Bilateral Repetitive Transcranial Magnetic Stimulation for Auditory Hallucinations

This study is an extension of an ongoing clinical trial (ClinicalTrials.gov identifier NCT
00308997) that was initiated in 2006. The primary objective of the ongoing clinical trial
(hereafter called the "parent trial") is to determine efficacy of rTMS in curbing auditory
hallucinations when delivered to a part of the left temporal lobe called Wernicke's area and
a corresponding region in the right temporal lobe. The parent trial appears to show robust
effects for active rTMS compared to effects of sham stimulation. However, observed
responses following active rTMS have often been incomplete. Moreover, in some cases there
has been a subsequent return of symptoms 1 to 6 months after the trial ended.

We consequently have initiated a trial where patients who have participated in the parent
trial and demonstrated an incomplete response or a subsequent return of symptoms may return
to receive additional active rTMS. We hypothesize that efficacy of suppressive rTMS will be
enhanced if directed simultaneously to right/left Wernicke's area (the site used in the
parent trial) as well as to a second site located in the opposite middle temporal cortex.
Roughly half of subjects in the re-enrollment will be randomized to receive active rTMS to
right/left Wernicke's area plus active rTMS to opposite hemisphere middle temporal region,
while half of subjects will be randomized to receive active rTMS to right/left Wernicke's
area plus sham rTMS to opposite hemisphere middle temporal region. The position of the
middle temporal regions will be determined by two recently completed brain imaging studies
of auditory hallucinations suggesting that activation in these sites triggers auditory
hallucinations. The two-position design will allow us to determine if active rTMS delivered
to the middle temporal cortex is superior in amplifying efficacy of active rTMS targeting
Wernicke's area and in reducing auditory hallucinations to sham stimulation to the same
site. The re-enrollment protocol will utilize two rTMS devices simultaneously where one
directly triggers the other.

We have added a third arm to the protocol (3/2012) where the same intervention described for
Arm 1 is provided to enrollees, but no randomization or comparison with Arm 2 is pursued.
The primary purpose of this Arm is to conduct fMRI neuroimaging studies prior to and
subsequent to the rTMS intervention. Our intent is to ascertain changes in regional brain
activation and connectivity that most robustly predict level of improvement in auditory
hallucinations elicited by bilateral rTMS as assessed by our primary outcome variables.
This combined fMRI/rTMS study will provide critical new insights into the neurobiological
basis of auditory hallucinations.

Inclusion Criteria:

- Previously enrolled in our "parent" rTMS trial with passage of at least six months
since last received active rTMS

Exclusion Criteria:

- Active substance abuse or alcohol abuse

- Pregnancy

- Dose or type of psychiatric medication changed within the 4 weeks prior to study
entry

- Recent head trauma, seizures, or significant unstable medical condition