Polypharmacy increases risk of NMS

A study from the UK examined 67 cases of neuroleptic malignant syndrome and 254 controls (1). The researchers made several interesting findings, in particular that patients on 3 or more antipsychotics had an odds ratio of 5.4 for NMS. This, along with evidence for increased risk of diabetes in patients on multiple antipsychotics (2), give reason to be cautious about antipsychotic polypharmacy.


1. Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome. Su Y-P, Chang C-K, Hayes RD, et al. Acta Psychiatr Scand. Published online 15 November 2013. Abstract

2. Treatment with antipsychotics and the risk of diabetes in clinical practice. Kessing LV, Thomsen AF, Mogensen UB, Andersen PK. Br J Psychiatry. 2010;197:266–271. Full text

A meta-analysis of anti-inflammatory agents in schizophrenia

The inflammatory hypothesis of schizophrenia is getting more attention recently along with research on the role of anti-inflammatory medications. A European group has published a meta-analysis of 26 randomized controlled trials that fulfilled their inclusion criteria testing the following agents with anti-inflammatory properties (1):

• aspirin
• celecoxib
• davunetide
• omega-3 fatty acids
• estrogens
• minocycline
• N-acetylcysteine (NAC)

The investigators calculated Hedge’s g to derive an effect size for reduction of psychotic symptom severity; results were significant for aspirin (ES=0.3), estrogens (ES=0.51), and NAC (ES=0.45). Two trials used aspirin at 1000 mg daily in combination with antipsychotic medication for 3-4 months. The estrogen trials involved mostly women subjects and used a wide range of doses for antipsychotic augmentation. The NAC findings are based on only one trial. Most of the studies did not involve subjects clearly defined as treatment-resistant, but until more evidence is available, the findings may be helpful in select treatment-resistant patients.


1. Sommer IE, Van Westrhenen R, Begemann M, et al. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2013 doi: 10.1093/schbul/sbt139 (published online October 8, 2013) Abstract

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.


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

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.

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.

Defining Treatment Resistance

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

Antipsychotic augmentation for clozapine resistance

A European team published a meta-analysis of combining clozapine with another antipsychotic in 2007 which was not encouraging for this strategy. Nonetheless, clinicians have persisted in combining clozapine with either first or second-generation antipsychotics. Is this entirely irrational or do practicing psychiatrists know something that researchers don’t?

The same team has published an updated meta-analysis comprising a total of 14 studies, including some unpublished data, with 734 subjects. All the studies were randomized, blinded, placebo-controlled, and a minimum of six weeks in duration. The coadminstered antipsychotics included amisulpride, aripirprazole, chlorpromazine, haloperidol, pimozide, risperidone, sertindole, and sulpiride.

The combined reduction in symptom scores favored combined therapy with an effect size of -0.239 (P = 0.028) and 95% confidence intervals of -0.452 to -0.026. The investigators examined the duration of cotherapy and found no advantage for treatment lasting ten or more weeks compared with less than ten weeks.

The researchers concluded that combining clozapine with another antipsychotic may offer on average “a small benefit.” Although this is the largest such meta-analysis to date, it offers only limited clinical guidance. Determining which patients may benefit from addition of which antipsychotic remains the practitioners’ quandary.

Taylor DM, Smith L, Gee SH, Nielsen J. Augmentation of clozapine with a second antipsychotic – a meta-analysis. Acta Psychiatr Scand. 2012;125:15–24.

Does lamotrigine augment clozapine?

Many of the patients referred to B.C psychosis Program are on clozapine or have received it in the past, and many have had a limited response. Clozapine-resistance is a big challenge for psychiatrists who manage chronic psychosis, and a recent quantitative review of clozapine augmentation strategies provides little guidance or solace. Stefan Leucht and colleagues examined randomized, masked, placebo-controlled studies

of at least two weeks duration in which another drug was added following at least four weeks of  clozapine therapy. Whenever possible, they used intention-to-treat data to calculate effect size.

The studies involved a range of medications including antidepressants, antipsychotics, glutamatergic agents, and antiepileptics. Lamotrigine is particularly of interest because Tiihonen’s group performed a meta-analysis in 2009 based on five studies that showed a significant effect for augmentation of clozapine. This group obtained unpublished data from studies that looked at lamotrigine added to a variety of antipsychotics, and intention-to-treat outcomes from the trial by Zocali, the largest study to date with 30 subjects on active therapy. Based on the 2009 meta-analysis, Goff commented that “the addition of lamotrigine in patients who remain symptomatic despite adequate clozapine treatment represents the most promising treatment option currently available.”

Although Tiihonen et al. found insignificant heterogeneity, Leucht et al. did find heterogeneity and concluded that the Zocali study was an outlier. They therefore excluded it from their final analysis. This is the crucial difference between the two meta-analyses and the reason for the sharply divergent conclusions. Four studies of lamotrigine augmentation are negative and one is positive. A closer look reveals that the Zocali trial was 24 weeks in duration, whereas the other trials were 10 to 14 weeks; could this be a crucial difference? Goff is still correct, and rather than throw lamotrigine overboard, we need a replication trial lasting 24 or 30 weeks. We know that the benefits of clozapine may take many months to be fully evident, so we should not expect that clozapine augmentation to be a quick affair.

As for other findings of the Leucht meta-analysis, sulpiride augmentation showed significant impact on both positive and negative symptoms, and citalopram showed significant impact on negative symptoms, but the findings are based on one trial each. A trial of an experimental glutamatergic agent showed a signal. This leaves us with few clear optins but some direction for further research.


Sommer IE, Begemann MJ, Temmerman A, Leucht S. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull. Mar 21 2011; Epub ahead of print; doi:10.1093/schbul/sbr004

Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: A systematic review and meta-analysis. Schizophr Res. 2009;109:10–14.

Goff DC. Review: lamotrigine may be an effective treatment for clozapine resistant schizophrenia. Evid Based Mental Health. 2009;12:111.

Zoccali R,Muscatello MR,Bruno A, Cambria R, et al. The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophr Res. 2007;93:109–116.