Increased cortical inhibition in persons with schizophrenia treated with clozapine

It has been previously demonstrated that unmedicated persons with schizophrenia have deficits in cortical inhibition (CI) as indexed with transcranial magnetic stimulation (TMS). This inhibition is largely mediated by cortical GABAergic mechanisms. It has also been demonstrated that these inhibitory deficits may be normalized with the use of atypical antipsychotic medications. The purpose of this study, therefore, was to examine the effects of clozapine on TMS measures of CI and to compare these effects to unmedicated persons with schizophrenia and healthy subjects. We used two TMS inhibitory paradigms: short interval intra-cortical inhibition (SICI) and the cortical silent period (CSP) to evaluate CI in 10 clozapine-treated persons with schizophrenia, 6 unmedicated persons with schizophrenia and 10 healthy subjects. Clozapine-treated persons with schizophrenia had significantly longer CSPs compared with healthy subjects and unmedicated persons with schizophrenia. There were no significant differences in SICI between groups, however, the severity of psychotic symptoms was correlated with reduced SICI across all persons with schizophrenia. Our findings suggest that clozapine treatment is associated with greater CI in persons with schizophrenia and this increase may be related to potentiation of cortical GABAergic receptor mediated inhibitory neurotransmission. Our results also confirm previous findings suggesting that deficits in CI are related to the severity of psychotic symptoms in persons with schizophrenia.

[1]  Jacob Cohen.  Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[2]  Z. Shahrivar,et al.  Structured Clinical Interview for DSM-IV (SCID): Persian Translation and Cultural Adaptation , 2007 .

[3]  C. Solaro.  Incidence of seizures in patients with multiple sclerosis treated with intrathecal baclofen , 2006, Neurology.

[4]  J. Lieberman,et al.  Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. , 2005, The New England journal of medicine.

[5]  A. Zador,et al.  Synaptic Mechanisms of Forward Suppression in Rat Auditory Cortex , 2005, Neuron.

[6]  D. Lewis,et al.  Cortical inhibitory neurons and schizophrenia , 2005, Nature Reviews Neuroscience.

[7]  Robert Freedman,et al.  Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients. , 2004, The American journal of psychiatry.

[8]  Robert Chen,et al.  Exploring the connectivity between the cerebellum and motor cortex in humans , 2004, The Journal of physiology.

[9]  Walter Paulus,et al.  The effect of lorazepam on the motor cortical excitability in man , 1996, Experimental Brain Research.

[10]  G. Sperk,et al.  GABA and its receptors in epilepsy. , 2004, Advances in experimental medicine and biology.

[11]  M. Franěk.  [History and the present of metabotropic GABAB receptor]. , 2004, Ceskoslovenska fysiologie.

[12]  Robert Chen,et al.  An automated method to determine the transcranial magnetic stimulation-induced contralateral silent period , 2003, Clinical Neurophysiology.

[13]  G. Cascino,et al.  Incidence of seizures in patients with multiple sclerosis: a population-based study. , 2002, Mayo Clinic proceedings.

[14]  P. Fitzgerald,et al.  A transcranial magnetic stimulation study of the effects of olanzapine and risperidone on motor cortical excitability in patients with schizophrenia , 2002, Psychopharmacology.

[15]  S. Kapur,et al.  Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation. , 2002, Archives of general psychiatry.

[16]  Robert Chen,et al.  Interactions between two different inhibitory systems in the human motor cortex , 2001, The Journal of physiology.

[17]  P. Bickford,et al.  Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia. , 2000, American journal of medical genetics.

[18]  R. Deisz,et al.  GABAB receptor-mediated effects in human and rat neocortical neurones in vitro , 1999, Neuropharmacology.

[19]  K J Werhahn,et al.  Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans , 1999, The Journal of physiology.

[20]  R. Buchanan,et al.  Diazepam treatment of early signs of exacerbation in schizophrenia. , 1999, The American journal of psychiatry.

[21]  Walter Paulus,et al.  Complete suppression of voluntary motor drive during the silent period after transcranial magnetic stimulation , 1999, Experimental Brain Research.

[22]  P. Rossini,et al.  Magnetic stimulation: motor evoked potentials. The International Federation of Clinical Neurophysiology. , 1999, Electroencephalography and clinical neurophysiology. Supplement.

[23]  B Conrad,et al.  Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia , 1998, Muscle & nerve.

[24]  B. Dean,et al.  Clozapine and olanzapine treatment decreases rat cortical and limbic GABA(A) receptors. , 1998, European journal of pharmacology.

[25]  F. Benes.  Model generation and testing to probe neural circuitry in the cingulate cortex of postmortem schizophrenic brain. , 1998, Schizophrenia bulletin.

[26]  F. Benes.  The role of stress and dopamine-GABA interactions in the vulnerability for schizophrenia. , 1997, Journal of psychiatric research.

[27]  Javier DeFelipe,et al.  Colocalization of parvalbumin and calbindin D-28k in neurons including chandelier cells of the human temporal neocortex , 1997, Journal of Chemical Neuroanatomy.

[28]  H. Tsuji,et al.  Intracortical facilitation and inhibition after transcranial magnetic stimulation in conscious humans. , 1997, The Journal of physiology.

[29]  S. Kapur,et al.  Serotonin-dopamine interaction and its relevance to schizophrenia. , 1996, The American journal of psychiatry.

[30]  E. G. Jones,et al.  Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. , 1995, Archives of general psychiatry.

[31]  I. Mody,et al.  Bridging the cleft at GABA synapses in the brain , 1994, Trends in Neurosciences.

[32]  Y. Kang,et al.  Spatiotemporally differential inhibition of pyramidal cells in the cat motor cortex. , 1994, Journal of neurophysiology.

[33]  C. Marsden,et al.  Corticocortical inhibition in human motor cortex. , 1993, The Journal of physiology.

[34]  R. Mutani,et al.  Magnetic brain stimulation: the silent period after the motor evoked potential. , 1992, Neurology.

[35]  M. Besson,et al.  Synergism between D1 and D2 dopamine receptors in the inhibition of the evoked release of [3H]GABA in the rat prefrontal cortex , 1991, Neuroscience.

[36]  F. Benes,et al.  Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. , 1991, Archives of general psychiatry.

[37]  M. Hallett,et al.  Spinal motor neuron excitability during the silent period after cortical stimulation. , 1991, Electroencephalography and clinical neurophysiology.

[38]  S N Davies,et al.  Paired‐pulse depression of monosynaptic GABA‐mediated inhibitory postsynaptic responses in rat hippocampus. , 1990, The Journal of physiology.

[39]  D. McCormick,et al.  GABA as an inhibitory neurotransmitter in human cerebral cortex. , 1989, Journal of neurophysiology.

[40]  G Honigfeld,et al.  Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. , 1988, Archives of general psychiatry.

[41]  R. C. Oldfield.  The assessment and analysis of handedness: the Edinburgh inventory. , 1971, Neuropsychologia.