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. 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 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

Meet Miriam Cohen, new access coordinator

Miriam Cohen has recently joined the BC Psychosis Program as our access and discharge coordinator. Miriam has extensive experience in mental health nursing, and she previously worked at UBC hospital as the coordinator for the Early Psychosis Intervention Program from 2000 until 2003 and continued in that role when the program moved to the community. More recently, she was the program director for child and adolescent psychiatry at BC Children’s Hospital, and she received the Oustanding Nurse Award from BC Mental Health and Addictions Services in 2008.

Miriam received her training at York University and Seneca College in Ontario, and completed her Bachelor of Science in Nursing at UBC in 1996. We are pleased to have her join our team; she already has ideas about improving the referral and admissions process.

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

Pimozide is ineffective for clozapine augmentation

Partial or non-response to clozapine is a challenging clinical situation. For these patients, who are considered refractory or ultra-resistant, we have limited options. Available evidence for augmenting clozapine is discouraging, but even negative trial results are valuable as a guide for what not to do. Exposing patients to ineffective treatments increases both costs and risk of adverse effects.

Pimozide, a potent D2 receptor antagonist, was found to be effective in a 1997 open-label clinical trial in partial clozapine responders. In a 2011 double-blind, placebo-controlled, 12-week trial in patients with partial or non-response to clozapine, pimozide at a mean dose of 6.5 mg daily was ineffective (1). A different U.S. group just published another randomized, double-blind, placebo-controlled trial of pimozide at 4 mg daily in patients with partial clozapine response (2). Using the BPRS, the Schedule for the Assessment of Negative Symptoms, and evaluations of verbal memory, working memory and executive function, the investigators found no significant differences between the groups at 12 weeks, although both showed improvement in the BPRS over time.

With two negative trials, it seems that pimozide as a clozapine augmentation agent can be put to rest. In fact, the entire strategy of adding first-generation D2 antagonists to clozapine for partial or non-repsonse is dubious.

References

1. Friedman JI, Lindenmayer JP, Alcantara F, et al. Pimozide augmentation of clozapine in patients with schizophrenia and schizoaffective disorder unresponsive to clozapine monotherapy. Neuropsychopharmacology. 2011;36:1289-1295. Full text

2. Gunduz-Bruce H, Oliver S, Gueorguieva R, et al. Efficacy of pimozide augmentation for clozapine partial responders with schizophrenia. Schizophr Res. 2013;143:344-347. 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.

A Canadian cohort of patients with treatment-resistant schizophrenia

Researchers at the Centre for Addiction and Mental Health in Toronto characterized a cohort of people with schizophrenia who had enrolled in a genetics study. In this convenience sample of 478 subjects, 156 were considered treatment resistant (TR) according to American Psychiatric Association guidelines. The APA guidelines define treatment resistance as “little or no symptomatic response to multiple (at least two) antipsychotic trials of an adequate duration (at least 6 weeks) and dose (therapeutic range).”

The investigators found no correlation between treatment resistance and sex; family history of psychosis; schizophrenia subtype; cannabis, alcohol or drug use; or number of cigarettes consumed daily. However, the TR patients had been ill for a mean of 21 years compared with 15 years for the non-TR group (P < .001). Among patients identified as having white European ancestry, 37% were TR, whereas 18% of nonwhites were TR (P =.03).

Several treatment factors were significantly correlated with treatment resistance. In the TR group, 33% were on clozapine compared with 13.3% in the non-TR group, and 25% of TR patients were on more than one antipsychotic, double the rate in the non TR group. Ten percent of the TR patients were on clozapine and at least one other antipsychotic. Furthermore, the TR patients had a mean of 3 failed medication trials, whereas the non-TR patients had a mean of 0.5 failed trials.

This nonrandom sample is not necessarily representative of all TR patients, so the significance of the lower rate among non-white patients is unclear. The study corroborates previous research indicating that treatment resistance occurs in chronic patients, and that polypharmacy is used possibly at the expense of clozapine.

References

Teo C, Borlido C, Kennedy JL, De Luca V. The role of ethnicity in treatment refractory schizophrenia. Compr Psychiatry. 2013;54(2):167-172. Link to abstract.

Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(Suppl):1-56.

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!