuitry, and sleep architecture. One study showed that bilateral low frequency (1-Hz) rTMS application
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over the DLPFC resulted in significant improvement in insomnia, which was negatively
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correlated with γ-aminobutyric acid (GABA) and brain-derived neurotrophic factor
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(BDNF) levels and positively correlated with motor evoked potentials.33 A
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neuroendocrinological explanation for how rTMS regulates sleep is supported by findings from a study in which stage 3 sleep was significantly improved by application of
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rTMS over the right DLPFC, compared to medication and psychotherapy control groups.
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The investigators found that rTMS decreased levels of thyroid hormones, adrenocorticotropic hormone, and thyroid stimulating hormone.49 Decreased activity in
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hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes might also
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mediate the effects of rTMS on sleep.49 From a cognitive processing perspective, one study suggested that low frequency rTMS applied to the right parietal cortex may inhibit negative attentional bias and thus improve insomnia.45 Another study showed that rTMS alters sleep architecture by increasing SWA.32 SWA is thought to be a reliable index of sleep homeostasis, as it increases and decreases in relation to increased and decreased sleep need.50 The effect of rTMS on SWA is hypothesized to be mediated by long-term potentiation,32 which reflects glutamatergic neural transmission.
Journal Pre-proof Additionally, the application of rTMS has been found to delay onset of rapid eye movement (REM) and prolong non-REM to REM cycle length.51
4.4 Limitations Interpretation of the present findings must be placed in the context of the limitations of an open-label trial of high frequency rTMS and a relatively small sample
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size. One potential confound of our study was that participants were permitted to
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continue psychotherapy for clinical reasons. Although few participants did so, and the
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modalities of therapy were diverse, future rTMS studies should endeavor to control for the potential impact of therapy in sleep and other outcomes, particularly for cognitive-
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behavioral therapy, which has been shown to have impact on insomnia. 52-54 Similarly,
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some participants in our study utilized hypnotic medications with a variety of
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neurochemical mechanisms. Although we controlled for presence or absence of hypnotic medication in our analyses, definitive studies on the effects of rTMS on sleep
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should consider eliminating hypnotic medication during rTMS or limiting to medications
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of a single mechanistic class and controlling statistically by calculating dose equivalents. Additionally, this retrospective analysis utilized self-report measures of sleep outcomes, including a one-item measure of hypersomnia. Future work on the effects of rTMS on sleep should employ quantitative and objective measures, such as polysomnography, and more rigorous clinical measures of sleep quality. It is important to note that this was an exploratory study, and future adequately-powered, sham-controlled studies will be critical for definitive conclusions.
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5. CONCLUSIONS In summary, rTMS was found to decrease hypersomnia, but not to improve insomnia, in adolescents with major depression, independent of concurrent hypnotic medications and depressive symptom improvement. Future work should include larger sample sizes, randomization with sham controls, and objective, quantitative
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measurements of sleep architecture to assess the sleep effects of rTMS in depressed
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adolescents. Future studies should also examine the effect of different rTMS dosing
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parameters and the ensuing clinical and neurophysiological effects on sleep.
Journal Pre-proof ABBREVIATIONS BDNF: brain-derived neurotrophic factor CDRS-R: Children’s Depression Rating Scale, Revised DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision FDA: U.S. Food and Drug Administration
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GABA: γ-aminobutyric acid
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HDRS: Hamilton Depression Rating Scale
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IDS-SR: Inventory of Depressive Symptomology-Self Rated
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K-SADS-PL: Schedule for Affective Disorders and Schizophrenia for School Aged Children – Present and Lifetime Version
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MDD: major depressive disorder
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L-DLPFC: left dorsolateral prefrontal cortex
MT: motor threshold
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Non-REM: non-rapid eye movement
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PSG: polysomnography
PSQI: Pittsburgh Sleep Quality Index QIDS-A17-SR: Quick Inventory of Depressive Symptomatology – Adolescent (17 Item) – Self Report REM: rapid eye movement rTMS: repetitive transcranial magnetic stimulation SWA: slow wave activity TMS: transcranial magnetic stimulation
Journal Pre-proof FIGURE TITLES AND CAPTIONS
Figure 1. Changes in Insomnia with rTMS. QIDS-A17-SR insomnia subscale scores plotted across clinical assessment time points during course of 30 high frequency rTMS treatments. Scores are estimated marginal means from the linear mixed model with fixed effects of time (representing rTMS treatment stage), depression severity (CDRS-R
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total score), age, and hypnotic medication use (present/absent). Error bars represent
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95% confidence intervals.
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Figure 2. Changes in Hypersomnia with rTMS. QIDS-A17-SR hypersomnia scores plotted across clinical assessment time points during course of 30 high frequency rTMS
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treatments. Scores are estimated marginal means from the linear mixed model with
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fixed effects of time (representing rTMS treatment stage), depression severity (CDRS-R total score), age, and hypnotic medication use (present/absent). Pairwise comparisons
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between time points with significant differences in mean hypersomnia scores are shown
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with adjusted p-values. Error bars represent 95% confidence intervals.
Journal Pre-proof TABLE TITLES
Table 1. Participant Characteristics and Clinical Outcomes.
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Table 2. Changes in Insomnia and Hypersomnia with rTMS.
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O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208-1216. https://doi.org/10.1016/j.biopsych.2007.01.018.
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George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010;67:507-516. https://doi.org/10.1001/archgenpsychiatry.2010.46.
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Croarkin PE, MacMaster FP. Transcranial magnetic stimulation for adolescent depression. Child Adolesc Psychiatr Clin N Am. 2019;28:33-43. https://doi.org/10.1016/j.chc.2018.07.003 .
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Rosenquist PB, Krystal A, Heart KL, Demitrack MA, McCall WV. Left dorsolateral prefrontal transcranial magnetic stimulation (TMS): sleep factor changes during treatment in patients with pharmacoresistant major depressive disorder. Psychiatry Res. 2013;205:67-73. https://doi.org/10.1016/j.psychres.2012.09.011.
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Wall CA, Croarkin PE, Sim LA, et al. Adjunctive use of repetitive transcranial magnetic stimulation in depressed adolescents: a prospective, open pilot study. J Clin Psychiatry. 2011;72:1263-1269. https://doi.org/10.4088/JCP.11m07003.
