Robert Zipursky, M.D.

Robert Zipursky

Dr. Zipursky served as the Tapscott Chair in Schizophrenia Studies from 2000 through 2006. During this time, Dr. Zipursky also served as the Clinical Director of the Schizophrenia and Continuing Care Program at the Centre for Addiction and Mental Health. In bringing these two roles together, Dr. Zipursky’s focus as Tapscott Chair was on creating synergy between the research, educational and clinical activities at the University of Toronto and at CAMH in order to stimulate teaching and translate new knowledge into improvements in care. These efforts were focused in a number of areas of schizophrenia research which are summarized below.

Early Intervention for Schizophrenia
Prior to assuming the Tapscott Chair, Dr. Zipursky had established the First Episode Psychosis Program at the Clarke Institute of Psychiatry/CAMH in order to advance the understanding of schizophrenia, to develop approaches to optimize the outcome from the schizophrenia, and to train expert clinicians and researchers in this area. The program included a unique dedicated inpatient research unit and outpatient clinic. As Tapscott Chair, Dr. Zipursky was able to develop Canada’s first home treatment team for first episode psychosis, The Home Intervention Program (HIP team). With the support of the CAMH Foundation, a unique community-based program was developed to help support young people who had experienced a first episode of psychosis to return to school, to work and to manage successfully with their friends and families. This new program, named “LEARN” (Learning, Education, Advocacy, Recreation Network) was created in a renovated youth-friendly space on St. Clair Avenue West in Toronto. Dr. Zipursky also established the PRIME (Prevention through Risk Identification, Management and Education) Clinic to meet the needs of young people at high risk of developing psychosis with the goal of developing effective interventions to prevent the development of psychosis. The PRIME Clinic carried out the first randomized controlled trials in North America aimed at preventing psychosis using antipsychotic medication (1) and cognitive behavioural therapy (2). Dr. Zipursky was a co-founder of the Ontario Working Group on Early Intervention in Psychosis. The advocacy efforts of this group led to the adoption of early intervention for psychosis as a policy priority by the Ontario Government in 2003 and to the introduction of new funding to establish early intervention teams in communities across Ontario in 2004. In 2002, Dr. Zipursky co-edited a new book, “The Early Stages of Schizophrenia”, which summarized progress in understanding and treating the first episode of schizophrenia.

Optimizing the antipsychotic treatment of schizophrenia
The First Episode Psychosis Program had been established in part to advance the study of schizophrenia with newly developed brain imaging technologies, specifically positron emission tomography (PET) and Magnetic Resonance Imaging (MRI). Dr. Zipursky and colleagues at the University of Toronto demonstrated that most patients being treated for a first episode of schizophrenia could be treated effectively with a small fraction of the doses of first generation antipsychotic medication that had been in common usage (3). While this was initially highly controversial, the research team including Dr. Shitij Kapur, Dr. Gary Remington together with Dr. Zipursky, were able to use PET to demonstrate that medications given at these low doses actually occupied a large enough percentage of dopamine D2 receptors in the brain to bring about an antipsychotic response (4, 5). This work has contributed to a dramatic change in how antipsychotic medications are prescribed for the treatment of schizophrenia. The new second generation antipsychotics were found in these studies to achieve similar levels of D2 receptor occupancy leading to the question of whether the new medications would still be found to be more effective if they were compared to lower doses of the older medications (6). This question was investigated directly through participation in a multicentre trial comparing one of the new medications, olanzapine, with the gold standard first generation medication, haloperidol, in patients experiencing a first episode of schizophrenia. This study demonstrated that at comparable levels of D2 receptor occupancy, a standard first generation antipsychotic and prototype second generation antipsychotic were equally efficacious (7).

Redefining the onset of action of antipsychotic medications
The initial studies of antipsychotic response in patients with a first episode of schizophrenia carried out by Dr. Zipursky and colleagues not only found that patients responded to very low doses of medication but that they were also responded very rapidly, within the first few weeks of treatment. It had been accepted wisdom in the field that antipsychotics had a delayed onset of action of 3 to 4 weeks. Using meta-analytic techniques with data synthesized from 20 years worth of clinical trials, Dr. Ofer Agid and colleagues in the Schizophrenia Program demonstrated that the onset of action of antipsychotic medication is not delayed but rather is most dramatic in the first 2 weeks of treatment and begins in hours to days (8). This work has now been extensively replicated and has had a major impact on our understanding of the optimal medical management of schizophrenia.

Investigating changes in cerebral gray matter volume in schizophrenia
Work by Dr. Zipursky in the 1980s and 1990s had demonstrated that patients with schizophrenia had on average smaller brain gray matter volumes and that these differences were more striking in patients who had been ill with schizophrenia for many years compared to those evaluated at the time of their first episode of psychosis (9, 10). There has been great interest in investigating whether these gray matter changes worsen over the course of the illness or whether those patients with more striking gray matter changes at illness onset are more likely to have a more severe course of illness. This question was investigated though the program’s involvement in a large multicentre study. It was found that significant changes in gray matter volumes did take place in the first two years of illness but that these may well be due to the effects of antipsychotic medications (11). This striking finding has now been replicated in clinical and animal studies and provides support to the possibility that treatment with antipsychotic medications may underlie the changes in brain structure that have been observed to progress over the course of schizophrenia.

