Topirimate as augmentation for antipsychotic treatment

With modulating dopamine as the primary pharmacotherapeutic option to treat schizophrenia, we are left unable to adequately treat at least 30% of our patients, Dr. Christoph Correll told the audience at the 2016 Pacific Psychopharmacology Conference in Vancouver. The evidence for combining dopamine antagonists, whether first- or second-generation antipsychotics, is not favorable according to a meta-analysis he described which is in review for publication. When only high-quality studies were included, which involved 14 trials with 938 subjects, the evidence for combining antipsychotics melted to nothing. Although it makes sense that using two medications with the essentially the same mechanism of action would not be synergistic, many practitioners nevertheless do just that.

Dr. Christoph Correll at the 2016 Pacific Psychopharmacology Conference

Dr. Christoph Correll at the 2016 Pacific Psychopharmacology Conference

Dr. Correll, who is Professor of Psychiatry at Hofstra Northwell School of Medicine and Medical Director of the Recognition and Prevention Program at the Zucker Hillside Hospital in Queens, New York, said that adding agents with a different mechanism of action may be more promising. Topirimate acts to inhibit activity in the glutamate-NMDA receptor complex and is approved as an anticonvulsant. It also counters the weight gain of psychotropic medications by reducing appetite and enhancing insulin sensitivity. He and six coauthors have recently published a meta-analysis of 16 randomized, controlled trials including a total of 934 patients who received topirimate adjunctive to antipsychotic therapy; outcome data included PANSS or BPRS total scores and body weight, and secondary outcomes included positive and negative symptoms and various metabolic measures including waist circumference and serum glucose.

The benefit for augmentation was significant as measured by total PANSS or BPRS for the entire group, and sensitivity analyses showed it held true with a dose of 150 mg per day or less, in first and multi-episode patients, and either with clozapine or non-clozapine antipsychotics. The effect was independently significant for positive and for negative symptoms. Topirimate was associated with a significant reduction in weight with a mean reduction of 2.75 kg; other metabolic measures were unchanged except for significant reduction in serum triglycerides and fasting insulin. Although discontinuation for adverse effects or inefficacy did not differ with topirimate or placebo, notable adverse effects of topirimate included concentration problems and paresthesias.

These studies were all short-term with a mean duration of 11.8 weeks, a problem with many clinical trials in psychiatry  given that schizophrenia is a chronic disorder and patients remain on  medication for months to years. Cognitive problems including word-finding difficulty are a known effect of topirimate, and in an illness in which cognitive impairment is inherent, this could be a major liability. Longer-term effects on cognition, metabolic outcomes and psychosis are needed. Will topirimate be the NMDA-modulating treatment that makes a difference or end up like lamotrigine, abandoned after a brief dalliance?

Reference

Zheng W, Xiang Y-T, Xiang Y-Q, Li X-B, Ungvari GS, Chiu HFK, Correll CU. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand. 2016:1–14. Published online 1 Sep 2016. Abstract

Riverview Refractory Psychosis Data Presented at International Psychiatry Congress

WIN_20150329_113434

 

View the poster in a PDF file here

Abstract

Treatment-resistant psychosis is a challenge to psychiatry and a substantial burden to health-care systems. The province of British Columbia in Canada has publicly funded, universal health care, and patients with treatment-resistant psychosis may receive care in a specialized residential program. Between 1993 and 2011, 663 patients were admitted to this program; this cohort contains one of the largest known series of patients with treatment-resistant schizoaffective disorder.

All patients were evaluated by a psychiatrist, social worker, pharmacist, nurse, general physician, and neuropsychologist. Records from previous hospital admissions were reviewed and all information was presented at a multidisciplinary conference. This resulted in a consensus DSM-III or -IV multiaxial diagnosis and a detailed treatment plan. Ratings of symptoms and functioning at admission and discharge included the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning Scale, the Social and Occupational Functioning Scale, and the Clinical Global Impression of Severity. A research psychologist compiled all data at the time of each patient’s hospitalization.

Patients who did not complete treatment or had a diagnosis other than schizophrenia (SZ), schizoaffective (SZA) or mood disorder (MD) were excluded; the following describes 551 included patients (SZ = 63%, SZA = 29%, MD = 8%). More than half were male (59%), and the mean duration of hospitalization was 30 weeks. The proportion receiving clozapine increased from 21% at admission to 61% at discharge. Those with a MD were less likely to receive clozapine than either SZ or SZA (SZ = 64%, SZA = 61%, MD = 41%). In each diagnostic group, both antipsychotic polypharmacy and the ratio of prescribed daily dose to defined daily dose (PDD/DDD) of antipsychotic medication decreased during hospital stay (polypharmacy: SZ: 52% to 16%, SZA: 52% to 14%, MD: 43% to 0%; PDD/DDD: SZ: 2.1 to 1.6, SZA: 2.1 to 1.4, MD: 1.6 to 1.1). The use of mood stabilizers declined in all groups, but antidepressant use declined only in SZ and SZA. Mean total PANSS score declined in all diagnostic groups, but most in MD, least in SZ, and intermediate in SZA.

In an intensive inpatient program for treatment-resistant psychosis, aggregate improvement occurred despite global reduction in medications while clozapine use nearly tripled. Lower total antipsychotic dose correlated with greater improvement at discharge.

