Repetitive Transcranial MAgnetic STimulation (rTMS) for MotoR and Mood Symptoms of Parkinson's Disease (MASTER-PD), a Multicenter Clinical Trial

Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive means of brain
stimulation which can produce changes to brain excitability. Following a series of daily
rTMS sessions, this modulation of neural circuits and other distant effects may help some of
the motor and neuropsychiatric symptoms of PD for months at a time. Recently, the FDA
approved daily rTMS over the prefrontal cortex as a treatment for medication-refractory
depression after demonstration of efficacy in sham-controlled trials and its safety profile.
Among several small and pilot studies of rTMS in PD patients, rTMS over either the motor
cortex or prefrontal cortex has been reported to show beneficial effects on motor and mood
(depression) symptoms with no serious adverse events. However, the relative effectiveness
of rTMS over motor, prefrontal, or both regions on both mood and motor symptoms, has yet to
be established in PD patients.

We propose to conduct a four-center, blinded, sham-controlled, randomized, parallel-group
study of fixed-dose, high-frequency rTMS in 160 PD patients who are experiencing depressive
symptoms despite an adequate trial of at least one antidepressant. Subjects will be
randomized to receive rTMS over either motor cortex, prefrontal cortex, both, or neither
(sham-rTMS). Subjects will receive rTMS for 25 minutes over either the prefrontal cortex
(the brain region associated with mood and depression), and/or primary motor cortex
(associated with motor control), and/or sham-rTMS. After 10 days of rTMS (or sham)
treatment over a 2-week period, all subjects will undergo a comprehensive assessment of
motor, mood, cognition and quality of life on the first working day after the last rTMS
treatment, and after 1, 3 and 6 months post-treatment. This study directly addresses the
expansion of rTMS as an alternative treatment for depression in the PD population and will
provide evidence as to whether motor cortex stimulation will provide additional and/or
separate benefit to motor symptoms.

Inclusion Criteria:

- Diagnosis of PD according to the UK Brain Bank Criteria, confirmed by a neurologist
with expertise in movement disorders.

- Minimum of 3 years since the formal diagnosis of PD, and requiring dopaminergic
therapy (at a minimum, on levodopa and/or dopamine agonist therapy).

- Minimum baseline OFF score on the motor UPDRS of 15 points of more.

- Lack of features suggestive of atypical parkinsonism, such as early prominent
cerebellar, pyramidal, or autonomic dysfunction; supranuclear gaze palsy; falls
within the first year of symptoms; hallucinations prior to initiating a dopaminergic
agent.

- No history of neuroleptics or other drugs that induce parkinsonism in the past 60
days.

- Currently optimally treated with medications and, in the view of the treating
neurologist, will unlikely be requiring anti-PD medication adjustments in the next 6
months.

- On a stable dose of all medications for 30 days (except anti-depressants— which
should be stable for at least 90 days).

- Lack of dementia such that, in the view of the enrolling investigator, the patient is
able to give proper informed consent. In addition, all patients must score at least a
26 out of 30 on the screening MMSE.

- HAM-D score > 12 on the first 17 questions of the scale, despite the current use of
antidepressant(s) for at least 90 days, or documentation of adequate trial of
antidepressants (i.e. at least 6 weeks on an optimal dose), or documentation of
intolerability to antidepressants.

- Untreated depression or on a stable dose of antidepressants for 90 days (untreated
patients need to have tried at least one antidepressant in the past).

- Age 21 years or older.

- Patient meets the criteria for a depressive disorder based on either the MINI
interview (major depression) or SCID (minor depression, or dysthymia).

Exclusion Criteria:

- Intracranial metallic bodies (e.g. from prior neurosurgical procedure).

- Signs or symptoms of increased intracranial pressure.

- Implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, TENS
unit or ventriculoperitoneal shunt.

- History of seizures or unexplained loss of consciousness.

- Possible pregnancy.

- Family history of medication refractory epilepsy.

- History of substance abuse within the last 6 months.

- History of known structural brain abnormality.

- History of exposure to repetitive TMS in the past (to minimizing risk of unblinding
sham condition).

- History of exposure to ECT in the past.

- Patients with suicidal ideation deemed by the investigator to be significant enough
to render the individual a suicidal risk.

- Patients with a history of hospitalization for suicidal ideation/attempts.

- Patients requiring hospitalization for their depression within the past six months
will not be allowed in the study. If a participating subject's depression worsens
during the study to a degree that hospitalization is deemed necessary, or if the
subject develops significant suicidal ideation, he/she will be withdrawn from the
study and referred to a psychiatrist for treatment.

- Patients with bipolar affective disorder and those whose depression is characterized
by psychotic features.

- Patients with a history of spontaneous hallucinations or delusions as well as those
with other underlying psychotic disorders (e.g., schizophrenia, schizoaffective
disorder, delusional disorder). The presence of visual illusions or hallucinations
deemed by the enrolling physician to be clearly related to antiparkinsonian
medications will be allowed but only if the enrolling physician believes that they
are stable and unlikely to require changes in medication (i.e., addition of an
antipsychotic or reduction in antiparkinsonian drug dosage). Patients with delusions
will be excluded.

- Subjects judged by the clinician investigator to have dementia (by DSM-IV and MMSE
criteria) will be excluded.

- Subjects judged by the clinician investigator to have dementia (by MoCA criteria)
will be excluded.

- Subjects with unstable medical condition such as diabetes, cardiac disease, and
hypertension.

- Subjects with brittle or severe motor fluctuation that will cause severe discomfort
during OFF medication testing at Baseline, immediately post-TMS, and at Months 1, 3,
and 6.

- Excessive alcohol use or taking one of the following exclusionary medications:
Imipramine, Amitriptyline, Doxepin, Nortriptyline, Maprotiline, Chlorpromazine,
Clozapine, Foscarnet, Ganciclovir, Ritonavir, Amphetamines (MDMA, ecstasy), cocaine,
phencyclidine (PCP, angel's dust), ketamine, gamma-hydroxybutyrate (GHB),
theophylline, and haloperidol.