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

10 msec

1 mV

10 msec

1 mV } SICI = GABAA

(Ziemann et al. 1996)

1 mV

40 msec

CSP = GABAB

(Siebner et al. 1998)}

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