rTMS in First Episode Psychosis

Schizophrenia is a chronic and disabling illness that typically begins in the late teen and
early adult years.1 This illness is associated with significant impairments in areas such as
independent living, social functioning, and vocational functioning.2 Indeed, only 10% of
people with schizophrenia are employed, translating into annual lost wages of nearly 15
billion dollars.3,4 Schizophrenia also represents an important societal burden as this
illness has been estimated to cost over 40 billion dollars each year in the United States
alone.5

Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment for neuropsychiatric
illness. A non-invasive intervention, rTMS utilizes the application of a repetitively pulsed
magnetic field over the scalp to induce an electric field within a discrete area of the
cerebral cortex. This electric field results in altered ion flow across the neuronal cellular
membrane and ultimately changes in neuronal polarization. The end result is altered neuronal
activity in the area of the cerebral cortex where the rTMS is applied.12 rTMS is a safe and
well-tolerated intervention that received FDA approval for treatment refractory major
depressive disorder in 2008 and has since become commonly used in clinical practice.13

This study proposes to examine the application of rTMS for the treatment of cognitive
dysfunction in FEP. This is an important population for study because if effective, rTMS may
represent a preventative treatment for the development of social and vocational impairment
that is associated with cognitive dysfunction in schizophrenia. This study will also seek to
refine the understanding of the brain circuitry that mediates the potential pro-cognitive
effects of rTMS through the use of functional magnetic resonance imaging (fMRI) at baseline
and following the course of rTMS administration.

Inclusion Criteria:

- 18-40 years of age at study entry

- Male or female

- DSM IV-TR Diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective
disorder as confirmed by Structured Clinical Interview for DSM-IV-TR (SCID)44

- Subjects in their first-episode of psychosis, defined as the onset of clinically
significant psychotic symptoms within the past five years as determined by first
medical record documentation of these conditions

- BACS composite t-score of 40 or less at baseline assessment

- Clinical stability as defined by:

- CGI-S score of less than or equal to 4 (moderately ill) at randomization AND

- Subjects must not have experienced an exacerbation of their illness within 4
weeks prior to randomization, leading to an intensification of psychiatric care
in the opinion of the investigator. Examples of intensification of care include,
but are not limited to: inpatient hospitalization, day/partial hospitalization,
outpatient crisis management, or psychiatric treatment in an emergency room AND

- Antipsychotic treatment stability for at least 4 weeks prior to randomization (no
change in antipsychotic dosing or addition of any new antipsychotic medication).

- Able to give informed consent

- Subjects must be willing and able to adhere to study schedule

- Outpatient or Inpatient treatment status

- Female subjects of childbearing potential must test negative for pregnancy at
screening and baseline visit

Exclusion Criteria:

- Life-time history of a seizure, excluding febrile seizures and those induced by
substance withdrawal

- Metallic objects planted in or near the head, including implanted pacemaker,
medication pump, vagal stimulator, deep brain stimulator, TENS unit,
ventriculoperitoneal shunt, or cochlear implants

- First degree relative (that is, biological father, mother, brother, sister, or child)
with idiopathic epilepsy or other seizure disorder

- History of significant neurological illness (including stroke, CNS infection with
persistent neurologic deficit, or other event deemed significant by PI)

- History of head trauma as defined by a loss of consciousness or a post-concussive
syndrome deemed significant by PI

- Pregnancy or breast feeding

- Known IQ < 70 based on medical history

- Current DSM-IV-TR diagnosis of alcohol or drug dependence (excluding nicotine or
caffeine)

- Subjects with current acute, serious, or unstable medical conditions, including, but
not limited to: inadequately controlled diabetes, asthma, COPD, severe
hypertriglyceridemia, recent cerebrovascular accidents, acute systemic infection or
immunologic disease, unstable cardiovascular disorders, malnutrition, or hepatic,
renal gastroenterological, respiratory, endocrine, neurologic, hematologic, or
infectious diseases based on medical history or physical examination.

- Subjects with contraindications to MRI or otherwise unable to tolerate MRI procedure

- Subjects considered a high risk for suicidal acts - active suicidal ideation as
determined by clinical interview OR any suicide attempt in 90 days prior to screening

- Subjects who have participated in a clinical trial with any pharmacological treatment
intervention for which they received study-related medication in the 4 weeks prior to
randomization

- Subjects who require concomitant treatment with prohibited medication, as specified in
Attachment 2

- Subjects with a history of electroconvulsive therapy