Response to clozapine in a clinically identifiable subtype of schizophrenia.
BACKGROUND
Genetic testing in psychiatry promises to improve patient care through advances in personalised medicine. However, there are few clinically relevant examples.


OBJECTIVE
To determine whether patients with a well-established genetic subtype of schizophrenia show a different response profile to the antipsychotic clozapine than those with idiopathic schizophrenia.


METHODS
We retrospectively studied the long-term safety and efficacy of clozapine in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS group) and half matched for age and clinical severity but molecularly confirmed to have no pathogenic copy number variant (idiopathic group).


RESULTS
Both groups showed similar clinical improvement and significant reductions in hospitalisations, achieved at a lower median dose for those in the 22q11.2DS group. Most common side-effects were similarly prevalent between the two groups, however, half of the 22q11.2DS group experienced at least one rare serious adverse event compared with none of the idiopathic group. Many were successfully retried on clozapine.


CONCLUSIONS
Individuals with 22q11.2DS-schizophrenia respond as well to clozapine treatment as those with other forms of schizophrenia, but may represent a disproportionate number of those with serious adverse events, primarily seizures. Lower doses and prophylactic (for example anticonvulsant) management strategies can help ameliorate side-effect risks. This first systematic evaluation of antipsychotic response in a genetic subtype of schizophrenia provides a proof-of-principle for personalised medicine and supports the utility of clinical genetic testing in schizophrenia.
Nancy J. Butcher, MSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Institute of Medical Science, University of Toronto, Toronto; Wai Lun Alan Fung, MD, ScD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto General Research Institute, University Health Network, Toronto, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome and Department of Psychiatry, University Health Network and Department of Psychiatry, University of Toronto, Toronto; Laura Fitzpatrick, Alina Guna, BSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto; Danielle M. Andrade, MD, MSc, FRCPC, Division of Neurology, Department of Medicine, University of Toronto, Toronto; Anthony E. Lang, MD, FRCPC, Institute of Medical Science, University of Toronto, Division of Neurology, Department of Medicine, University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto Western Hospital Research Institute, University Health Network and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto; Eva W. C. Chow, MD, MPH, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto; Anne S. Bassett, MD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Institute of Medical Science, University of Toronto, Toronto General Research Institute, University Health Network, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome, Department of Medicine and Department of Psychiatry, University Health Network, Department of Psychiatry, University of Toronto, Ontario, Canada.
Nancy J
NJ
Butcher
Nancy J. Butcher, MSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Institute of Medical Science, University of Toronto, Toronto; Wai Lun Alan Fung, MD, ScD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto General Research Institute, University Health Network, Toronto, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome and Department of Psychiatry, University Health Network and Department of Psychiatry, University of Toronto, Toronto; Laura Fitzpatrick, Alina Guna, BSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto; Danielle M. Andrade, MD, MSc, FRCPC, Division of Neurology, Department of Medicine, University of Toronto, Toronto; Anthony E. Lang, MD, FRCPC, Institute of Medical Science, University of Toronto, Division of Neurology, Department of Medicine, University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto Western Hospital Research Institute, University Health Network and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto; Eva W. C. Chow, MD, MPH, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto; Anne S. Bassett, MD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Institute of Medical Science, University of Toronto, Toronto General Research Institute, University Health Network, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome, Department of Medicine and Department of Psychiatry, University Health Network, Department of Psychiatry, University of Toronto, Ontario, Canada.
Wai Lun Alan
WL
Fung
Nancy J. Butcher, MSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Institute of Medical Science, University of Toronto, Toronto; Wai Lun Alan Fung, MD, ScD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto General Research Institute, University Health Network, Toronto, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome and Department of Psychiatry, University Health Network and Department of Psychiatry, University of Toronto, Toronto; Laura Fitzpatrick, Alina Guna, BSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto; Danielle M. Andrade, MD, MSc, FRCPC, Division of Neurology, Department of Medicine, University of Toronto, Toronto; Anthony E. Lang, MD, FRCPC, Institute of Medical Science, University of Toronto, Division of Neurology, Department of Medicine, University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto Western Hospital Research Institute, University Health Network and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto; Eva W. C. Chow, MD, MPH, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto; Anne S. Bassett, MD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Institute of Medical Science, University of Toronto, Toronto General Research Institute, University Health Network, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome, Department of Medicine and Department of Psychiatry, University Health Network, Department of Psychiatry, University of Toronto, Ontario, Canada.
Laura
L
Fitzpatrick
Nancy J. Butcher, MSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Institute of Medical Science, University of Toronto, Toronto; Wai Lun Alan Fung, MD, ScD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto General Research Institute, University Health Network, Toronto, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome and Department of Psychiatry, University Health Network and Department of Psychiatry, University of Toronto, Toronto; Laura Fitzpatrick, Alina Guna, BSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto; Danielle M. Andrade, MD, MSc, FRCPC, Division of Neurology, Department of Medicine, University of Toronto, Toronto; Anthony E. Lang, MD, FRCPC, Institute of Medical Science, University of Toronto, Division of Neurology, Department of Medicine, University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto Western Hospital Research Institute, University Health Network and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto; Eva W. C. Chow, MD, MPH, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto; Anne S. Bassett, MD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Institute of Medical Science, University of Toronto, Toronto General Research Institute, University Health Network, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome, Department of Medicine and Department of Psychiatry, University Health Network, Department of Psychiatry, University of Toronto, Ontario, Canada.
