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

This study will test whether repetitive transcranial magnetic stimulation (rTMS) is helpful in treating negative symptoms and social deficits of schizophrenia. This will be the first rTMS study to assess social function and social cognition.

1. Hypoactivity in the dorsolateral prefrontal cortex (DLPFC) has been implicated in generating the negative symptoms of schizophrenia. Abnormalities in the left inferior parietal lobe (IPL) have also been associated with negative symptoms. We hypothesize that high frequency rTMS applied to the hypoactive left DLPFC or to the left IPL in individuals with schizophrenia will reduce negative symptom severity more than sham (placebo) rTMS as assessed by the Positive and Negative Syndrome Scale (PANSS) negative symptoms subscale.
2. We hypothesize that high frequency rTMS applied to the left DLPFC or to the left IPL in schizophrenia patients will improve social dysfunction more than sham (placebo) rTMS as assessed by the Social Adjustment Scale, the Social Adaptation Self-Evaluation Scale and the Social Functioning Scale.

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.

Eligibility Criteria:
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.