Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis Co-Authors: Danilo de Jesus, Natasha Radhu, Faranak Farzan, Daniel Blumberger, Tarek Rajji, Paul Fitzgerald,

Disclosures TSK, DJ, NR, FF, DM, TKR, PBF ZJD Nothing to disclose Research and equipment support from Brainsway Inc Advisory board of Hoffmann-La Roche Limited and Merck Speaker support from Sepracor and Eli Lilly

Schizophrenia Debilitating illness affecting 1% of population Characterized by delusions, hallucinations, and neurocognitive symptoms Subset of these patients are treatment resistant (TRS) minimal response to typical & atypical antipsychotics Often requires use of antipsychotic clozapine

SCZ & Cortical Inhibition Healthy individuals able to filter emotionally irrelevant stimuli (conversation, noise, thoughts, impulses) Evidence suggests patients with schizophrenia unable to filter irrelevant stimuli Deluge of these internal/external stimuli may be final common pathway through which delusions and hallucinations become manifested Healthy people  hear a noise that’s not important to you, you can not recognize it and ignore it Schizophrenic  hear a noise, think it’s something extremely important

Evidence for CI Deficits in SCZ Anatomic – Reduced GABA interneurons1 Physiologic – P50 Auditory gating deficits2 Neurophysiology – Previous TMS studies3,4 Multiple converging lines of evidence: -anatomic (these mediate CI) (del Rio and deFelipe 1997) -neurophysiology (P50 suppression related to presynaptic GABA-B receptors on excitatory cells that input to pyramidal cells) (Freedman et al. 2000) -in vitro studies (direct in vitro binding of clozapine to GABA-B) (Wu et al. 2011) -previous TMS studies ((Daskalakis et al. 2008, Liu et al. 2009)) 1. Del Rio and deFelipe 1997, 2. Freedman et al. 2000, 3. Daskalakis et al. 2008 4. Liu et al. 2009

TMS Schematic -Transcranial magnetic stimulation involves a moving magnetic field that induces a current inside the brain -can be used for therapeutic or investigative purposes

CI Measurement If you stimulate motor cortex get various measures of cortical inhibition To measure cortical inhibition with TMS you attach the EMG monitor to the hand (specifically the Abductor pollicis brevis muscle) You then place the TMS over the corresponding motor cortex and induce a stimulus causing muscle contraction

} } CI Measurement CSP = GABAB (Siebner et al. 1998) SICI = GABAA 1 mV 40 msec CSP = GABAB (Siebner et al. 1998) } 10 msec 1 mV } SICI = GABAA (Ziemann et al. 1996) Depending on how the stimulus is applied, it can measure different inhibitory systems They are connected to the GABA systems because of their IPSP’s CSP: a strong stimulus is applied which causes suppression of motor activity. Duration of this motor activity is a measure of the amount of GABA-B related cortical inhibition. related to GABAB IPSPs (e.g., Siebner et al. 1998) SICI: two pulses are applied: a weak one (conditioning) 1-5ms prior to the strong testing stimulus. Ratio of peak amplitudes is a measure of the amount of GABA-A related cortical inhibition. related to GABAA IPSPs (e.g., Ziemann et al. 1996) ICF: not technically CI measure, but may interact with CI. This is NMDA mediated. same as SICI, except the conditioning stimulus was done 10-20ms prior to testing stimulus short-interval cortical inhibition means that a ‘conditioning stimulus’ is applied 1-5 ms prior to the test stimulus

Previous TMS CI Studies in SCZ Daskalakis et al. 2008 This study was the first to show that clozapine treated patients significantly longer than healthy patients or unmedicated patients

Previous TMS CI Studies in SCZ Liu et al. 2009 This study looked at multiple medications Clozapine was significantly greater than other medications and unmedicated Significantly larger effect size, especially with the CSP

Objective To measure TMS indices of CI in TRS patients before and after clozapine treatment Determine if change in TMS indices correlates with clinical response Problem with both prior studies is that they were cross-sectional. There is the question that patients on clozapine may represent a unique subpopulation neurophysiologically We designed this study to try and answer the question “Is treatment resistance or clozapine the reason for the increased cortical inhibition seen in previous studies?” Hypothesis: clozapine itself rather than treatment resistance is responsible for changes in TMS measures

Methods – Patients 16 patients with DSM-IV diagnosis of schizophrenia or schizoaffective disorder Inclusion Criteria: Between 18-65 years old Medication resistance (2 trials of antipsychotics, at least 1 atypical) Willing to switch to clozapine Exclusion Criteria: self-reported comorbid medical illness history of drug or alcohol abuse/dependence active suicidal ideation traumatic brain injury

Methods - Controls 15 subjects age and sex matched Recruited from separate study TMS indices measured at baseline

Methods – Study Design TMS indices and symptoms were measured at each assessment Symptoms measured by Positive and Negative Syndrome Scale (PANSS) Baseline assessment performed prior to starting clozapine Follow-up assessments at 6 weeks and 6 months after starting clozapine

Methods – CI Measurement Resting motor threshold (RMT): lowest stimulation intensity that creates MEP peak of 50μV in at least 5 of 10 consecutive trials in relaxed APB muscle CSP Motor cortex stimulated at 140% of RMT Duration defined as MEP onset to return of EMG activity SICI/ICF Conditioning stimulus at 80% of RMT Testing stimulus at 140% of RMT Ratio defined as conditioned/unconditioned MEP SICI: Inter-stimulus interval of 2 or 4ms ICF: Inter-stimulus interval of 10, 15, or 20ms

Results - Demographics SCZ: 11, SCZ-A: 5 Male: 11, Female: 5 Age: 33.3 (±10.9) years Baseline medications (no data for 1 patient): 14/15 antipsychotics 6/15 antidepressants 5/15 benzodiazepines 2/15 mood stabilizers

Results - CSP -pts: 6 weeks vs baseline – signficant, 6 months vs baseline – not significant, 6 weeks vs 6 months – not significant

Results – CSP Change and Symptoms -no correlation (p>0.05) -note however that 2/3 responders have change in the CSP >50ms

Results – SICI & ICF Not significant. Possibly increased SICI at 6 months

Potential Limitations Sample size Medications CI Measured in motor region Longitudinal control group -size: limits conclusions re: significance -medications: on a variety of medications at baseline. May impact TMS measures differently -motor: only measured CI in motor region, which may not accurately reflect effect of clozapine on CNS. However previous evidence suggests that the motor region is an acceptable estimate of non-motor region -control group: ideally we would have a non-medicated schizophrenia group of patients to monitor change in CSP over time, or non-clozapine medicated patients. However the former is ethically not feasible, the latter was technically challenging due to drop-outs

Conclusion Supports clozapine mediation of GABAB CI Consistent with pharmacological studies1 Consistent with previous TMS studies2,3 Potentially reduced SICI with long-term clozapine treatment GABAB receptor may represent a novel neurotransmitter target for treatment refractory schizophrenia 1. Wu et al. 2011, 2. Daskalakis et al. 2008, 3. Liu et al. 2009

Conclusion

Results – CLZ Dose & CSP Extra slide, in case asked questions