Fidel Vila-Rodriguez Joins BC Psychosis Program

FVR_BCPP

Fidel Vila-Rodriguez, MD recently joined the BC Psychosis Program as a staff psychiatrist. Dr. Vila received his medical degree in 2000 at the University Autonoma of Barcelona in Barcelona, Spain and completed a residency in psychiatry at San Joan de Deu Mental Health Services. After graduation, he was an attending psychiatrist at El Prat Mental Health Team as well as a clinical research fellow in schizophrenia. Dr. Vila received his Master of Advance Studies in Neuroscience in 2007 at the University of Barcelona. After coming to Canada in 2006 and graduating from the UBC Psychiatry residency program, Dr. Vila has been practicing in the area of neurostimulation at Vancouver General Hospital and Saint Paul’s Hospital.

Dr. Vila is a Clinical Assistant Professor in the Department of Psychiatry at UBC, and his research interests include understanding the pathogenic mechanisms of and treatment for psychosis and mood disorders. He has extensively published in international peer-reviewed journals and has received many awards for his work including the Tsung-Yi Li Award for Clinical Research, the George Davidson Scholarship Award, and the significant Contribution to Research Award.

Another passion of Dr. Vila’s is soccer. He volunteers as a board member for the Vancouver Street Soccer League, an organization that strives to improve the lives of people with mental illness, addiction, and homelessness through team sports.

Famotidine for treatment-resistant schizophrenia

Psychiatrists regard the histamine-receptor antagonism of antipsychotics mostly as a nuisance given its relationship to sedation and weight gain. Some evidence, including research on animal models and preliminary human investigations, suggest that in fact it has a therapeutic role for schizophrenia. Recent research has found that clozapine is an inverse agonist at H2 receptors, meaning that it reduces H2 receptor activity below its baseline (1).

A Finnish team has completed a four-week randomized, controlled, and double-masked trial of famotidine, a selective H2 antagonist now marketed as an over-the-counter remedy for heartburn (2). They recruited 30 patients with treatment-resistant schizophrenia, mean age about 51 years, who were on a variety of antipsychotics and had residual functional impairment; 11 of them were on clozapine. They assessed them with the Scale for Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANNS), and the CGI. The active-treatment group received 100 mg of famotidine twice daily; no significant adverse reactions occurred, but 3 subjects receiving placebo dropped out “for unclear reasons.”

In comparison with the placebo group, the famotidine group had a significant reduction in mean PANSS total score and PANSS general subscale score and in mean CGI. The mean total PANSS score decreased 11% in the famotidine group and 1% in the placebo group. The researchers acknowledged that their study was too brief and had too few subjects to adequately investigate famotidine, and they suggested a follow-up trial with at least 80 subjects for 8 to 10 weeks to test the potential of this well-tolerated medication in treatment-resistant patients.

References

1. Humbert-Claude M, Davenas E, Gbahou F, et al. Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo. Psychopharmacology. 2012;220:225-241.

2. Meskanen K, Ekelund H, Laitinen J et al. A randomized clinical trial of histamine 2 receptor antagonism in treatment-resistant schizophrenia. J Clin Psychopharmacol. 2013;33:472-478.

Reduction in cortical thickness in treatment-resistant schizophrenia

Reduced grey-matter volume and cortical thickness are well documented in people with schizophrenia, but few studies have examined structural changes in treatment-resistant schizophrenia (TRS). In this study from Brazil, the researchers examined cortical thickness by means of MRI volumetrics in three groups: 61 patients with TRS, 67 patients with non-TRS, and 80 unaffected controls (1). The mean age of all subjects was about 34 years and two-thirds were men. The mean PANSS score of the TRS group was 63.4, significantly greater than the mean score of the non-TRS group which was 54.6. Of the TRS patients, 72% were receiving clozapine whereas the majority of non-TRS patients were receiving either olanzapine, quetiapine, or risperidone.

In comparison with the control group, the TRS group had significant reduction in cortical thickness in four regions of the right hemisphere, including the precentral, middle temporal, and lateral occipital gyri; and six regions of the left hemisphere, including the middle temporal, middle frontal, lateral orbitofrontal, and superior temporal gyri. In comparing the TRS and non-TRS groups, the investigators found a significant reduction in thickness of the left dorsolateral prefrontal cortex in the TRS patients, even when controlling for duration of illness and dose of medication.

The investigators cite existing research suggesting that dysfunction of the dorsolateral prefrontal cortex, which is associated with working memory in healthy subjects, may correlate with poor treatment response. For instance, a 2003 study found that greater cortical volume in this region predicts good response to clozapine (2). Studies that examine the dynamics of volume loss prospectively might help determine the correlates of regional cortical thinning in TRS.

1. Zugman A, Gadelha A, Assuncao I, et al. Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia. Schizophr Res. 30 May 2013. doi: 10.1016/j.schres.2013.05.002. [Epub ahead of print] Abstract

2. Molina V, Reig S, Sarramea F, et al. Anatomical and functional brain variables associated with clozapine response in treatment-resistant schizophrenia. Psychiatry Res. 2003;124(3):153-161. Abstract

Clinical Neurosciences Postscript

The BC Schizophrenia Society has posted a video recording of Clinical Neurosciences 2013 conference online. You can see and hear Dr. Herb Meltzer discussing treatment resistance, Dr. Bill MacEwan on the Vancouver Hotel Study, and even me (Randall White) describing the BC Psychosis Program.

