Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Panic Disorder With Comorbid Major Depression

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the efficacy of 1-Hz rTMS applied to the right Dorsolateral Prefrontal Cortex (DLPFC) in patients with Panic Disorder (PD) and comorbid Major Depressive Disorder (MDD) who have not fully responded to conventional therapies. The investigators hypothesize that: compared to sham (placebo), active rTMS will improve symptoms of PD and MDD as assessed with the Panic Disorder Severity Scale (PDSS), Hamilton Depression Rating Scale (HDRS), and Clinical Global Impression (CGI); active (but not sham) rTMS will normalize levels of motor cortex excitability relative to pre-treatment baseline.

Detailed Description
-----------------
This study tests the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in the treatment of Panic Disorder (PD) with comorbid Major Depression (MDD). Despite major advances in the treatment of PD, standard therapeutic interventions are not effective for all patients, and the most common reasons for treatment failure in PD are side effects and major depression comorbidity. rTMS is a non-invasive procedure that allows stimulation of the brain using magnetic fields. Some studies have reported that rTMS may be helpful in reducing panic and depressive symptoms. While promising, prior research has several limitations (e.g., relatively small sample sizes, relatively short durations of treatment, and lack of sham (placebo) comparison). This study addresses the drawbacks of prior work, and will provide data that will be important in determining whether rTMS can be useful for PD patients with comorbid MDD and resistant to conventional therapies. In this trial, 20 adult outpatients with PD and comorbid MDD, that have been only partially responsive to conventional therapies, will be randomly assigned to one of two treatment groups (active low frequency (1 Hz) rTMS or sham-placebo) applied to the right Dorsolateral Prefrontal Cortex (DLPFC) daily for up to four weeks. If rTMS will be added onto ongoing pharmacotherapy, the doses must have been stable for 1 month prior to study entry. The right DLPFC was selected because it is one among several brain regions implicated in PD, and functional abnormalities in DLPFC have also been consistently replicated in MDD. Pilot work indicates that stimulation of right DLPFC with low frequency rTMS was beneficial in patients with PD and MDD. Low frequency rTMS has the added benefit of a better safety profile (i.e. low risk of seizure) compared to high frequency rTMS. Rating scales for symptom change will be obtained at baseline, during the rTMS course, and at the end of 4 weeks of treatment. Patients who do not meet response criteria after four weeks of sham will be offered an open-label cross-over phase for an additional four weeks of daily active rTMS treatment while partial responders to either active or sham will be offered an open-label cross-over phase for an additional four weeks of daily active rTMS treatment. Patients who meet response criteria in either the randomized phase or the cross-over phase will continue routine clinical care under the supervision of their treating psychiatrist, and will be invited back for a repeat assessment at 1, 3 and 6 months to determine the persistence of benefit.

Official Title
-----------------
Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Panic Disorder (PD) With Comorbid Major Depression