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Wall CA, Croarkin PE, McClintock SM, et al. Neurocognitive effects of repetitive transcranial magnetic stimulation in adolescents with major depressive disorder. Front Psychiatry. 2013;4:165. https://doi.org/10.3389/fpsyt.2013.00165.
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Wall CA, Croarkin PE, Maroney-Smith MJ, et al. Magnetic resonance imagingguided, open-label, high-frequency repetitive transcranial magnetic stimulation for adolescents with major depressive disorder. J Child Adolesc Psychopharmacol. 2016;26:582-589. https://doi.org/10.1089/cap.2015.0217.
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Thase ME, Simons AD, Reynolds III CF. Abnormal electroencephalographic sleep profiles in major depression: association with response to cognitive behavior therapy. Arch Gen Psychiatry. 1996;53:99-108. https://doi.org/10.1001/archpsyc.1996.01830020013003
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Thase ME. Depression and sleep: pathophysiology and treatment. Dialogues Clin Neurosci. 2006;8:217-226.
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Huber R, Esser SK, Ferrarelli F, Massimini M, Peterson MJ, Tononi G. TMSinduced cortical potentiation during wakefulness locally increases slow wave activity during sleep. PLoS ONE. 2007;2:e276. https://doi.org/10.1371/journal.pone.0000276.
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Trotti LM, Saini P, Freeman AA, et al. Improvement in daytime sleepiness with clarithromycin in patients with GABA-related hypersomnia: clinical experience. J Psychopharmacol (Oxf). 2013;28:697-702. https://doi.org/10.1177/0269881113515062.
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Frase L, Maier JG, Zittel S, et al. Bifrontal anodal transcranial direct current stimulation (tDCS) improves daytime vigilance and sleepiness in a patient with organic hypersomnia following reanimation. Brain Stimul. 2015;8:844-846. https://doi.org/10.1016/j.brs.2015.05.009.
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Pascual-Leone A, Tormos JM, Keenan J, Tarazona F, Cañete C, Catalá MD. Study and modulation of human cortical excitability with transcranial magnetic stimulation. J Clin Neurophysiol. 1998;15:333-343. https://doi.org/10.1097/00004691-199807000-00005.
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Brakemeier E-L, Luborzewski A, Danker-Hopfe H, Kathmann N, Bajbouj M. Positive predictors for antidepressive response to prefrontal repetitive transcranial magnetic stimulation (rTMS). J Psychiatr Res. 2007;41:395-403. https://doi.org/10.1016/j.jpsychires.2006.01.013.
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Nishida M, Kikuchi S, Nisijima K, Suda S. Actigraphy in patients with major depressive disorder undergoing repetitive transcranial magnetic stimulation: an open label pilot study. J ECT. 2017;33:36-42. https://doi.org/10.1097/yct.0000000000000352.
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Pellicciari MC, Cordone S, Marzano C, et al. Dorsolateral prefrontal transcranial magnetic stimulation in patients with major depression locally affects alpha power of REM sleep. Front Hum Neurosci. 2013;7:433. https://doi.org/10.3389/fnhum.2013.00433.
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Saeki T, Nakamura M, Hirai N, et al. Localized potentiation of sleep slow-wave activity induced by prefrontal repetitive transcranial magnetic stimulation in patients with a major depressive episode. Brain Stimul. 2013;6:390-396. https://doi.org/10.1016/j.brs.2012.08.004.
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Antczak JM, Poleszczyk A, Wichniak A, Rakowicz M, Parnowski TJ. The influence of the repetitive transcranial magnetic stimulation on sleep quality in depression. Psychiatr Pol. 2017;51:845-857. https://doi.org/10.12740/pp/68503.
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Brakemeier E-L, Wilbertz G, Rodax S, et al. Patterns of response to repetitive transcranial magnetic stimulation (rTMS) in major depression: replication study in drug-free patients. J Affect Disord. 2008;108:59-70. https://doi.org/10.1016/j.jad.2007.09.007.
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Lowe A, Rajaratnam SM, Hoy K, Taffe J, Fitzgerald PB. Can sleep disturbance in depression predict repetitive transcranial magnetic stimulation (rTMS) treatment response? Psychiatry Res. 2013;210:121-126. https://doi.org/10.1016/j.psychres.2013.04.028.
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Huang Z, Li Y, Bianchi MT, et al. Repetitive transcranial magnetic stimulation of the right parietal cortex for comorbid generalized anxiety disorder and insomnia: a randomized, double-blind, sham-controlled pilot study. Brain Stimul. 2018. https://doi.org/10.1016/j.brs.2018.05.016.
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Sánchez-Escandón O, Arana-Lechuga Y, Terán-Pérez G, et al. Effect of lowfrequency repetitive transcranial magnetic stimulation on sleep pattern and quality of life in patients with focal epilepsy. Sleep Med. 2016;20:37-40. https://doi.org/10.1016/j.sleep.2015.11.022.
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van Dijk KD, Møst EIS, Van Someren EJW, Berendse HW, van der Werf YD. Beneficial effect of transcranial magnetic stimulation on sleep in Parkinson's disease. Mov Disord. 2009;24:878-884. https://doi.org/10.1002/mds.22462.
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Park EJ, Lee SJ, Koh DY, Han YM. Repetitive transcranial magnetic stimulation to treat depression and insomnia with chronic low back pain. Korean J Pain. 2014;27:285-289. https://doi.org/10.3344/kjp.2014.27.3.285.
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Jiang C-g, Zhang T, Yue F-g, Yi M-l, Gao D. Efficacy of repetitive transcranial magnetic stimulation in the treatment of patients with chronic primary insomnia. Cell Biochem Biophys. 2013;67:169-173. https://doi.org/10.1007/s12013-0139529-4.
50.
Greene RW, Frank MG. Slow wave activity during sleep: functional and therapeutic implications. Neuroscientist. 2010;16:618-633. https://doi.org/10.1177/1073858410377064.
51.
Cohrs S, Tergau F, Riech S, et al. High-frequency repetitive transcranial magnetic stimulation delays rapid eye movement sleep. Neuroreport. 1998;9:3439-3443. https://doi.org/10.1097/00001756-199810260-00019.
52.
Trauer JM, Qian MY, Doyle JS, Rajaratnam SM, Cunnington D. Cognitive behavioral therapy for chronic insomnia: a systematic review and meta-analysis. Ann Intern Med. 2015;163:191-204. https://doi.org/10.7326/m14-2841.
