Repetitive Transcranial Magnetic Stimulation as Therapy for Depression in Amyotrophic Lateral Sclerosis

A Pilot Study of Repetitive Transcranial Magnetic Stimulation for Improvement of Depression in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of central and peripheral motor neurons. ALS leads to death usually within 3 to 5 years from the onset of the symptoms. Available treatment can prolong the disease duration but cannot modify the disease course. Depression is a frequent complication of ALS, which further decreases quality of life and the available data concerning effectivity of antidepressant drugs are conflicting. Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive method of modulation of brain plasticity with confirmed antidepressive effect. The purpose of this study is to compare the effectiveness of rTMS in improving the depression in patients with ALS with placebo stimulation. Intervention will include 10 daily sessions. In each session 3000 magnetic pulses will be administered over the left dorsolateral prefrontal cortex. Assessment depression severity will be made before and after therapy, as well as two and four weeks later.

Study Overview

• Status: Withdrawn
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Device: active repetitive transcranial magnetic stimulation; Device: sham repetitive transcranial magnetic stimulation

Detailed Description

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of central and peripheral motor neurons. ALS leads to death usually within 3 to 5 years from the onset of the symptoms. Available treatment can prolong the disease duration but cannot modify the disease course. Depression is a frequent complication of ALS, which further decreases quality of life and the available data concerning effectivity of antidepressant drugs are conflicting. Similarly, the apathy may also complicate ALS and worsen the prognosis. Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive method of modulation of brain plasticity with proved antidepressive effect in patients suffering from major depression and in depression associated with several neurological disorders such as Parkinson's disease or stroke.

The purpose of this study is to compare the effectiveness rTMS in improving the depression and - as a secondary outcome - the apathy and daily functioning in patients with ALS.

Intervention will include ten daily sessions of rTMS. In each session 3000 magnetic pulses will be administered over the left dorsolateral prefrontal cortex. Stimulation intensity will equal 120% of the motor threshold value for the right first dorsal interosseus.

Assessment of depression severity and of apathy and daily functioning will be made before and after therapy, as well as two and four weeks later.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Poland
  • Kraków, Poland, 31503
    • Jagiellonian University Medical College, Department of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of definite or probable ALS according to el Escorial criteria (Brooks et al. 2000)
• Depression defined as the score in Beck's Depression Inventory ≥14
• Mini-Mental State Examination score ≥26

Exclusion Criteria:

• Psychiatric symptoms, which may negatively influence patient's tolerance and adherence to therapy
• Respiratory insufficiency and other complications od advanced stages of ALS, which may compromise patient's ability to undergo the study procedure
• Contraindications for rTMS as listed by the Guidelines of the International Federation of Clinical Neurophysiology (Rossi et al. 2009) i.e. seizure in the past, epilepsy, presence of magnetic material in the reach of magnetic field, pregnancy, likelihood to get pregnant, intracranial electrodes, cardiac pacemaker or intracardiac lines, frequent syncopes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: active repetitive transcranial magnetic stimulation; 10 hertz (Hz) rTMS will be administered over the left dorsolateral prefrontal cortex. Therapy will include 10 daily sessions (on consecutive week days). In every sessions 3000 magnetic pulses of 120% of the resting motor threshold intensity will be elicited.	Device: active repetitive transcranial magnetic stimulation; High frequency rTMS to induce the long term potentiation in the left dorsolateral prefrontal cortex
Sham Comparator: sham repetitive transcranial magnetic stimulation; Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue.	Device: sham repetitive transcranial magnetic stimulation; High frequency rTMS to induce the long term potentiation in the left dorsolateral prefrontal cortex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beck's Depression Inventory ater rTMS, total score, range 0 to 63, with higher values representing a worse outcome	Change from baseline score in the Beck's Depression Inventory to the measurement taken directly after finishing rTMS.	Before rTMS, directly (on the same day) after finishing rTMS
Beck's Depression Inventory first follow up, total score, range 0 to 63, with higher values representing a worse outcome	Change from baseline score in the Beck's Depression Inventory to the measurement taken two weeks after finishing rTMS.	Before rTMS, two weeks after finishing rTMS
Beck's Depression Inventory second follow up, total score, range 0 to 63, with higher values representing a worse outcome	Change from baseline score in the Beck's Depression Inventory to the measurement taken four weeks after finishing rTMS.	Before rTMS, four weeks after finishing rTMS

