PhD ThesisThe atypical antipsychotic clozapine is a widely prescribed and effective treatment for
the positive and negative symptoms of schizophrenia, but reports of side effects are
common. In one study EEG abnormalities were observed in 53% of patients treated
with clozapine, and the absence or presence of EEG abnormalities correlated with the
plasma clozapine concentration.
Here, epileptiform activity was present in conventional EEG recordings from a 32 year
old male patient with psychiatric illness taking clozapine for 3 weeks. Brief (ca.100ms),
transient epileptiform spikes occurred at a frequency of approximately 2 per h and
originated primarily in parietal cortex. One month after withdrawal of clozapine,
epileptiform spikes were no longer present.
An in vitro model was developed using the equivalent region of association cortex,
namely 2⁰ somatosensory cortex, in normal rat brain slices to probe such activity with
increased spatial and temporal resolution, and to investigate mechanisms underlying its
generation. Wide band in vitro recordings revealed that clozapine (10-20µM) induced
regular, frequent very fast oscillations (VFO, > 70Hz) in this region. These VFO
comprised short transient high frequency discharges and were maximal in patches along
layer V. The atypical antipsychotic olanzapine, but not the classical antipsychotic
haloperidol, also induced prominent VFO in this region.
Sharp electrode intracellular recordings revealed that there was almost no correlation
between the somatic activity of layer V regular spiking (RS) pyramidal cells and field
VFO, but layer V intrinsically bursting (IB) cells did correlate to some extent with the
local field. Interestingly, IB cell spikelets were also weakly correlated with field VFO
suggesting a role for axonal hyperexcitability in this cell type in the mechanism.
Clozapine-induced VFO persisted following blockade of AMPA, NMDA, and GABAA
chemical synaptic receptors, and the gap junction blockers carbenoxolone and quinine
also failed to significantly attenuate the power of this activity. Although octanol
abolished clozapine-induced VFO, it was not clear that this effect resulted from
blockade of gap junctions as this drug also blocks spikes.
In addition to VFO events, clozapine (10-20µM) also induced occasional, spontaneous
transient paroxysmal discharges, similar to the EEG phenomena, in 33% (11/33 slices)
of slices in vitro. Sharp electrode intracellular recordings revealed that clozapine-
induced full paroxysmal discharges were associated with spikes, EPSPs and IPSPs in
layer V RS and IB cells, suggesting that these events were mediated via chemical
synaptic transmission in both of these cell types. Multi-electrode array recordings of
local field potentials and units suggested that clozapine-induced paroxysmal events
started superficially in association cortex, moved deeper and then propagated
horizontally along these deep layers.
The onset of clozapine-induced VFO was accompanied by a significant elevation in
parvalbumin immunoreactivity, particularly in layer II-IV, where there was a greater
than twofold increase in the signal, and this may be relevant to the therapeutic action of
the drug