53.
van Straten A, van der Zweerde T, Kleiboer A, Cuijpers P, Morin CM, Lancee J. Cognitive and behavioral therapies in the treatment of insomnia: a meta-analysis. Sleep Med Rev. 2018;38:3-16. https://doi.org/10.1016/j.smrv.2017.02.001.
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Dewald-Kaufmann J, de Bruin E, Michael G. Cognitive behavioral therapy for insomnia (CBT-i) in school-aged children and adolescents. Sleep Med Clin. 2019;14:155-165. https://doi.org/10.1016/j.jsmc.2019.02.002 .
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54.
Sex
CDRS-R Total Score
PrerTMS 1
Posta rTMS 1
67
25
Yes
6
2
1
0
melatonin, eszopiclone
citalopram 40 mg
F
75
36
Yes
2
1
3
2
none
escitalopram 20 mg
F
71
41
No
3
2
1
0
none
citalopram 40 mg
F
61
33
Yes
4
3
0
0
none
sertraline 100 mg
F
70
34
Yes
1
0
2
1
melatonin
escitalopram 20 mg
F
59
38
Yes
6
2
2
2
melatonin
citalopram 40 mg
M
62
28
Yes
4
5
2
1
melatonin
sertraline 100 mg
F
61
32
Yes
5
3
1
0
none
fluoxetine 20 mg
F
65
26
Yes
7
6
1
1
melatonin, diphenhydramine
escitalopram 20 mg
M
79
46
No
2
6
2
2
none
mirtazapine 45 mg
M
49
35
Yes
1
1
3
3
none
desvenlafaxine 100
M
60
37
Yes
4
4
3
2
none
milnacipran 100 mg
F
68
37
Yes
9
4
0
0
none
escitalopram 10 mg
F
82
68
No
5
4
0
0
diphenhydramine
desvenlafaxine 50 m
F
63
60
No
F
67
65
No
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Yes
Posta rTMS 2
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M
Concurrent Medication(s)
PrerTMS 3
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Posta rTMS 21
QIDS-A17-SR Hypersomnia
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F
PrerTMS 58
QIDS-A17-SR Insomnia
Antidepressant Response to b rTMS
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y)
Journal Pre-proof
Hypnotic melatonin
Antidepressant Daily Dose fluoxetine 30 mg
7
5
1
0
none
escitalopram 5 mg
6
6
0
0
none
sertraline 50 mg
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ur
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tions: CDRS-R, Children’s Depression Rating Scale, Revised; QIDS-A 17-SR, Quick Inventory of Depressive Symptomatology – Adolescent (17 Item) – Self Report; rTMS, repe anial magnetic stimulation. mmediately follow ing conclusion of 30 treatments of rTMS. for clinical response defined as having a post-rTMS CDRS-R total score < 40.
Journal Pre-proof Estimated Marginal Mean ± SE rTMS Treatment 10
rTMS Treatment 20
rTMS Treatment 30
6-month Follow-Up
Insomnia
3.971 ± 0.621
3.516 ± 0.507
3.807 ± 0.501
3.509 ± 0.527
2.816 ± 0.576
Hypersomnia
1.435 ± 0.287
0.846 ± 0.245
0.743 ± 0.243
0.839 ± 0.253
0.559 ± 0.269
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Baseline
QIDS-A17-SR subscale
Journal Pre-proof ETHICAL STATEMENT
All study procedures were approved by the local institutional review boards. Informed consent was provided by minor participants’ parents or guardians, with adolescents providing written assent, while adult participants age 18 or older provided written
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informed consent.
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CONFLICTS OF INTEREST
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Financial support (presence or absence): Research reported in this publication was
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supported by the National Institutes of Health under award R01 MH113700 (Dr. Croarkin). The content of this publication is solely the responsibility of the authors and
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does not necessarily represent the official views of the National Institutes of Health.
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Neuronetics, Inc. provided equipment support for the study. Role of the Sponsor: The
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supporters had no role in the design, analysis, interpretation, or publication of the study.
Conflict of interest: Dr. Croarkin has received research grant support from Pfizer, Inc.; equipment support from Neuronetics, Inc.; and received supplies and genotyping services from Assurex Health, Inc. for investigator-initiated studies. He is the primary investigator for a multicenter study funded by Neuronetics, Inc. and a site primary investigator for a study funded by NeoSync, Inc. Dr. Croarkin is a paid consultant for Procter & Gamble Company. Dr. Lewis receives research support from the Brain and
Journal Pre-proof Behavior Research Foundation and has served as a site co-investigator on multicenter trials funded by Neuronetics, Inc. and NeoSync, Inc. The other authors have no
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disclosures or potential conflicts of interest to declare.
Journal Pre-proof HIGHLIGHTS
3. Current Knowledge: Sleep disturbance is a common and incompletely understood symptom impacting the functioning of adolescents with depression. There are limited interventions that address sleep disturbances in depression, and often treatment (i.e., antidepressant medications) has an adverse effect on
of
sleep architecture.
ro
4. Study Impact: Recent research has examined the safety and clinical effects of
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repetitive transcranial magnetic stimulation (rTMS) for depression in adolescents.
re
This open-label, pilot study examined the potential impact of rTMS on insomnia and hypersomnia in a sample of adolescents with treatment-resistant depression
Jo
ur
na
lP
and found that rTMS results in an improvement in hypersomnia.
Figure 1
Figure 2
A. Irem Sonmez, M. Utku Kucuker, Charles P. Lewis, Bhanu Prakash Kolla, Deniz Doruk Camsari, Jennifer L. Vande Voort, Kathryn M. Schak, Simon Kung, Paul E. Croarkin PII:
S0278-5846(19)30550-0
DOI:
https://doi.org/10.1016/j.pnpbp.2019.109763
Reference:
PNP 109763
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date:
5 July 2019
Revised date:
13 September 2019
Accepted date:
18 September 2019
Please cite this article as: A.I. Sonmez, M.U. Kucuker, C.P. Lewis, et al., Improvement in hypersomnia with high frequency repetitive transcranial magnetic stimulation in depressed adolescents: Preliminary evidence from an open-label study, Progress in Neuropsychopharmacology & Biological Psychiatry(2018), https://doi.org/10.1016/ j.pnpbp.2019.109763
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2018 Published by Elsevier.
