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rTMS as an add-on Therapy in Patients With Post-stroke Depression

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ClinicalTrials.gov Identifier: NCT03761303
Recruitment Status : Recruiting
First Posted : December 3, 2018
Last Update Posted : December 12, 2018
Sponsor:
Information provided by (Responsible Party):
Dr. rer. nat. Simone B. Schmidt, BDH-Klinik Hessisch Oldendorf

Brief Summary:
About 50% of all stroke patients develop post-stroke depression (PSD). A meta-analysis has shown that rTMS treatment can reduce depressive symptoms in PSD patients. In addition to rTMS alone for the improvement of depression, the question arises as to whether a combination therapy of rTMS plus antidepressant medication can achieve a stronger or longer-term effect in PSD patients. Unfortunately, there are currently no trials of combination therapy with rTMS and drug therapy in PSD patients. Therefore, this study will investigate whether combination therapy of antidepressant and rTMS can provide additional relief of depressive symptoms compared to antidepressant and sham rTMS therapy. It is assumed that the additional active rTMS achieves a faster normalization of affect and drive than with a sham rTMS, so that the patients benefit from neurorehabilitation measures earlier and more sustainably.

Condition or disease Intervention/treatment Phase
Post-stroke Depression Device: active rTMS Device: sham rTMS Not Applicable

Detailed Description:

Depression is one of the most common forms of mental illness. According to studies by the World Health Organization (WHO), the World Bank and the European Brain Council [1], depression is the leading disease in Europe and Germany since the early 1990s.

Besides drug or psychotherapeutic treatment, repetitive transcranial magnetic stimulation (rTMS) is currently being used as a new non-invasive therapy for depression. The rTMS applies an electromagnetic coil to the patient's head, creating a magnetic field. Impulses emanating from the coil trigger a multitude of reactions at the point of stimulation which, for example, can alter the metabolism, lead to a release of neurotransmitters and a change in gene expression [2-3]. Pulses with a frequency ≤1Hz lead to a reduction of the excitability of the neurons and to an inhibition of cortical activity. In contrast, frequencies ≥5 Hz increase the excitability of neurons and increase cortical activity [4-5].

A large number of studies has already shown that rTMS in depressive patients leads to an improvement in depressive symptoms and has been shown to have an antidepressant effect [6]. In the United States, rTMS has been approved by the Food and Drug Administration (FDA) since 2008 as a treatment for patients with depression who do not respond to antidepressant drug therapy. The FDA recommends a high-frequency (10Hz) rTMS on the left dorsolateral prefrontal cortex (DLPFC) five days a week for four to six weeks [7]. The stimulation of the DLPFC is based on the valence hypothesis that the right hemisphere specializes in the processing of negative emotions and the left hemisphere is specialized in the processing of positive emotions [8] and the DLPFC controls emotional processing [9-10]. Activation of the left DLPFC is therefore associated with the processing of positive emotions [11].

About 50% of all stroke patients develop post-stroke depression (PSD) [12]. A meta-analysis has shown that rTMS treatment can reduce depressive symptoms in PSD patients [13]. In addition to rTMS alone, it is unkown if a combination therapy of rTMS plus antidepressant medication can achieve a stronger or longer-term antidepressive effect in PSD patients. Unfortunately, there are currently no trials of combination therapy with rTMS and drug therapy in PSD patients. Previous studies with depressive patients provide both results that suggest an additional effect of combination therapy [14-19] and results that found no difference between drug-only therapy and combination with rTMS [20-24]. The comparability of the studies is difficult due to the heterogeneity of the study designs. However, it is noticeable that a younger age (<50 years), an intervention duration of rTMS of four weeks, a higher dose of the antidepressant, an inter-train interval (interval between the trains) of <30 seconds and a total number of pulses of <1250 per day, associated with positive effects. However, further studies are needed that address the issue of an additional effect of combination therapy. In addition, a neurological disease was considered to be an exclusion criterion in some of the studies performed [14-15; 20; 23]. It is therefore questionable whether the study results can be transferred to PSD patients.

Therefore, this study will investigate whether combination therapy of antidepressant and rTMS can provide additional relief of depressive symptoms compared to antidepressant and sham rTMS therapy. It is assumed that the additional active rTMS achieves a faster normalization of affect and drive than with a sham rTMS, so that the patients benefit from neurorehabilitation measures earlier and more sustainably.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

All patients will receive standard antidepressant therapy with 15 mg escitalopram (Selective Serotonin Reuptake Inhibitor) per day during the study. The dose of escitalopram is increased in all included patients from 5mg/day (day 1-3), over 10mg/day (day 4-6) to 15mg/day (from day 7).

Patients in the experimental group (active rTMS stimulation) receive active 10 Hz rTMS stimulation over the left dorsolateral prefrontal cortex (DLPFC) over a period of 20 days, seven days a week (20 sessions). The comparison group receives a duration of equal long sham-stimulation.

For transcranial magnetic stimulation, the Stimulator "PowerMAG Research 100" (Mag & More, Munich, Germany) is used with a cooled double coil (PMD70-pCool).

Masking: Double (Participant, Investigator)
Masking Description:

The randomization of the patients is carried out by a non-medical employee. This co-worker maintains a randomly generated randomization list, indicating to the particular study code (e.g., TMS-PSD-001; TMS-PSD-002), whether to perform an active or sham treatment. The employee pulls a number from an envelope before beginning the intervention of each enrolled patient and then looks at the list to identify the particular group assignment. There will always be randomization packages of ten patients each. Once these are used up, a new list and a new envelope with study codes are prepared.