BDNF variant may predict treatment resistance

Among subjects in the CATIE trial of antipsychotic effectiveness, a large U.S. study of schizophrenia treatment, 74 genes were associated with treatment failure as defined by antipsychotic discontinuation (1). Some of the identified genes code for proteins relevant to schizophrenia research, including brain-derived neurotrophic factor (BDNF). The role of BDNF in the pathophysiology of psychosis was reviewed by Nurjono et al., who highlighted research showing correlation of serum BDNF and positive symptoms, and reduction of BDNF-related mRNA in the hippocampus and frontal lobe of schizophrenia patients (2). Furthermore, certain single-nucleotide polymorphisms (SNPs) of the BDNF gene, including Val66Met, correlate with aspects of the disease.

Using the 74 candidate genes from CATIE as a point of departure, Zhang et al. compared SNP frequency in 89 patients on clozapine, who represented a treatment-resistant cohort, to SNP frequency in 190 patients not on clozapine (3). The mean age of subjects was 38.8 years and all were Caucasian. The only SNPs significantly associated with clozapine therapy were located on the BDNF gene. The minor alleles of three BDNF SNPs showed a dose-response such that homozygotes had the greatest likelihood of clozapine therapy and heterozygotes had an intermediate likelihood compared with major allele homozygotes, who had the lowest likelihood of clozapine therapy.

The minor allele of the Val66Met polymorphism results in BDNF with methionine instead of valine at codon 66. In prior research in patients with schizophrenia, the met allele was associated with reduced frontal gray matter, larger lateral ventricles, and impaired short-term episodic memory. Men with schizophrenia who were homozygous for the met allele developed psychosis earlier than heterozygotes or major-allele homozygotes (2).

Studies in Asians and Caucasians found that the BDNF met allele is not associated with increased risk for schizophrenia (1). However, in the presence of schizophrenia, available research indicates that the met allele is associated with a more severe and possibly treatment-resistant form of the disease. Zhang et al. suggest that the mechanism may be related to reduced synaptic plasticity and hippocampal dysfunction, phenotypic expressions of the met allele in healthy humans. Further research in people with schizophrenia who are met carriers may help elucidate the origins of treatment resistance and the pharmacogenetics of clozapine.

References

1. Nurjono M, Lee J, Chong SA. A review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin Psychopharmacol Neurosci. 2012;10:61-70. Full text

2. Need AC, Keefe RS, Ge D, et al. Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis. Eur J Hum Genet. 2009;17:946–957. Full text

3. Zhang JP, Lencz T, Geisler S, Derosse P, Bromet EJ, Malhotra AK. Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia. Schizophr Res. 2013 Feb 19. doi:pii: S0920-9964(13)00058-3. 10.1016/j.schres.2013.01.020 [Epub ahead of print]. Abstract

Clinical Neurosciences Conference 2013

Treatment resistant schizophrenia (TRS) is a clinical challenge for mental health professionals, patients and families. Dr. Herbert Meltzer, Professor of Psychiatry at Northwestern Feinberg School of Medicine in Evanston, Illinois, spoke about his research on this disorder at the Clinical Neurosciences 2013 conference in Vancouver on March 8, 2013. Dr. Meltzer was an investigator in the 1988 pivotal U.S. clozapine trial. He emphasized that clozapine remains the best treatment and is greatly underutilized in North America. He shared data of a 15-year follow-up of clozapine-treated patients indicating that their reduction in psychosis and functional gains persisted and in some cases continued to improve. The one domain in which the outcomes were worse was cognition as measured by the Wisconsin Card Sort test.

For TRS patients who cannot tolerate clozapine, we need more options. Dr. Meltzer has recently investigated high-dose second-generation antipsychotics such as olanzapine, risperidone, and lurasidone. In a 2008 trial of high-dose olanzapine (mean dose 34 mg daily) compared with clozapine (mean dose 564 mg daily) in TRS, he found no difference between the treatments at 6 months, although olanzapine caused more weight gain. This may seem like a long time to wait, but full clozapine response may take as long or longer.

He has also examined high-dose risperidone for TRS in the form of risperidone microsphere depot injections, 100 mg every 2 weeks, compared with a more conventional dose of 50 mg every 2 weeks for 6 months. He found no difference between the doses, which had less robust outcomes than clozapine, but he added that the serum levels of risperidone were not higher than in oral dosing. Dr. Meltzer said that were he to investigate further, he would consider testing 150 mg of risperidone microspheres every 2 weeks.

In other presentations, Dr. Ofer Agid discussed the algorithm for first-episode schizophrenia that he and his team devised at the Centre for Addiction and Mental Health in Toronto. Drs. Debbie Thompson and Joing Wu presented their experience and data from the Fraser Health Psychosis Treatment Optimization Program. Dr. Bill MacEwan, who organizes the annual conference, discussed findings from the Vancouver Hotel Study, and Andrea Jones described distinguishing characteristics of substance-induced psychosis in polysubstance users.

The speaker who perhaps most captivated the audience was Erin Hawkes, a woman living with schizophrenia who discussed her experience as a patient in B.C. hospitals. She has courageously spoken and written about being psychotic, refusing medication, and being restrained and injected. Although she now accepts her diagnosis and treatment, what she underwent was at times degrading and traumatizing. She reminded the audience that small acts of kindness and a gentle approach can make a difference when someone is in great distress and turmoil.

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.