Journal Pre-proof [Category: Original Article] Improvement in Hypersomnia with High Frequency Repetitive Transcranial Magnetic Stimulation in Depressed Adolescents: Preliminary Evidence from an Open-Label Study
A. Irem Sonmez, MD 1* M. Utku Kucuker, MD 1*
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Charles P. Lewis, MD 1
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Bhanu Prakash Kolla, MD, MRCPsych1,2
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Deniz Doruk Camsari, MD1 Jennifer L. Vande Voort, MD1
Simon Kung, MD1
1
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Author Affiliations:
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Paul E. Croarkin, DO, MSCS1†
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Kathryn M. Schak, MD1
2
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Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA Center for Sleep Medicine, Mayo Clinic, Rochester, Minnesota, USA
*
Authors contributed equally.
†
Reprints: Paul E. Croarkin, DO, MSCS, Department of Psychiatry and Psychology,
Mayo Clinic, 200 First St SW, Rochester, MN 55905 Email: [email protected] Telephone: (507) 293-2557 Fax: (507) 293-3933
Journal Pre-proof Abstract word count: 247 Brief Summary word count: 96 Text word count: 3,030
No. of tables: 2
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No. of figures: 2
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All authors have seen and approved the manuscript.
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Declarations for each author:
Financial support (presence or absence): Research reported in this publication was
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supported by the National Institutes of Health under award R01 MH113700 (Dr.
na
Croarkin). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
ur
Neuronetics, Inc. provided equipment support for the study. Role of the Sponsor: The
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supporters had no role in the design, analysis, interpretation, or publication of the study. Conflict of interest: Dr. Croarkin has received research grant support from Pfizer, Inc.; equipment support from Neuronetics, Inc.; and received supplies and genotyping services from Assurex Health, Inc. for investigator-initiated studies. He is the primary investigator for a multicenter study funded by Neuronetics, Inc. and a site primary investigator for a study funded by NeoSync, Inc. Dr. Croarkin is a paid consultant for Procter & Gamble Company. Dr. Lewis receives research support from the Brain and Behavior Research Foundation and has served as a site co-investigator on multicenter
Journal Pre-proof trials funded by Neuronetics, Inc. and NeoSync, Inc. The other authors have no disclosures or potential conflicts of interest to declare.
Running title: Reduced hypersomnia with rTMS in depressed adolescents
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Clinical Trial Registry:
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Clinicaltrials.gov Identifiers: NCT00587639, NCT01502033, NCT01804270
Journal Pre-proof ABSTRACT
Study Objectives Sleep disruption is a significant symptom of major depressive disorder (MDD). To our knowledge, no prior work has examined the impact of repetitive transcranial magnetic stimulation (rTMS) on sleep disturbances in adolescents with MDD.
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Methods
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Seventeen adolescents with treatment-resistant depression received 30 daily sessions
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of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex (L-DLPFC). Clinical
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symptoms were assessed at baseline; after 10, 20, and 30 treatments; and at a 6-month follow-up visit. Insomnia was measured with a 3-item subscale of the Quick Inventory of
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Depressive Symptomatology – Adolescent (17 Item) – Self Report (QIDS-A17-SR).
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Hypersomnia was measured with a single QIDS-A17-SR item. Depression severity was rated with the Children’s Depression Rating Scale, Revised (CDRS-R). The effect of
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rTMS on sleep was examined via linear mixed model analyses, with fixed effects of time
Results
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(as a proxy of treatment), depression severity, age, and hypnotic medication use.
No significant main effect of time was observed on the insomnia subscale (F4,43.442 = 1.078, p = .379). However, there was a significant main effect of time on the QIDS-A17-SR hypersomnia score (F4,46.124 = 2.733, p = .040), with significant improvement from baseline to treatment 10 (padj = .019) and from baseline to 6-month follow-up (padj = .044). In exploratory sensitivity analyses, response/nonresponse to rTMS for overall depressive symptoms had no significant effect on sleep outcomes.
Journal Pre-proof Conclusions rTMS may have intrinsic effects on hypersomnia apart from its antidepressant effects in depressed adolescents. Future work should utilize sham controls and objective, quantitative measurements of sleep architecture to assess effects of rTMS in depressed
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adolescents.
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Keywords:
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Adolescent; depression; hypersomnia; insomnia; repetitive transcranial magnetic
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stimulation (rTMS).
Journal Pre-proof HIGHLIGHTS
1. Current Knowledge: Sleep disturbance is a common and incompletely understood symptom impacting the functioning of adolescents with depression. There are limited interventions that address sleep disturbances in depression, and often treatment (i.e., antidepressant medications) has an adverse effect on
of
sleep architecture.
ro
2. Study Impact: Recent research has examined the safety and clinical effects of
-p
repetitive transcranial magnetic stimulation (rTMS) for depression in adolescents.
re
This open-label, pilot study examined the potential impact of rTMS on insomnia and hypersomnia in a sample of adolescents with treatment-resistant depression
Jo
ur
na
lP
and found that rTMS results in an improvement in hypersomnia.
Journal Pre-proof 1. INTRODUCTION
Insomnia, non-restorative sleep, and hypersomnia are common symptoms of major depressive disorder (MDD), with 80% of depressed patients reporting some form of sleep disruption.1 This may be a particularly important target for intervention for adolescents, who have increased sleep requirements.2 Sleep also plays an essential
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role in cognitive development.3 A recent meta-analysis of 19 studies in children aged 5-
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13 years found that longer sleep durations were associated with better cognitive
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functioning, including memory, attention, processing speed, and intelligence.4 Sleep in children has an important function in daytime performance and healthy cognitive
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development.5-7
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Sleep problems during childhood are likely a risk factor8 or initial symptom of
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depression among adolescents.9,10 Additionally, insomnia or hypersomnia may serve as early markers of depression relapse. Insufficient sleep may also be a risk factor for
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increased suicidal ideation in adolescents 11 as well as adults.12 Thus, sleep
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disturbances in the context of depression may have diagnostic, pathophysiological, and therapeutic significance.