Alina
A
Guna
Nancy J. Butcher, MSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Institute of Medical Science, University of Toronto, Toronto; Wai Lun Alan Fung, MD, ScD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto General Research Institute, University Health Network, Toronto, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome and Department of Psychiatry, University Health Network and Department of Psychiatry, University of Toronto, Toronto; Laura Fitzpatrick, Alina Guna, BSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto; Danielle M. Andrade, MD, MSc, FRCPC, Division of Neurology, Department of Medicine, University of Toronto, Toronto; Anthony E. Lang, MD, FRCPC, Institute of Medical Science, University of Toronto, Division of Neurology, Department of Medicine, University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto Western Hospital Research Institute, University Health Network and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto; Eva W. C. Chow, MD, MPH, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto; Anne S. Bassett, MD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Institute of Medical Science, University of Toronto, Toronto General Research Institute, University Health Network, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome, Department of Medicine and Department of Psychiatry, University Health Network, Department of Psychiatry, University of Toronto, Ontario, Canada.
Danielle M
DM
Andrade
Nancy J. Butcher, MSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Institute of Medical Science, University of Toronto, Toronto; Wai Lun Alan Fung, MD, ScD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto General Research Institute, University Health Network, Toronto, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome and Department of Psychiatry, University Health Network and Department of Psychiatry, University of Toronto, Toronto; Laura Fitzpatrick, Alina Guna, BSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto; Danielle M. Andrade, MD, MSc, FRCPC, Division of Neurology, Department of Medicine, University of Toronto, Toronto; Anthony E. Lang, MD, FRCPC, Institute of Medical Science, University of Toronto, Division of Neurology, Department of Medicine, University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto Western Hospital Research Institute, University Health Network and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto; Eva W. C. Chow, MD, MPH, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto; Anne S. Bassett, MD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Institute of Medical Science, University of Toronto, Toronto General Research Institute, University Health Network, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome, Department of Medicine and Department of Psychiatry, University Health Network, Department of Psychiatry, University of Toronto, Ontario, Canada.
Anthony E
AE
Lang
Nancy J. Butcher, MSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Institute of Medical Science, University of Toronto, Toronto; Wai Lun Alan Fung, MD, ScD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto General Research Institute, University Health Network, Toronto, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome and Department of Psychiatry, University Health Network and Department of Psychiatry, University of Toronto, Toronto; Laura Fitzpatrick, Alina Guna, BSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto; Danielle M. Andrade, MD, MSc, FRCPC, Division of Neurology, Department of Medicine, University of Toronto, Toronto; Anthony E. Lang, MD, FRCPC, Institute of Medical Science, University of Toronto, Division of Neurology, Department of Medicine, University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto Western Hospital Research Institute, University Health Network and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto; Eva W. C. Chow, MD, MPH, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto; Anne S. Bassett, MD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Institute of Medical Science, University of Toronto, Toronto General Research Institute, University Health Network, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome, Department of Medicine and Department of Psychiatry, University Health Network, Department of Psychiatry, University of Toronto, Ontario, Canada.
Eva W C
EW
Chow
Nancy J. Butcher, MSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Institute of Medical Science, University of Toronto, Toronto; Wai Lun Alan Fung, MD, ScD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto General Research Institute, University Health Network, Toronto, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome and Department of Psychiatry, University Health Network and Department of Psychiatry, University of Toronto, Toronto; Laura Fitzpatrick, Alina Guna, BSc, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto; Danielle M. Andrade, MD, MSc, FRCPC, Division of Neurology, Department of Medicine, University of Toronto, Toronto; Anthony E. Lang, MD, FRCPC, Institute of Medical Science, University of Toronto, Division of Neurology, Department of Medicine, University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto Western Hospital Research Institute, University Health Network and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto; Eva W. C. Chow, MD, MPH, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto; Anne S. Bassett, MD, FRCPC, Clinical Genetics Research Program, Centre for Addiction and Mental Health, Institute of Medical Science, University of Toronto, Toronto General Research Institute, University Health Network, The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome, Department of Medicine and Department of Psychiatry, University Health Network, Department of Psychiatry, University of Toronto, Ontario, Canada.
Anne S
AS
Bassett
D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003024:Clozapine / Q000008:administration & dosage* / Q000009:adverse effects; D004062:DiGeorge Syndrome / Q000188:drug therapy / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D057915:Drug Substitution; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D009205:Myocarditis / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics; D012640:Seizures / Q000139:chemically induced; D016896:Treatment Outcome; D055815:Young Adult
D014150:Antipsychotic Agents; D003024:Clozapine