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised after rTMS, total score, range 0 to 40 with higher values representing a better outcome	Change from baseline score in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised to the measurement taken directly after finishing rTMS.	Before rTMS, directly (on the same day) after finishing rTMS
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised first follow up, total score, range 0 to 40 with higher values representing a better outcome	Change from baseline score in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised to the measurement taken two weeks after finishing rTMS.	Before rTMS, two weeks after finishing rTMS
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised second follow up, total score, range 0 to 40 with higher values representing a better outcome	Change from baseline score in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised to the measurement taken directly after finishing rTMS.	Before rTMS, four weeks after finishing rTMS
Apathy Evaluation Scale Clinical Version ater rTMS, total score, range 18 to 72 with higher values representing a worse outcome	Change from baseline score in the Apathy Evaluation Scale Clinical Version to the measurement taken taken directly after finishing rTMS.	Before rTMS, directly (on the same day) after finishing rTMS
Apathy Evaluation Scale Clinical Version first follow up, total score, range 18 to 72 with higher values representing a worse outcome	Change from baseline score in the Apathy Evaluation Scale Clinical Version to the measurement taken two weeks after finishing rTMS.	Before rTMS, two weeks after finishing rTMS
AES-C second follow up, total score, range 18 to 72 with higher values representing a worse outcome	Change from baseline score in the Apathy Evaluation Scale Clinical Version to the measurement taken four weeks after finishing rTMS.	Before rTMS, four weeks after finishing rTMS

Collaborators and Investigators

• Sponsor: Jagiellonian University
• Investigators: Principal Investigator: Jakub M Antczak, MD, Department of Neurology, Jagiellonian University Medical College

Publications and helpful links

General Publications

• Lefaucheur JP, Andre-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipovic SR, Hummel FC, Jaaskelainen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schonfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2014 Nov;125(11):2150-2206. doi: 10.1016/j.clinph.2014.05.021. Epub 2014 Jun 5.
• Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14.
• Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9. doi: 10.1080/146608200300079536. No abstract available.
• Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J, Barbosa ER, Valente KD, Pascual-Leone A, Marcolin MA. Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1171-4. doi: 10.1136/jnnp.2003.027060.
• Shen X, Liu M, Cheng Y, Jia C, Pan X, Gou Q, Liu X, Cao H, Zhang L. Repetitive transcranial magnetic stimulation for the treatment of post-stroke depression: A systematic review and meta-analysis of randomized controlled clinical trials. J Affect Disord. 2017 Mar 15;211:65-74. doi: 10.1016/j.jad.2016.12.058. Epub 2017 Jan 10.

Study record dates

Study Major Dates

• Study Start (Anticipated): November 15, 2019
• Primary Completion (Anticipated): June 30, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: March 26, 2019
• First Submitted That Met QC Criteria: March 26, 2019
• First Posted (Actual): March 27, 2019

Study Record Updates

• Last Update Posted (Actual): February 10, 2020
• Last Update Submitted That Met QC Criteria: February 6, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; depression; rTMS
• Additional Relevant MeSH Terms: Behavioral Symptoms; Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Depression; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: JagiellonianU61

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: After completing the study, the details of neurophysiologic diagnostics including motor threshold, the age and gender as well as individual scores of Mini-Mental State Examination, Beck depression inventory, AES-C and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised will be made available to other researchers on request.
• IPD Sharing Time Frame: The data will become available after the study is published.
• IPD Sharing Access Criteria: On request send by e-mail: jantczak@cm-uj.krakow.pl
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No