Repetitive transcranial magnetic stimulation (rTMS) involves the stimulation of cortical neurons with magnetic pulses and is now widely available as a clinical treatment for adults. Current TMS treatments cleared by the U.S. Food and Drug Administration (FDA) typically involve 5 daily treatments per week, for 4 to 6 weeks, with 10-Hz, 120% motor threshold (MT) stimulation applied to the left dorsolateral prefrontal cortex (LDLPFC).13 rTMS is now an established FDA-approved treatment for MDD in adults14,15
Journal Pre-proof and a promising (but not FDA-approved) treatment for depression in youth,16 although its effects on sleep are largely unknown in this population. Preliminary studies have examined the impact of rTMS on sleep in adults.17 To our knowledge, no prior work has examined the impact of rTMS on sleep disturbances in adolescents with MDD. This exploratory post hoc analysis aimed to examine the impact of high frequency rTMS on sleep disturbances in a sample of 17 outpatient adolescents (ages
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13-19) with treatment-resistant MDD who were treated concurrently with antidepressant
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medication. We examined sleep as an outcome distinct from depression severity in
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view of both the clinical significance of sleep disturbance and the fact that sleep
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problems may not necessarily align with overall depression severity. We hypothesized that clinical measures of insomnia and hypersomnia would improve over the course of
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2. METHODS
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treatment with rTMS.
2.1 Overview Data for the present study were pooled from 3 protocols (NCT00587639, NCT01502033, NCT01804270) with consistent methodology in providing open-label, adjunctive rTMS for adolescents with treatment-resistant depression. The three trials utilized similar rTMS devices, coil localization procedures, and identical stimulation parameters. All participants were outpatients who were taking antidepressant
Journal Pre-proof medications concurrently. Results of antidepressant and neurocognitive outcomes from these trials have been published previously.18-20 All study procedures were approved by the local institutional review boards. Informed consent was provided by minor participants’ parents or guardians, with adolescents providing written assent, while adult participants age 18 or older provided written informed consent.
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2.2 Study Participants
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Participants were recruited from clinic and community referrals. Eligible
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participants were adolescents between the ages of 13 and 19 years with a current diagnosis of MDD according to Diagnostic and Statistical Manual of Mental Disorders,
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Fourth Edition, Text Revision (DSM-IV-TR) criteria,21 and with history of at least one
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failed antidepressant trial as defined by the Antidepressant Treatment History Form
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(ATHF).22 The Children’s Depression Rating Scale, Revised (CDRS-R),23 a 17-item clinician-rated scale incorporating reports from both parent and adolescent, was utilized
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to assess depressive symptom severity. For eligibility, participants required a score of
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40 or greater at study entry. Exclusion criteria consisted of diagnoses of schizophrenia, schizoaffective disorder, bipolar spectrum disorder, substance abuse or dependence, somatoform disorders, dissociative disorders, posttraumatic stress disorder, obsessivecompulsive disorder, eating disorders, mental retardation, seizure disorders, or other neurologic conditions. All participants received urine pregnancy and toxicology screens; negative toxicology results (and a negative pregnancy test for female participants) were necessary for enrollment. General TMS safety criteria, including but not limited to the
Journal Pre-proof absence of a seizure history and absence of metal objects around the head and neck area, were required for enrollment.
2.3 Clinical Assessments Participants were interviewed by a board-certified child and adolescent psychiatrist. The baseline assessments included comprehensive clinical evaluation and
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semi-structured diagnostic interview with the Schedule for Affective Disorders and
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Schizophrenia for School Aged Children – Present and Lifetime Version (K-SADS-PL).24
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Clinical symptoms were assessed at baseline, at 10, 20, and 30 treatments, and
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at a 6-month follow-up visit. Depression severity was rated with the CDRS-R.23 The summary raw score was used as the measure of depression severity. Clinical response
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was defined as a CDRS-R score less than 40 at the end of 30 treatments. Insomnia
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was measured with a 3-item subscale of the Quick Inventory of Depressive Symptomatology – Adolescent (17 Item) – Self Report (QIDS-A17-SR),25 a patient-
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completed questionnaire of depressive symptoms. The subscale included items
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assessing difficulty falling asleep, sleep restlessness and middle insomnia, and early awakening (see supplemental materials); each item is rated on an ordinal scale of 0 to 3, for an insomnia subscale with a potential range of 0 to 9. A separate QIDS-A17-SR item specifically assessing hypersomnia (ordinal scale, range 0 to 3; see supplemental materials) was treated as a separate outcome variable. QIDS-A17-SR sleep items were utilized to evaluate sleep outcomes instead of the single sleep item on the CDRS-R because of their capacity to capture greater dimensionality of sleep disturbances, particularly hypersomnia.
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2.4 Concurrent Treatments All participants continued to receive their established treatment regimens during the rTMS phase of the study. Psychotherapy was allowed if no change in therapist, type of therapy, or frequency of visits occurred in the 4 weeks prior to or during rTMS. All participants were on stable doses of antidepressant medications and/or previously
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prescribed hypnotics during the course of 30 rTMS treatments. Stimulants,
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antipsychotics, and anticonvulsant mood stabilizers were not allowed during the 6-week
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active treatment period. Participants could undergo changes to medications,
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2.5 rTMS Treatment Protocol
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psychotherapy, or both during the follow-up phase after rTMS treatment had concluded.
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High-frequency rTMS (10-Hz, 120% MT, 3000 stimuli/session in 40-pulse trains with a 26-second inter-train interval) was delivered to the left dorsolateral prefrontal
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cortex (L-DLPFC) in 30 sessions over 6-8 weeks. In trial 1, rTMS was delivered using
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the Neuronetics Model 2100 Therapy System (Neuronetics, Inc., Malvern, PA, USA); in trials 2 and 3, treatments were delivered using the NeuroStar®Therapy System (Neuronetics, Inc., Malvern, PA, USA). One study utilized the 5-cm L-DLPFC localization method (measurement from the area of motor cortex producing maximal abductor pollicis brevis contraction),19 while the other two employed neuroanatomical, magnetic resonance imaging-guided coil targeting of the L-DLPFC for TMS treatment.20 The MT was assessed with a visualization of movement technique. Repeat MT
Journal Pre-proof determinations occurred after every 10 treatments. Ear plugs were used during rTMS sessions to minimize the risk of auditory threshold changes and for participant comfort.
