Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia...
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![Page 1: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/1.jpg)
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,
![Page 2: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/2.jpg)
Disclosures
• TSK, DJ, NR, FF, DM, TKR, PBF– Nothing to disclose
• ZJD– Research and equipment support from Brainsway
Inc– Advisory board of Hoffmann-La Roche Limited and
Merck– Speaker support from Sepracor and Eli Lilly
![Page 3: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/3.jpg)
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
![Page 4: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/4.jpg)
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
![Page 5: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/5.jpg)
Evidence for CI Deficits in SCZ
• Anatomic – Reduced GABA interneurons1 • Physiologic – P50 Auditory gating deficits2
• Neurophysiology – Previous TMS studies3,4
1. Del Rio and deFelipe 1997, 2. Freedman et al. 2000, 3. Daskalakis et al. 2008 4. Liu et al. 2009
![Page 6: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/6.jpg)
TMS Schematic
![Page 7: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/7.jpg)
CI Measurement
![Page 8: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/8.jpg)
CI Measurement
10 msec
1 mV
10 msec
1 mV } SICI = GABAA
(Ziemann et al. 1996)
1 mV
40 msec
CSP = GABAB
(Siebner et al. 1998)}
![Page 9: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/9.jpg)
Previous TMS CI Studies in SCZ
Daskalakis et al. 2008
![Page 10: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/10.jpg)
Previous TMS CI Studies in SCZ
Liu et al. 2009
![Page 11: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/11.jpg)
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
![Page 12: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/12.jpg)
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
![Page 13: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/13.jpg)
Methods - Controls
• 15 subjects age and sex matched• Recruited from separate study• TMS indices measured at baseline
![Page 14: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/14.jpg)
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
![Page 15: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/15.jpg)
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
![Page 16: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/16.jpg)
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
![Page 17: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/17.jpg)
Results - CSP
![Page 18: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/18.jpg)
Results – CSP Change and Symptoms
![Page 19: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/19.jpg)
Results – SICI & ICF
![Page 20: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/20.jpg)
Potential Limitations
• Sample size• Medications• CI Measured in motor region• Longitudinal control group
![Page 21: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/21.jpg)
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
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Conclusion
![Page 23: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/23.jpg)
Results – CLZ Dose & CSP
![Page 24: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia Presenter: Tyler Kaster Supervisor: Zafiris Daskalakis.](https://reader035.fdocuments.in/reader035/viewer/2022062802/56649e9c5503460f94b9d295/html5/thumbnails/24.jpg)