66th Annual American Psychiatric Association Institute on Psychiatric Services in San Francisco

66th Annual American Psychiatric Association Institute on Psychiatric Services in San Francisco

Randall is pleased to be attending the 66th Annual American Psychiatric Association Institute on Psychiatric Services in San Francisco. He presented findings on 630 patients treated during 1993-2010 on the refractory psychosis ward at Riverview Hospital, British Columbia.

To view his abstract, click here.

Follow the conference on Twitter: #IPS2014

The refractory psychosis ward at Riverview Hospital between 1993 & 2010

Riverview Psychiatric Hospital Coquitlam BC

OBJECTIVES: Patients in British Columbia who have treatment-resistant psychosis may receive care in a publicly funded academic program where each patient undergoes a multidisciplinary diagnostic evaluation. We describe this assessment process and present findings on a series of patients including a large number with treatment-resistant schizoaffective (SZA) disorder.

METHOD: All patients admitted to the refractory psychosis ward at Riverview Hospital between 1993 and 2010 had failed to respond to at least two previous antipsychotic trials. A psychiatrist, social worker, pharmacist, nurse, general physician, and neuropsychologist evaluated each patient. All available summaries of previous psychiatric admissions were reviewed, and medical, pharmacological, social and behavioural histories were recorded. All information was presented at a case conference and a DSM-IV multiaxial diagnosis reflected agreement between at least two psychiatrists and a psychologist. Symptom ratings included the Positive and Negative Syndrome Scale, the Global Assessment of Functioning, and the Clinical Global Impression-Severity scale.

FINDINGS: Of the 642 patients who were admitted, 92 did not complete treatment (died, were transfered or left against advice) or received a diagnosis other than schizophrenia (SZ), SZA or mood disorder (MD). Consensus diagnosis differed from referral diagnosis in 27% of cases. Of 378 patients referred with SZ, the consensus diagnosis was SZ in 78%, SZA in 15%, MD in 2%, and other in 5%. Of the 145 referred with SZA, the consensus diagnosis was SZA in 63%, SZ in 26%, MD in 3%, and other in 2%. Two thirds of the SZA group were bipolar type. People with confirmed MD or SZA tended to be older and had a longer illness duration, and were more likely to be female, noncaucasian, and married. Functioning and symptom severity in the preceding year and at admission were worse in SZ than SZA patients. PANSS positive scores were greater for SZ and SZA than MD, and PANSS negative scores were more severe in SZ than SZA or MD. Prior depressive episodes were very common in MD (98%) and SZA (89%), but 35% of SZ patients also had a previous depressive episode. Lifetime substance use disorder was found in 63% and recent substance abuse in 35% of patients, and these proportions did not differ across diagnoses. At admission, SZA patients were more likely than SZ patients to have been on a mood stabilizer, but the mean number of antipsychotics and total amount (defined daily dose) did not differ.

CONCLUSION: In a series of patients with treatment-resistant psychosis, the most common diagnosis was SZ, but 29% had SZA. SZA patients were frequently misdiagnosed in the community, and compared to SZ patients, tended to have better baseline functioning, lower symptom severity, were older, and had been ill longer.

Dr. Leona Adams joins BCPP

Dr. Leona Adams joined the BC Psychosis Program in December. In addition to her role as a psychiatrist with the BCPP, she will continue on staff at St. Paul’s Hospital where she works on an acute inpatient unit, and where she has been involved in collaborative care in the infectious disease clinic.

Dr. Adams obtained her medical degree in 2002 at the University of British Columbia Faculty of Medicine and completed her psychiatry residency at Dalhousie University in Halifax. She is a fellow of the Royal College of Physicians of Canada and a Clinical Instructor in Psychiatry at UBC. In addition to her various activities as a physician, she is a member of the Good Noise Vancouver Gospel Choir. I have attended a number of their concerts and recommend it highly!

Welcome!

The B.C. Psychosis Program at Detwiller Pavilion, UBC hospital, admitted its first patients on Feb 23, 2012. As heir to the Refractory Psychosis ward at Riverview Hospital, the program accepted nine patients from Riverview who were not yet ready to go home. Since then, patients have been admitted from Fraser Health, Vancouver Coastal Health, and Vancouver Island. We have space for patients from Interior and Northern Health Authorities and look forward to referrals from those regions. We have a presence on the Web and our referral forms are available for download.

Many people played a role in organizing the program and helping in the transition from Riverview to UBC Hospital. I was selected to be medical director in December 2011 well after this process was underway. I have not even met some of the people who were instrumental in making the program come together in February with the infrastructure and personnel we need to function. Although I risk offense by leaving some important names out, I want to thank certain people for helping me as I took on this job. They include Bill MacEwan whose counsel has been invaluable, Carole Rudko and Derek Lyons for all the work they’ve done in hiring and training our staff, and Leslie Arnold whose vision and personal interest in this project have made it possible. Sean Flynn, Diane Fredrikson and Veerle Willaeys are physician colleagues who are working to make our clinical program excellent. Bill Honer, Laura Case and Soma Ganesan have provided vital advice and support to me and our team. The steering committee, which includes people from all Health Authorities, continues to meet monthly and is our conduit to the province.

Creating a provincial resource in the ivory tower of UBC is a challenge given the distance to places like Campbell River, Terrace and every other town in B.C. where people and families are affected by severe psychosis. The B.C. Psychosis Program needs to be accessible to them just as it is to people in Vancouver. But the benefit of being at UBC is the ability to attract excellent staff and to create a site for significant research on treatment-resistant psychosis.