Treatment of Negative Symptoms of Schizophrenia With Transcranial Magnetic Stimulation (TMS)

Most treatments for schizophrenia are helpful in treating positive symptoms (e.g.
hallucinations), whereas negative symptoms (e.g. low social drive) are only partially
responsive to medication. Repetitive transcranial magnetic stimulation (rTMS) is a
noninvasive way of stimulating the brain that has been FDA approved for the treatment of
depression and has shown promise in schizophrenia.

In rTMS therapy, a device called a "magnetic stimulator" provides electrical energy to a
magnetic coil that delivers a magnetic field. When the coil is placed against the surface of
the head, the magnetic field can cause parts of the brain to either increase or decrease in
activity, depending on how quickly the magnetic pulses are delivered. This study is designed
to test whether high-frequency rTMS delivered to an area near the front of the head, called
the dorsolateral prefrontal cortex, can improve the "negative symptoms" of schizophrenia,
which include decreased thinking, difficulty motivating, and social withdrawal.

Participation in the first phase of the study consists of sessions lasting about 45 minutes
per day, 5 days a week, for 4 weeks. Twenty-four subjects will be randomly assigned to
receive four weeks of either active (real) rTMS or inactive (sham) rTMS. Patients will
receive magnetic resonance imaging (MRI) of their brains to help locate where the rTMS
should be applied. Symptoms will be rated at baseline, during the rTMS course, and at the
end of the 4 weeks. Patients who do not meet response criteria after the four weeks of the
randomized phase will be offered active (real) daily rTMS for an additional four weeks in
the open phase of the study. All patients will have two monthly repeat assessments after
their last rTMS session to examine the persistence of benefit.

We will also collect measures of motor cortex excitability (performed with single pulse TMS)
at baseline, at the end of the randomized and, if applicable, the open study phase, and at
each of the two follow-up assessments to determine whether changes in these measures
correlate with clinical improvement.

In addition, we will look at brain dynamics using electroencephalography (EEG) pre- and
post-rTMS in the first and last sessions of each study phase. We will also assess the
effects of rTMS on cigarette use, as schizophrenia patients are known to have increased
prevalence of nicotine dependence. There is also preliminary evidence that high frequency
rTMS to the left DLPFC decreases cigarette smoking.

Inclusion Criteria:

- Male or female inpatients or outpatients, 18 to 55 years of age.

- Primary diagnosis by DSM-IV criteria for Schizophrenia or Schizoaffective Disorder.

- Capacity and willingness to give informed consent.

- Engaged in ongoing treatment with a psychiatrist.

- PANSS negative symptoms subscale score of ≥ 15.

- English speaking.

- Patients must have stable symptoms as defined by not requiring a change in
antipsychotic medication for at least 4 weeks or at least 2 weeks for other
psychotropic agents (e.g. antidepressants) prior to entering the study. Patients will
not be included in the study if the research team thinks that modifications could be
made to maximize their medication regimen at initial evaluation.

- Able to adhere to the treatment schedule.

- Able to commute to NYC for daily treatments (Monday - Friday) for at least 4 weeks.

Exclusion Criteria:

- Individuals diagnosed by the investigator with the following conditions (current
unless otherwise stated): Current affective disorder including Major Depressive
Disorder, Bipolar Affective Disorder; substance abuse or dependence within the past
year (except nicotine and caffeine).

- An Axis II Personality Disorder, which in the judgment of the investigator may hinder
the patient in completing the procedures required by the study protocol.

Other exclusion criteria include those common to every TMS protocol:

- Individuals with a clinically defined neurological disorder or insult including, but
not limited to: Any condition likely to be associated with increased intracranial
pressure; Space occupying brain lesion; Any history of seizure EXCEPT those
therapeutically induced by ECT; History of cerebrovascular accident; Transient
ischemic attack within two years; Cerebral aneurysm; Dementia; Parkinson's disease;
Huntington's chorea; or Multiple sclerosis.

- Increased risk of seizure for any reason, including prior diagnosis of increased
intracranial pressure (such as after large infarctions or trauma), history of
epilepsy or seizure in first-degree relatives, having metal inside the head, or
history of significant head trauma with loss of consciousness for 5 minutes.

- Prior adverse reaction to TMS.

- History of treatment with rTMS therapy for any disorder.

- Cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute,
unstable cardiac disease.

- Intracranial implant (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.

- Current illicit drug use.

- Clinically significant laboratory abnormality, in the opinion of the investigator.
(Note: Clinically significant laboratory abnormality refers to patient lab results
that fall outside the established normal ranges, may be indicative of the presence of
a medical condition, and are not thought to reflect an artifact or routine lab error
(e.g. hemolysis). Results of laboratory tests are reviewed by the study physician
prior to any treatment. Abnormal lab results of clinical significance that cannot be
resolved (e.g. by repeating the test to rule out laboratory error or poor quality of
the original sample) will lead to exclusion from the study.)

- Known or suspected pregnancy.

- Women who are breast-feeding.

- Women of child-bearing potential not using a medically accepted form of contraception
when engaging in sexual intercourse.

- Wearing medicinal skin patches during the MRI scan.