Conditions
-----------------
Panic Disorder, Major Depressive Disorder

Intervention / Treatment
-----------------
* Device: Active Repetitive Transcranial Magnetic Stimulation (rTMS)
* Device: Sham Repetitive Transcranial Magnetic Stimulation (rTMS)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with a primary diagnosis of Panic Disorder and Major Depressive Disorder, as confirmed by the Structured Clinical Interview for the DSM-IV-TR (SCID) Residual panic attacks and MDD symptoms, defined as a total PDSS score of ≥ 20 and HDRS-17 score ≥18, despite treatment with an adequate trial of a serotonin reuptake inhibitor (SRI) A duration of the index episode of at least a month will be included. An adequate SRI trial is defined as treatment for at least 6-8 weeks on the SRI, that meets the maximum recommended dosage level for PD and MDD (fluoxetine 40-60 mg/d, sertraline 100-200 mg/d, paroxetine 40-60 mg/d, fluvoxamine 200-300 mg/d, citalopram 40-60 mg/d, escitalopram 20-30 mg/d). Individuals who cannot tolerate medications of class and dose at the specified duration as described above will also be included. Patients currently on medication must be at the same stable dose(s) for one month prior to enrollment and be willing to continue at the same dose(s) through the duration of the study. Exclusion Criteria: Individuals diagnosed with bipolar disorder (lifetime), any psychotic disorder (lifetime), or an Axis II personality disorder A history of substance abuse or dependence within the past year (except nicotine and caffeine) Significant acute suicide risk will be excluded. Other exclusion criteria include those common to every TMS protocol: Individuals with a clinically defined neurological disorder, with an increased risk of seizure for any reason, with a history of treatment with TMS, deep brain stimulation for any disorder will be excluded. Patients with cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute, unstable cardiac disease, with intracranial implants (e.g. aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed will be excluded. Current use of any investigational drug, any medications with proconvulsive action, such as bupropion, maprotiline, tricyclic antidepressant, clomipramine, classical antipsychotics, and daily use of any medications with a known inhibitory effect on cortical excitability measures (e.g., anticonvulsants, standing doses of benzodiazepines, sedative/hypnotics, and atypical antipsychotics) will not be permitted. If participating in psychotherapy, patients must have been in stable treatment for at least three months prior to entry into the study, with no anticipation of change in frequency therapeutic sessions, or the therapeutic focus over the duration of the TMS trial. Finally, current significant laboratory abnormality, known or suspected pregnancy, women who are breast-feeding or women of childbearing potential not using a medically accepted form of contraception when engaging in sexual intercourse will also be excluded.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active rTMS<br>Active Repetitive Transcranial Magnetic Stimulation (rTMS) | Device: Active Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Strong electromagnetic field ( 2Tesla) generated briefly ( 1ms) but repetitively (1Hz) for 30min, five sessions a week for up to eight weeks.<br>* Other names: Magstim, Magstim Rapid, Magstim Rapid2;|
| Sham Comparator: Sham rTMS<br>Sham Repetitive Transcranial Magnetic Stimulation (rTMS) | Device: Sham Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Generates a field with the same parameters as active rTMS (see active arm for parameters), however, the actual magnetic fields are blocked by an electromagnetic shield built into a sham coil. The field is impeded from stimulating the brain.<br>* Other names: Magstim, Magstim Rapid, Magstim Rapid2;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Panic Disorder Severity Scale (PDSS) | The Panic Disorder Severity Scale is a questionnaire developed for measuring the severity of panic disorder symptoms. The PDSS consists of seven items, each rated on a 5-point scale, which ranges from 0 to 4. The items assess panic frequency, resulting distress, panic-focused anticipatory anxiety, phobic avoidance of situations and of physical sensations, impairment in occupational and social functioning. The overall assessment is made by a total score, which is calculated by summing the scores for all seven items. The total scores range from 0 to 28. Higher scores indicate high levels of panic symptomatology. Reduction in score from baseline indicates clinical improvement of panic symptoms. | 4 weeks | 
| Hamilton Depression Rating Scale (HDRS), 28 Item Version | The Hamilton Rating Scale for Depression (HRSD) is a multiple item questionnaire used to provide an indication of depression severity. The 28-, rather then 17- or 24-, item version was used to assess subjects in this protocol. 28-item minimum score = 0 28-item maximum score = 84 Higher scores indicate high levels of symptomatology. Reduction in score from baseline indicates clinical symptom improvement. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Improvement (CGI-S) | Minimum CGI-S score: 1 Maximum CGI-S score: 7 Higher scores indicate the presence of high symptom severity. Decrease in scores from baseline reflects clinical symptom improvement. Patients will be classified as responders with a CGI-S = 1 or 2; and partial responders CGI-S = 3. = Normal, not at all ill = Borderline mentally ill = Mildly ill = Moderately ill = Markedly ill = Severely ill = Among the most extremely ill patients | 4 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TMS, Dorsolateral Prefrontal Cortex