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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
– 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
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
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
TMS Schematic
CI Measurement
CI Measurement
1 mV
40 msec
}
CSP = GABAB
(Siebner et al. 1998)
1 mV
10 msec
1 mV
10 msec
}
SICI = GABAA
(Ziemann et al. 1996)
Previous TMS CI Studies in SCZ
Daskalakis et al. 2008
Previous TMS CI Studies in SCZ
Liu et al. 2009
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
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
Results – CSP Change and Symptoms
Results – SICI & ICF
Potential Limitations
•
•
•
•
Sample size
Medications
CI Measured in motor region
Longitudinal control group
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