• Hallucination change score [ Time Frame: Measured at every week ] [ Designated as safety issue: No ]
• Clinical Global Improvement Scale [ Time Frame: Measured at every week ] [ Designated as safety issue: No ]
• Frequency subscale of Auditory Hallucinations Rating Scale [ Time Frame: Measured at baseline and every week ] [ Designated as safety issue: No ]

• Summed scores of Auditory Hallucination Rating Scale [ Time Frame: Measured at baseline and every week ] [ Designated as safety issue: No ]
• PANSS composite positive symptoms scale [ Time Frame: Measured at baseline and every week ] [ Designated as safety issue: No ]
• PANSS composite negative symptom scale [ Time Frame: Measured at baseline and every week ] [ Designated as safety issue: No ]
• PANSS total score [ Time Frame: Measured at baseline and every week ] [ Designated as safety issue: No ]
• California Verbal Learning Test (CVLT) [ Time Frame: Measure at baseline and after Week 4 ] [ Designated as safety issue: Yes ]

This trial is designed to determine if administering repetitive transcranial magnetic stimulation (rTMS) simultaneously to two sites in the temporal lobes, one on the left and one on the right, produces greater improvements in "voices" and other symptoms of schizophrenia compared to rTMS given to just one site in the temporal lobes.

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 re-enrollment 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.

• Device: Magstim Rapid 2 system triggering Magstim Super Rapid system
  Week 1 treatment includes rTMS for 5 sessions to either to left or right Wernicke's area (BA22) synchronous with rTMS to opposite hemisphere middle temporal cortex (BA21). Week 2 treatment includes rTMS given for 5 sessions with positions reversed (e.g., if Wernicke's stimulation was on the left during Week 1, position of rTMS will switch to the right side during Week 2 and vice-versa). As in Week 1, active rTMS will also be given synchronously to the opposite hemisphere middle temporal cortex. Weeks 3 and 4 include 10 stimulation sessions to the configuration of sites producing greater improvement in comparing results of Week 1 and Week 2. rTMS for each stimulation session will be given at 1-Hertz (once per second) for 16 minutes without interruption.
• Device: Magstim Rapid-2 system triggering Magstim Super Rapid system
  Week 1 includes repetitive rTMS for 5 sessions to either to left or right Wernicke's area (BA22) synchronous with sham rTMS to opposite hemisphere middle temporal cortex (BA21). Week 2 includes rTMS given for 5 sessions with positions reversed (e.g., if Wernicke's stimulation was on the left during Week 1, position of rTMS will switch to the right side during Week 2 and vice-versa). As in Week 1, sham rTMS will also be given synchronously to the opposite hemisphere middle temporal cortex. Weeks 3 and 4 include 10 stimulation sessions to the configuration of sites producing greater improvement in comparing results of Week 1 and Week 2. rTMS for each stimulation session will be given at 1-Hertz (once per second) for 16 minutes without interruption.

• 1: Experimental
  Active bilateral rTMS to left/right Wernicke's area and opposite side middle temporal gyrus
  Intervention: Device: Magstim Rapid 2 system triggering Magstim Super Rapid system
• 2: Active Comparator
  Active rTMS to left/right Wernicke's region plus sham rTMS to opposite hemisphere middle temporal cortex
  Intervention: Device: Magstim Rapid-2 system triggering Magstim Super Rapid system

• Hoffman RE, Gueorguieva R, Hawkins KA, Varanko M, Boutros NN, Wu YT, Carroll K, Krystal JH. Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample. Biol Psychiatry. 2005 Jul 15;58(2):97-104.
• Hoffman RE, Boutros NN, Hu S, Berman RM, Krystal JH, Charney DS. Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. Lancet. 2000 Mar 25;355(9209):1073-5.

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