Defining the extent of antipsychotic-induced weight gain
The introduction of second generation antipsychotic medications was associated with a reduction in the incidence of uncomfortable acute extrapyramidal side effects as stiffness, tremor and restlessness which were very common with the first generation antipsychotic medications. However, second generation medications were observed to lead to substantial weight gain. Dr. Zipursky and colleagues were able to demonstrate using data acquired from a randomized controlled trial that one of the newer second generation antipsychotic medications, olanzapine, resulted in much greater weight gain than had previously been reported. By using a design that involved a large number of patients who had received very little previous treatment and following their weight gain for two years, it was possible to show that patients being treated for a first episode of psychosis with olanzapine gained over 15 kg on average (12). Accurately establishing the weight gain risk associated with olanzapine heightened awareness of the serious metabolic risks associated with the prescription of antipsychotic medications and has intensified efforts to prevent this serious adverse event through preventive approaches.

Characterizing the clinical outcome from schizophrenia
Schizophrenia has long been considered a progressive disease in which those affected experience a marked and protracted deterioration in their mental health and their ability to function. Through a systematic review of the literature on outcome from a first episode of schizophrenia, Dr. Natasja Menezes, working together with Dr. Zipursky, demonstrated that the clinical outcome from a first episode of schizophrenia may be more favourable than previously reported and that the percentage of patients with either a good outcome or a poor outcome appears to remain stable over time (13). This finding adds to a growing body of literature that suggests that schizophrenia may not be an inherently progressive illness; with both optimal treatment and adherence, stabilization and recovery can be expected for a majority of patients.

Tapscott Chair in Schizophrenia Studies
University of Toronto
2000 – 2006

Further Reading:  The Myth of Schizophrenia as a Progressive Brain Disease

Selected References

1. McGlashan, T., Zipursky, R.B., Perkins, D., Addington, J., Miller, T., Woods, S., Hawkins, K., Hoffman, R., Lindborg, S., Trzaskoma, Q., Tohen, M., Breier, A. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006;163(5):790-9.
2. Addington J, Epstein I, Liu L, French P, Boydell KM, Zipursky RB. A randomized controlled trial of cognitive behavioral therapy for individuals at clinical high risk of psychosis. Schizophr Res. 2011;125(1):54-61.
3. Zhang-Wong J, Zipursky RB, Beiser M, Bean G. Optimal haloperidol dosage in first-episode psychosis. Canadian Journal of Psychiatry. 1999;44(2):164-7.
4. Kapur S, Remington G, Jones C, Wilson AA, DaSilva J, Houle S, Zipursky RB. High levels of dopamine D2 receptor occupancy with low dose haloperidol treatment: A PET study. Am J Psychiatry. 1996;153:948-50.
5. Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000;157(4):514-20.
6. Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry. 1999;156(2):286-93.
7. Lieberman, J.A., Tollefson, G., Tohen, M., Green, A.I., Gur, R.E., Kahn, R., McEvoy, J., Perkins, D., Sharma, T., Zipursky, R.B., Wei, H., Hamer, R.M. Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized double-blind trial of olanzapine vs haloperidol. Am J Psychiatry. 2003;160:1396-404.
8. Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry. 2003;60(12):1228-35.
9. Zipursky RB, Lim KO, Sullivan EV, Brown BW, Pfefferbaum A. Widespread cerebral gray matter volume deficits in schizophrenia. Arch Gen Psychiatry. 1992;49(3):195-205.
10. Zipursky RB, Lambe EK, Kapur S, Mikulis DJ. Cerebral gray matter volume deficits in first episode psychosis. Arch Gen Psychiatry. 1998;55(6):540-6.
11. Lieberman, J. A., Tollefson, G.D., Charles, C., Zipursky, R.B., Sharma, T., Kahn, R.S., Keefe, R.S., Green, A.I., Gur, R.E., McEvoy, J., Perkins, D., Hamer, R. M., Gu, H., Tohen, M. Antipsychotic drug effects on brain morphology in first-episode psychosis. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry. 2005;62(4):361-70.
12. Zipursky, R.B., Gu, H., Green, G., Perkins, D., Tohen, M., McEvoy, J., Strakowski, S., Sharma, T., Kahn, R., Gur, R., Tollefson, G., Lieberman, J.; HGDH Study Group. Course and predictors of weight gain in people with first-episode psychosis treated with olanzapine or haloperidol. British Journal of Psychiatry 2005;187:537-43.
13. Menezes NM, Arenovich T, Zipursky RB. A systematic review of longitudinal outcome studies of first-episode psychosis. Psychological Medicine. 2006;36(10):1349-62.