12-month trial of clozapine augmentation with aripiprazole or haloperidol

The latest trial for clozapine-resistant patients comes from Italy (1). The Clozapine Haloperidol Aripiprazole Trial (CHAT) is a multicentre, randomized, 12-month trial of patients with schizophrenia and persistent positive symptoms despite at least six months of clozapine therapy at a minimum dose of 400 mg. Outcome measures included the Brief Psychiatric Rating Scale and, for subjective rating of adverse effects, the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). The primary outcome was treatment discontinuation, “a pragmatic and reliable estimate of treatment efficacy and tolerability” according to the authors.

Based on a power calculation, the investigators intended to recruit 194 participants but randomized 106 patients, about 65% men and with a mean age of 41 years. In addition to clozapine, patients received either haloperidol or aripirpazole for 12-months. Baseline demographics and BPRS scores did not significantly differ between the groups. The dose of adjunctive antipsychotic was adjusted according to clinical response, and the patients could receive any necessary additional medications including mood stabilizers and antidepressants. Although the investigators did not report the mean dose of adjunctive antipsychotics in this publication, they reported in 2011 that at month 3, the mean aripiprazole dose was 11.8 mg and the mean haloperidol dose was 2.8 mg (2).

During the study, 19 aripirpazole and 15 haloperidol patients withdrew, which was not significantly different. At 6 months, the mean BPRS score in the aripirpazole group had decreased by 8.8, and in the haloperidol group, by 8.1; the improvement persisted at 12 months. By 3 months the mean LUNERS score decreased significantly in the aripirpazole group but not in the haloperidol group, which indicated that patients taking aripirpazole reported a decrease in adverse effects whereas those taking haloperidol did not.
Both aripirpazole and haloperidol showed effectiveness in augmenting clozapine, but aripirpazole was better tolerated by self-report. Despite this apparent preference for aripirpazole, the groups had a comparable rate of treatment discontinuation: about a third of patients dropped out, most during the first 6 months of augmentation. The findings of the study are limited by lack of statistical power and of a placebo arm. The researchers claim, however, that CHAT is the longest non-industry-sponsored RCT of treatment-resistant schizophrenia.

Reference

1. Cipriani A, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia. J Clin Psychopharmacol. 2013;33: 533-537. Abstract

2. Barbui C, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial. J Clin Psychopharmacol. 2011;31: 266-273. Abstract

Benzoate and not benzodiazepines for antipsychotic augmentation

Dr. Jari Tiihonen, Professor of Clinical Neuroscience at the Karolinska Institure in Stockholm, Sweden, discussed findings from his research on polypharmacy in people with schizophrenia on September 20 at the 7th Annual Pacific Psychopharmacology Conference. Using national databases in Finland, his team examined prescription medications and all-cause mortality in a cohort of 2,588 patients during 7 years. Antipsychotic polypharmacy was not associated with increased mortality, and antidepressant use was associated with a decreased risk of death by suicide. In contrast, benzodiazepine use was associated with an increase in suicide and all-cause mortality. Dr. Tiihonen speculated that the sedative effects of benzodiazepines may predispose to unintentional injuries, and withdrawal symptoms may increase agitation and dysphoria which could elevate the risk of suicide.

As for new findings in treatment-resistant schizophrenia, Dr. Tiihonen mentioned the recently published clinical trial of famotidine (see my blog post of July 14). His group is now attempting a replication for which they plan to recruit 140 patients. He also called attention to a randomized clinical trial of sodium benzoate at a dose of 1 gram daily which was presented at the December, 2012 meeting of the American College of Neuropsychopharmacology. The researchers added benzoate or placebo to treatment of 52 patients with chronic schizophrenia “stabilized with antipsychotics for 3 months or longer.” According to the abstract posted on the ACNP Web site, at 6 weeks of treatment, the benzoate group showed significant improvement in PANSS total, positive, and negative scales, as well as in overall neurocognition. The effect size on PANSS total was 1.76, which is very large. It’s not clear if these patients met the usual definition of treatment resistance, i.e. poor response to adequate trials of two antipsychotics, but we should know more soon as the study is in press.

Reference

Tsai GE, Lane H-Y, Green MF. A randomized, double-blind, placebo-controlled add-on treatment of benzoate, a D-amino acid oxidase Inhibitor, for schizophrenia. Neuropsychopharmacology. 2012; 38: S198-S313. Available at: http://www.nature.com/npp/journal/v38/n1s/full/npp2012220a.html (poster T162)

The skeptical UK view of second-generation antipsychotics

Professor Tim Kendall, director of the National Collaborating Centre for Mental Health in the United Kingdom, gave a plenary lecture on “The Rise and Fall of the Atypical Antipsychotics” at the 7th Annual Pacific Psychopharmacology Conference on 20 September 2013, in Coquitlam, BC. According to Dr. Kendall, the National Institute for Health and Care Excellence (NICE), for which the National Collaborating Centre provides expertise in its psychiatric guideline development, concluded in a 2002 appraisal that the atypical antipsychotics might have greater efficacy and fewer adverse effects than typical antipsychotics. In 2009, NICE issued an updated guideline for schizophrenia treatment based on new evidence and multiple pairwise meta-analyses and found that the atypical or second-generation antipsychotics do not constitute a special class. In his view, the distinction is merely a marketing tool.

In selecting a medication, Dr. Kendall said we should ask our patients, “Would you rather be fat or stiff?” because the decision often comes down to whether patients can better tolerate extrapyramidal or metabolic adverse effects. An exception is clozapine, which falls into the “fat” category but remains the choice for treatment resistance; otherwise NICE does not recommend any specific antipsychotic over another.

A simultaneous economic analysis of antipsychotic treatment also produced provocative findings. Although the price of antipsychotic medications can vary widely, the model found no significant difference in cost effectiveness among the seven antipsychotics included in the analysis (amisulpride, aripiprazole, haloperidol, olanzapine, paliperidone, risperidone, zotepine). The driver of cost is relapse and hospitalization; drug-acquisition cost plays a minor role in the overall expense of a patient’s care. The lesson is that whatever medication a given patient is willing to take and can tolerate may improve adherence, reduce relapse, and save the immense price of inpatient treatment.

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