2.6 Statistical Analyses For the primary aim, the effects of rTMS on insomnia and hypersomnia were examined via linear mixed model analyses. Two separate models were constructed
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(one with the QIDS-A17-SR insomnia subscale as dependent variable, the other with the
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QIDS-A17-SR hypersomnia item as dependent variable), each with fixed effects of time
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(representing treatment stage; five levels included baseline, 10 treatments, 20
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treatments, 30 treatments, and 6-month follow-up assessment), depression severity (CDRS-R score), age, and concurrent hypnotic medication use (dichotomized as
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present/absent). The two-tailed significance level was set at α = .05. For models with a
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significant main effect of time, post hoc pairwise comparison of estimated marginal means of sleep outcomes was conducted between baseline and each subsequent time
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point (for a total of four pairwise comparisons), adjusting for multiple comparisons using
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the Šidák correction. Exploratory analyses were conducted to examine the possible influence of rTMS response/nonresponse (for overall depressive symptoms) on sleep outcomes. Separate linear mixed models, with a repeated effect of time, were used to test the main effect of dichotomized response/nonresponse status on the QIDS-A17-SR insomnia and hypersomnia outcomes, again covarying for age and hypnotic medication status. All statistical analyses were performed using IBM SPSS Statistics, Version 25 (IBM Corp., Armonk, NY, USA).
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RESULTS
There were 21 participants enrolled in the three original studies. Four participants withdrew early after 1, 1, 5, and 17 treatment sessions due to difficulty with
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tolerability (3 participants) and emergent suicidal ideation (1 participant)18,20 and were
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not included in this analysis. Demographic and clinical characteristics of the 17
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adolescents who completed the course of rTMS treatment are shown in Table 1.
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Twelve female and 5 male participants with major depression between the ages of 13 and 19 years (mean ± standard deviation, 15.94 ± 1.35 years) were included. At
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baseline, depression severity was high (mean CDRS-R total score, 65.71 ± 8.16). All
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participants remained on antidepressant pharmacotherapy while receiving rTMS, and seven also took a hypnotic medication. Following the completion of rTMS, mean
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depression severity had improved (mean CDRS-R total score, 38.94 ± 13.61). Twelve
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participants were determined to have achieved clinical response (CDRS-R total score < 40) by the end of the rTMS course. Of the 14 participants who returned for the 6month evaluation, depressive symptoms remained lower than at baseline (mean CDRSR total score, 32.71 ± 11.50). Three participants who completed rTMS did not have 6month follow-up data. For sleep disturbance outcomes (QIDS-A17-SR insomnia and hypersomnia subscales), estimated marginal means and standard errors at each time point are reported in Table 2. In the linear mixed model analysis, there was no significant main
Journal Pre-proof effect of time (F4,43.442 = 1.078, p = .379), depression severity (F1,72.130 = 1.386, p = .243), age (F1,14.043 = 1.378, p = .260), or hypnotic medication (F1,13.789 = 0.003, p = .959) on QIDS-A17-SR insomnia subscale scores (Figure 1). However, in the linear mixed model examining the effect of rTMS on hypersomnia, time (treatment stage) had a significant main effect on QIDS-A17-SR hypersomnia scores (F4,46.124 = 2.733, p = .040; Figure 2). Depression severity (F1,71.369 = 0.292, p = .590), age (F1,14.186 = 0.728, p = .408), and
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hypnotic medications (F1,14.060 = 0.066, p = .801) did not have a significant main effect on
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QIDS-A17-SR hypersomnia scores. In pairwise comparisons between baseline and
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subsequent time points, there was a significant reduction in mean hypersomnia score
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between baseline and treatment 10 (padj = .019), and between baseline and 6-month follow-up (padj = .044), although not between baseline and treatment 20 (padj = .053) or
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baseline and treatment 30 (padj = .209).
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In the exploratory sensitivity analyses examining the effect of antidepressant response to rTMS on sleep outcomes, responder status did not have a significant main
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effect on either insomnia (F1,13.156 = 2.109, p = .170) or hypersomnia (F1,13.399 = 1.252,
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p = .283).
4. DISCUSSION
These preliminary data suggest that rTMS may have intrinsic sleep effects apart from its antidepressant effects in depressed adolescents. To our knowledge, this is the
Journal Pre-proof first study to suggest that hypersomnia improves over the course of 30 sessions of high frequency rTMS in adolescents with treatment-resistant depression. Although depressive symptom severity improved in this sample as well, this change appears unrelated to improvement in hypersomnia. Furthermore, improvements in hypersomnia were unrelated to concurrent hypnotic medications.
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4.1 Mechanisms of Insomnia and Hypersomnia in Depression
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Sleep problems are common in depression, and a bidirectional causal
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relationship may exist. Adolescents with insomnia are at increased risk of depression,
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while adolescents with depression have higher rates of sleep problems.26 Sleep disturbances also have been found to be associated with depression severity and
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suicide risk.27 Sleep problems also predict treatment outcomes, as shown by higher
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rates of insomnia in study groups with persistent MDD after treatment. 9,28 The pathophysiology of sleep problems, especially insomnia, in the context of depression
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has been a focus of prior research, but definitive explanations remain elusive.
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Alterations in slow wave activity (SWA) and timing of sleep point to disruption in homeostatic mechanisms. By contrast, changes in sleep structure in depressed individuals, such as REM latency, increase in stage 1 sleep, and early waking, suggest alterations in circadian rhythm as potential mechanisms. The positive effect of sleep deprivation on mood implies that both of these mechanisms could be involved. 29 Involvement of the limbic system and brain stem-thalamic nuclei pathways in both depression and sleep disorders points to a potential shared pathophysiology originating from these neural circuits.30
Journal Pre-proof Depression with hypersomnia is also relatively common and could represent a distinct subtype of MDD.9 Patients with comorbid hypersomnia and MDD have been reported to have greater symptom burden and functional impairment.31 Hypersomnia could represent an important treatment target in patients with MDD and could be an indicator of differential treatment response. One hypothesized explanation for hypersomnia is that as depressed patients have decreased slow wave sleep,
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hypersomnia may compensate for this by extending sleep duration.30 rTMS also might
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improve hypersomnia by increasing SWA,32 thus decreasing need for compensatory
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sleep. Another explanation for the effects of rTMS on sleep is related to neuronal excitability.33 One case report and another case series showed an association between
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improvement in hypersomnia symptoms and increased neuronal excitability.34,35 As
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high frequency rTMS has been shown to increase neuronal excitation,36 significant
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improvement in hypersomnia might be caused by the excitability-enhancing effects of
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high frequency rTMS used in our study.
