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.
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.
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
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.
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
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.
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.
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.
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!
A friend and colleague, Dr. Kate Tairyan, sent me a link to a commentary in the New York Times by Paul Steinberg, a U.S. psychiatrist. I happen to be in the United States visiting family for the holidays and this article made me grateful to have the opportunity to practice psychiatry in a functional health care system instead of a dysfunctional patchwork of public and private health care payers and deliverers. Although Canadian health care institutions are imperfect,the inadequacy of mental health care in the United States for the neediest patients is tragic and as we have witnessed in 2012, even lethal.
Happy New Year and I hope that our efforts at the BC Psychosis Program will continue to improve in 2013.
Although clinicians and researchers have not reached consensus on diagnosing treatment-resistant schizophrenia (TRS), most of us use the same working definition. For instance, the Canadian Psychiatric Association treatment guidelines suggest that patients who fail to respond to two antipsychotic trials are treatment resistant. Persistent positive symptoms and functional impairment are the essential factors in TRS, and the significance of the diagnosis lies in determining when a clozapine trial is appropriate, a high-stakes decision for an individual patient.
In a paper published in Psychiatry Research (ref), a group of Canadian and Japanese psychiatrists have proposed a definition that takes into account medication unresponsiveness and functional impairment. Based on a literature review, they endorse the widespread criterion for TRS of failure of two different antipsychotics, each attaining a chlorpromazine-equivalent daily dose of at least 600 mg for a duration at least six consecutive weeks. The authors do not specify any particular classes of antipsychotics given the limited evidence that non-clozapine antipsychotics differ in efficacy.
An important factor is how well previous treatment response is documented. The authors indicate that the failure to respond to past trials should be “clearly documented and unequivocal.” The use of quantitative measures such as the PANSS and BPRS is ideal but is rare in routine practice, so instead the authors suggest treatment failure as end-point of CGI-Severity scale of 4 or greater and Global Assessment of Function (GAF) of 50 or less. If the past trials are not adequately documented, failure of one prospective trial would be required to satisfy this criterion.
Once the presence of TRS is confirmed, the authors propose that response to treatment would require a score on CGI-Improvement scale of 1 or 2 or a decrease of 20% on the PANSS or BPRS, along with and an 20-point or greater increase in GAF. They define a partial response as a CGI-Improvement score of 3 or a 10-19% improvement in PANSS or BPRS, along with GAF improvement of 10-19 points.
At the BC Psychosis Program, we are fortunate to have the resources that allow us to employ standardized instruments such as the PANSS, CGI scale and GAF at baseline and at discharge to document patients’ response to treatment. One point of this article is that simply using the CGI and GAF, which take little time, would be very helpful for subsequent care givers in understanding a patient’s response to prior medication trials.
Suzuki T, Remington G, Mulsant BH et al. Defining treatment-resistant schizophrenia and response to antipsychotics: A review and recommendation. Psychiatry Res. 2012;197(1-2):1-6. Abstract
Dr. Harish Neelakant recently joined the BC Psychosis Program as a psychiatrist. He came to B.C. from the United Kingdom where he completed his residency in psychiatry in Newcastle-upon-Tyne in 2006. He has a special interest in cognitive therapy for psychosis and during his residency, he worked under Professor Douglas Turkington, a leader in the field. After his training, Dr. Neelakant worked in an early psychosis program in the U.K. which implemented the use of mobile devices, a complementary multidisciplinary model, care-giver support and collaboration, and primary medical care involvement. Since 2009 he has worked at the South and Midtown mental health teams in Vancouver and with the Vancouver Acute Home-Based Treatment team. In his practice, Dr. Neelakant is interested in prevention of stigma, prevention and early detection of psychosis, and a integrative approach to patient care
As more and more hospitals eliminate smoking on their grounds, including Vancouver Coastal Health, health professionals will benefit from reduced exposure to second-hand smoke. At the same time, they have to help patients adapt to forced abstinence. Many smokers with mental illness want to quit but may not be ready to give up tobacco at the time of hospitalization, and taking cigarettes away is another loss of autonomy to which inpatients must adjust. This raises ethical questions among staff, and compounding the ambivalence toward smoke-free policies is anxiety about symptom exacerbation or even aggression related to forced abstinence. One study of a general psychiatry inpatient service found that forced tobacco abstinence was in fact associated with unplanned discharge and seclusion (1). However, research on outpatients with schizophrenia found that acute nicotine abstinence was associated with a transient increase in negative but not positive symptoms (2).
The restlessness and anxiety that patients in nicotine withdrawal experience may nevertheless be interpreted as psychotic exacerbation. A study in an emergency psychiatric setting showed that nicotine replacement is effective in patients with schizophrenia (3). The authors found that compared to placebo, a 21-mg nicotine patch led to a 23% reduction at 24 hours in the Agitated Behavior Scale. This is similar to the effect of a dose of antipsychotic, suggesting that managing nicotine withdrawal may reduce use of sedating medication.
At the BC Psychosis Program beginning November 20th, newly admitted patients are not able to smoke, and it is important for them to be prepared for this when they arrive. We suggest that patients who smoke and are traveling from distant communities by medical transport receive nicotine replacement en route. All smokers at BCPP receive nicotine replacement therapy, and only when they have independent passes off grounds will they be able to use tobacco products if they choose to do so.
1. Prochaska JJ, Gill P, Hall SM. Treatment of tobacco use in an inpatient psychiatric setting. Psychiatr Serv. 2004;55:1265–1270. Full text
2. Dalack GW, Becks L, Hill E, Pomerleau OF, Meador-Woodruff JH. Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia.
Neuropsychopharmacology. 1999;2:195-202. Full text
3. Allen MH, Debanne M, Lazignac C, et al. Effect of nicotine replacement therapy on agitation in smokers with schizophrenia: a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2011;168:395–399. Full text