In addition, the "real" and the placebo coils are coded before starting studies (eg "A" and "B"). Only the uninvolved employee is the assignment to the real - or placebo coil known. The uninvolved employee randomly assigns the study code containing the information on which coil to use ("A" or "B"). In this way a blinding of performing physician, patient and the evaluating scientist is guaranteed.

Primary Purpose: Treatment
Official Title: Investigation of the Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) as an add-on Therapy in Patients With Post-stroke Depression (PSD)
Actual Study Start Date : May 1, 2018
Estimated Primary Completion Date : November 1, 2021
Estimated Study Completion Date : November 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: active rTMS
Patients in the intervetion group (active rTMS stimulation) receive active 10 Hz rTMS stimulation over the left dorsolateral prefrontal cortex (DLPFC) over a period of 20 days, seven days a week (20 sessions).
Device: active rTMS
The rTMS coil is applied tangentially to the head surface above the left DLPF (corresponding to position F3 of the international 10-20 system). For the stimulation intensity, the motor rest threshold of the patient is determined. The motor rest threshold is defined as the minimum intensity that triggers an EMG response with an amplitude> 50 μV in the first right interosseus dorsalis muscle in at least 5 out of 10 cases. The stimulation intensity within the rTMS therapy is 80 percent of the motor rest threshold. In one session, 1,000 pulses are applied in 10 trains at a frequency of 10 Hz (1 train = 100 pulses in 10 s). Between the individual trains there is an inter-train interval of 28 seconds. The total duration of a session is 5:52 minutes. In total, the patient recieve 20 sessions.

Sham Comparator: sham rTMS
Patients in the control group receive sham rTMS stimulation over the left dorsolateral prefrontal cortex (DLPFC) over a period of 20 days, seven days a week (20 sessions).
Device: sham rTMS
Patients in the intervetion group (active rTMS stimulation) receive active 10 Hz rTMS stimulation over the left dorsolateral prefrontal cortex (DLPFC) over a period of 20 days, seven days a week (20 sessions).




Primary Outcome Measures :
  1. Changes of Hamilton Depression Rating Scale [HAM-D; 17 Item Version] [ Time Frame: For the clinical assessment of the severity of depression, the HAM-D is collected at the following times: day -7; baseline (day 1 before rTMS stimulation); day 2, day 8, day 15 and day 22). ]
    The primary endpoint is the change in the HAM-D score. A decrease of at least 50% from baseline on day 29 is considered clinically significant. From this, the responder rate is determined.


Secondary Outcome Measures :
  1. HAM-D score ≤8 Points [ Time Frame: baseline (day 1 before rTMS stimulation); day 22 ]
    A HAM-D score of ≤8 points is considered a decline in depression and is used to record the remission rate. It is expected that the decrease in the HAM-D from baseline (baseline) to the end of the study (day 22) in the active rTMS group is significantly greater than in the sham rTMS group.

  2. HAM-D score (day -baseline) [ Time Frame: baseline (day 1 before rTMS stimulation); day 36 ]
    To analyze the long-term effect the HAM-D score will evaluated at day 36 (follow up). It is expected that the decrease in the HAM-D score from baseline to the follow-up (day 36) is significantly greater in the active rTMS group than in the sham rTMS group.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • first insult
  • Post-stroke Depression (17 item version of the Hamilton Depression Rating Scale [HAM-D]> 18 points)
  • capacity to consent

Exclusion Criteria:

  • insufficient cardiorespiratory stability
  • previous depression or previous use of antidepressants
  • pre-stroke psychological illnesses (eg psychosis, bipolar disorder)
  • severe cognitive impairment
  • aphasia
  • lefthanded
  • decreased seizure threshold or history of epileptic seizures
  • taking medicines that lower the seizure threshold (local anesthetics, cortisone, alcohol, neuroleptics)
  • hemorrhages and cerebral edema (e.g., subarachnoid haemorrhage, intracerebral hemorrhage, subdural hematoma, epidural hematoma)
  • fresh and healed head wounds near the area to be stimulated
  • missing bone cover (relief spread)
  • colonization with a germ requiring isolation (e.g., MRSA, 3MRGN, 4MRGN)
  • recent myocardial infarction or higher grade cardiac arrhythmias
  • contraindications to rTMS: Metallic or magnetic implants containing iron, cobalt or nickel (e.g., pacemakers, brain pacemakers, automatic insulin pumps, electrodes, plates, clips, implanted hearing aids, dental implants, metal endoprostheses, metal parts, or metal fragments in the body).
  • pregnancy
  • no consent for study participation by the patient

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03761303


Contacts
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Contact: Simone B Schmidt, Dr. 0049 5152 781 215 si.schmidt@nkho.de

Locations
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Germany
Institute for rehabilitative Research, BDH-Clinic Hessich Oldendorf Recruiting
Hessisch Oldendorf, Lower Saxony, Germany, 31840
Contact: Simone B Schmidt, Dr.    0049 5152 781 215    si.schmidt@nkho.de   
Sponsors and Collaborators
BDH-Klinik Hessisch Oldendorf

Publications of Results:

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Responsible Party: Dr. rer. nat. Simone B. Schmidt, Postdoctoral Researcher, BDH-Klinik Hessisch Oldendorf
ClinicalTrials.gov Identifier: NCT03761303     History of Changes
Other Study ID Numbers: rTMS-PSD
First Posted: December 3, 2018    Key Record Dates
Last Update Posted: December 12, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr. rer. nat. Simone B. Schmidt, BDH-Klinik Hessisch Oldendorf:
rTMS
Escitalopram
add-on therapy
Additional relevant MeSH terms:
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Stroke
Depression
Depressive Disorder
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Behavioral Symptoms
Mood Disorders
Mental Disorders