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4.2 Current Evidence about the Clinical Effects of rTMS on Sleep The clinical utility of rTMS treatment on circadian rhythm and sleep disturbances in MDD in adults is still debated. Evidence on the effects of rTMS on sleep remains equivocal, with rTMS being linked to improved overall sleep37-39 or changes in sleep physiology40 in some studies, as well as having no effect on sleep in others.17,41-44 One recent open-label trial of depressed young adults found that rTMS treatment had no significant effect on sleep as measured by actigraphy.43 To our knowledge, no prior studies have examined the impact of rTMS on sleep in adolescents with depression.
Journal Pre-proof In a study that examined the effect of bilateral low frequency (1-Hz) rTMS over the DLPFC in primary insomnia patients, marked reduction was seen in Pittsburgh Sleep Quality Index (PSQI) scores compared to pre-treatment.33 Another study examined the effect of low frequency (1-Hz) rTMS over the right parietal lobe in patients with comorbid generalized anxiety disorder and insomnia, finding a significant improvement in insomnia symptoms as measured by a reduction in PSQI scores.45 In a
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population of 24 patients with focal epilepsy, low frequency (1-Hz) rTMS application
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over epileptic foci resulted in a significant increase in sleep efficiency and in total sleep
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time.46 This study also showed a significant decrease in sleep latency and number of
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awakenings as measured by polysomnography (PSG).46 5-Hz rTMS application over bilateral parietal cortices in Parkinson’s disease patients resulted in significant
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improvement in sleep fragmentation and sleep efficiency, along with a significant
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decrease in the average duration of nocturnal awakenings. This change was not related to changes in mood or motor symptoms.47
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By contrast, a double-blind
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randomized controlled study examining the effect of 10-Hz, 3000 pulses/session rTMS
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to the L-DLPFC for depression found no significant difference between sham and active TMS groups in sleep factors on the Hamilton Depression Rating Scale (HDRS) at 10, 20, and 30 treatments.14 Another randomized controlled study that examined the effect of high frequency rTMS (10-Hz, 3000 pulses/session, L-DLPFC) on MDD found no significant difference between sham and active TMS groups in sleep factors on the HDRS and Inventory of Depressive Symptomology-Self Rated (IDS-SR) scales at any point during the treatment.17
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4.3 Possible Mechanisms for the Effects of rTMS on Sleep The exact mechanisms involved in the impact of rTMS on sleep are unknown. Several hypotheses examine the potential roles of neuroplasticity, neuroendocrinological systems, neurotransmitters, neural circuitry, and sleep architecture. One study showed that bilateral low frequency (1-Hz) rTMS application
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over the DLPFC resulted in significant improvement in insomnia, which was negatively
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correlated with γ-aminobutyric acid (GABA) and brain-derived neurotrophic factor
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(BDNF) levels and positively correlated with motor evoked potentials.33 A
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neuroendocrinological explanation for how rTMS regulates sleep is supported by findings from a study in which stage 3 sleep was significantly improved by application of
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rTMS over the right DLPFC, compared to medication and psychotherapy control groups.
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The investigators found that rTMS decreased levels of thyroid hormones, adrenocorticotropic hormone, and thyroid stimulating hormone.49 Decreased activity in
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hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes might also
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mediate the effects of rTMS on sleep.49 From a cognitive processing perspective, one study suggested that low frequency rTMS applied to the right parietal cortex may inhibit negative attentional bias and thus improve insomnia.45 Another study showed that rTMS alters sleep architecture by increasing SWA.32 SWA is thought to be a reliable index of sleep homeostasis, as it increases and decreases in relation to increased and decreased sleep need.50 The effect of rTMS on SWA is hypothesized to be mediated by long-term potentiation,32 which reflects glutamatergic neural transmission.
Journal Pre-proof Additionally, the application of rTMS has been found to delay onset of rapid eye movement (REM) and prolong non-REM to REM cycle length.51
4.4 Limitations Interpretation of the present findings must be placed in the context of the limitations of an open-label trial of high frequency rTMS and a relatively small sample
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size. One potential confound of our study was that participants were permitted to
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continue psychotherapy for clinical reasons. Although few participants did so, and the
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modalities of therapy were diverse, future rTMS studies should endeavor to control for the potential impact of therapy in sleep and other outcomes, particularly for cognitive-
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behavioral therapy, which has been shown to have impact on insomnia. 52-54 Similarly,
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some participants in our study utilized hypnotic medications with a variety of
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neurochemical mechanisms. Although we controlled for presence or absence of hypnotic medication in our analyses, definitive studies on the effects of rTMS on sleep
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should consider eliminating hypnotic medication during rTMS or limiting to medications
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of a single mechanistic class and controlling statistically by calculating dose equivalents. Additionally, this retrospective analysis utilized self-report measures of sleep outcomes, including a one-item measure of hypersomnia. Future work on the effects of rTMS on sleep should employ quantitative and objective measures, such as polysomnography, and more rigorous clinical measures of sleep quality. It is important to note that this was an exploratory study, and future adequately-powered, sham-controlled studies will be critical for definitive conclusions.
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5. CONCLUSIONS In summary, rTMS was found to decrease hypersomnia, but not to improve insomnia, in adolescents with major depression, independent of concurrent hypnotic medications and depressive symptom improvement. Future work should include larger sample sizes, randomization with sham controls, and objective, quantitative
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measurements of sleep architecture to assess the sleep effects of rTMS in depressed
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adolescents. Future studies should also examine the effect of different rTMS dosing
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parameters and the ensuing clinical and neurophysiological effects on sleep.
