Clonazepam Effects on Brain Oscillations and Cognition in Schizophrenia

Schizophrenia is a common, disabling mental illness with a considerable public health impact.
Cognitive dysfunction (e.g in attention, memory, etc.) is an enduring feature of the illness,
a strong predictor of functional outcome, and presently has no established treatment.
Therefore, advances in treatment of cognition in schizophrenia are likely to alleviate a
significant health burden. Deficits in executive control functions, such as those measurable
on task-switching paradigms, are among the most important cognitive deficits in
schizophrenia, and arise from disturbances in distributed neural networks operated by the
prefrontal cortex. An important phenomenon that underpins cortical information processing are
oscillations in brain activity that can be measured both with intracranial electrical
recordings and at the scalp with EEG. These networks and their cortical oscillatory
signatures are also strongly modulated by cortical interneurons that use gamma-amino butyric
acid (GABA) as a neurotransmitter. Post-mortem evidence suggests that GABAergic neurons are
altered in schizophrenia. Furthermore, studies in animals, using optogenetic manipulations
that are restricted to a subset of cortical GABA neurons, also suggest that GABA neurons can
be selectively modulated to improve PFC-dependent cognition in animal models of
schizophrenia. This includes experiments that involve administration of sub-sedating doses of
clonazepam, a representative FDA-approved medication from the benzodiazepine class.

Therefore, this neurochemical system represents a novel set of candidate treatment targets
that are both implicated in the pathophysiology of schizophrenia and the potential
remediation of associated cognitive dysfunction.

Inclusion Criteria:

- Subjects will be included if they are adults (18-55 years old) who currently meet
criteria for schizophrenia, schizophreniform disorder or schizoaffective disorder from
the DSM-IV (295.X).

- Healthy control subjects: 18-55 years of age.

Exclusion Criteria:

- All subjects will be excluded if they have a history of any substance-related disorder
(by DSM-IV, other than cannabis abuse) in the prior 6 months, or repeated positive
urine drug screens for other illicit substances. They will also be excluded if they
are clinically-unstable, have significant baseline or emergent suicide risk (by
Columbia Suicide Severity Risk Scale), estimated IQ < 70, or EEG contraindications.
Subjects must also have no major medical or neurological illness, or significant head
trauma.

- Active pregnancy or lactation will also be considered contraindications for treatment
with clonazepam, and as criteria for exclusion.

Excluded medications:

- Prospective subjects will be excluded if they are currently in treatment with
benzodiazepines, anticonvulsants, and medications such as zolpidem and baclofen, each
of which directly affect GABA neurons or may be associated with changes in GABA system
function.

- Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or
their formulation, or sensitivity/hypersensitivity to clonazepam will be criteria for
exclusion.

- Healthy controls must be free of a diagnosis of a chronic or recurrent Axis I (or
certain Axis II) psychiatric disorder and will be excluded if they have a first degree
relative with a psychotic disorder.

- Education, parental education, ethnicity, handedness, and native language will be used
as exclusionary factors as necessary to maintain balanced groups. This information is
collected during the telephone screen to ensure group balance.