Journal Pre-proof ABBREVIATIONS BDNF: brain-derived neurotrophic factor CDRS-R: Children’s Depression Rating Scale, Revised DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision FDA: U.S. Food and Drug Administration
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GABA: γ-aminobutyric acid
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HDRS: Hamilton Depression Rating Scale
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IDS-SR: Inventory of Depressive Symptomology-Self Rated
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K-SADS-PL: Schedule for Affective Disorders and Schizophrenia for School Aged Children – Present and Lifetime Version
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MDD: major depressive disorder
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L-DLPFC: left dorsolateral prefrontal cortex
MT: motor threshold
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Non-REM: non-rapid eye movement
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PSG: polysomnography
PSQI: Pittsburgh Sleep Quality Index QIDS-A17-SR: Quick Inventory of Depressive Symptomatology – Adolescent (17 Item) – Self Report REM: rapid eye movement rTMS: repetitive transcranial magnetic stimulation SWA: slow wave activity TMS: transcranial magnetic stimulation
Journal Pre-proof FIGURE TITLES AND CAPTIONS
Figure 1. Changes in Insomnia with rTMS. QIDS-A17-SR insomnia subscale scores plotted across clinical assessment time points during course of 30 high frequency rTMS treatments. Scores are estimated marginal means from the linear mixed model with fixed effects of time (representing rTMS treatment stage), depression severity (CDRS-R
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total score), age, and hypnotic medication use (present/absent). Error bars represent
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95% confidence intervals.
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Figure 2. Changes in Hypersomnia with rTMS. QIDS-A17-SR hypersomnia scores plotted across clinical assessment time points during course of 30 high frequency rTMS
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treatments. Scores are estimated marginal means from the linear mixed model with
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fixed effects of time (representing rTMS treatment stage), depression severity (CDRS-R total score), age, and hypnotic medication use (present/absent). Pairwise comparisons
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between time points with significant differences in mean hypersomnia scores are shown
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with adjusted p-values. Error bars represent 95% confidence intervals.
Journal Pre-proof TABLE TITLES
Table 1. Participant Characteristics and Clinical Outcomes.
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Table 2. Changes in Insomnia and Hypersomnia with rTMS.
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54.
Sex
CDRS-R Total Score
PrerTMS 1
Posta rTMS 1
67
25
Yes
6
2
1
0
melatonin, eszopiclone
citalopram 40 mg
F
75
36
Yes
2
1
3
2
none
escitalopram 20 mg
F
71
41
No
3
2
1
0
none
citalopram 40 mg
F
61
33
Yes
4
3
0
0
none
sertraline 100 mg
F
70
34
Yes
1
0
2
1
melatonin
escitalopram 20 mg
F
59
38
Yes
6
2
2
2
melatonin
citalopram 40 mg
M
62
28
Yes
4
5
2
1
melatonin
sertraline 100 mg
F
61
32
Yes
5
3
1
0
none
fluoxetine 20 mg
F
65
26
Yes
7
6
1
1
melatonin, diphenhydramine
escitalopram 20 mg
M
79
46
No
2
6
2
2
none
mirtazapine 45 mg
M
49
35
Yes
1
1
3
3
none
desvenlafaxine 100
M
60
37
Yes
4
4
3
2
none
milnacipran 100 mg
F
68
37
Yes
9
4
0
0
none
escitalopram 10 mg
F
82
68
No
5
4
0
0
diphenhydramine
desvenlafaxine 50 m
F
63
60
No
F
67
65
No
of
Yes
Posta rTMS 2
ro
M
Concurrent Medication(s)
PrerTMS 3
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Posta rTMS 21
QIDS-A17-SR Hypersomnia
re
F
PrerTMS 58
QIDS-A17-SR Insomnia
Antidepressant Response to b rTMS
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y)
Journal Pre-proof
Hypnotic melatonin
Antidepressant Daily Dose fluoxetine 30 mg
7
5
1
0
none
escitalopram 5 mg
6
6
0
0
none
sertraline 50 mg
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tions: CDRS-R, Children’s Depression Rating Scale, Revised; QIDS-A 17-SR, Quick Inventory of Depressive Symptomatology – Adolescent (17 Item) – Self Report; rTMS, repe anial magnetic stimulation. mmediately follow ing conclusion of 30 treatments of rTMS. for clinical response defined as having a post-rTMS CDRS-R total score < 40.
Journal Pre-proof Estimated Marginal Mean ± SE rTMS Treatment 10
rTMS Treatment 20
rTMS Treatment 30
6-month Follow-Up
Insomnia
3.971 ± 0.621
3.516 ± 0.507
3.807 ± 0.501
3.509 ± 0.527
2.816 ± 0.576
Hypersomnia
1.435 ± 0.287
0.846 ± 0.245
0.743 ± 0.243
0.839 ± 0.253
0.559 ± 0.269
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Baseline
QIDS-A17-SR subscale
Journal Pre-proof ETHICAL STATEMENT
All study procedures were approved by the local institutional review boards. Informed consent was provided by minor participants’ parents or guardians, with adolescents providing written assent, while adult participants age 18 or older provided written
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informed consent.
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CONFLICTS OF INTEREST
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Financial support (presence or absence): Research reported in this publication was
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supported by the National Institutes of Health under award R01 MH113700 (Dr. Croarkin). The content of this publication is solely the responsibility of the authors and
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does not necessarily represent the official views of the National Institutes of Health.
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Neuronetics, Inc. provided equipment support for the study. Role of the Sponsor: The
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supporters had no role in the design, analysis, interpretation, or publication of the study.
Conflict of interest: Dr. Croarkin has received research grant support from Pfizer, Inc.; equipment support from Neuronetics, Inc.; and received supplies and genotyping services from Assurex Health, Inc. for investigator-initiated studies. He is the primary investigator for a multicenter study funded by Neuronetics, Inc. and a site primary investigator for a study funded by NeoSync, Inc. Dr. Croarkin is a paid consultant for Procter & Gamble Company. Dr. Lewis receives research support from the Brain and
Journal Pre-proof Behavior Research Foundation and has served as a site co-investigator on multicenter trials funded by Neuronetics, Inc. and NeoSync, Inc. The other authors have no
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disclosures or potential conflicts of interest to declare.
Journal Pre-proof HIGHLIGHTS
3. Current Knowledge: Sleep disturbance is a common and incompletely understood symptom impacting the functioning of adolescents with depression. There are limited interventions that address sleep disturbances in depression, and often treatment (i.e., antidepressant medications) has an adverse effect on
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sleep architecture.
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4. Study Impact: Recent research has examined the safety and clinical effects of
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repetitive transcranial magnetic stimulation (rTMS) for depression in adolescents.
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This open-label, pilot study examined the potential impact of rTMS on insomnia and hypersomnia in a sample of adolescents with treatment-resistant depression
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and found that rTMS results in an improvement in hypersomnia.
Figure 1
Figure 2