Long-term benzodiazepine use is associated with increased mortality in people with schizophrenia

What I did before

When psychiatric patients are treated in an emergency department, they are often hypervigilant, manic, or otherwise in an excited, agitated state. The current standard of care to manage acute agitation in adults is using an antipsychotic medication and a benzodiazepine, often loxapine or haloperidol and lorazepam. For patients who have schizophrenia, antipsychotic medication alone often treats such symptoms in the longer term, yet many patients are discharged with a benzodiazepine prescription continue long-term benzodiazepine use possibly because the community clinician hopes to avoid triggering a relapse in discontinuing the medication. As a psychiatrist who has worked on acute and tertiary inpatient units, I have discharged patients on benzodiazepines with the expectation it would eventually be discontinued, but I have also seen many patients for whom it never was.

What changed my practice

Then, in 2013 while at the 7th Annual Pacific Psychopharmacology Conference, I was introduced to research showing that people with schizophrenia on chronic benzodiazepine therapy have an increased risk for suicide and all-cause mortality. I kept these observations in the back of my mind and was further alarmed in 2016 when another article from the same researchers found high-dose benzodiazepine use, but not lesser doses, was associated with increased suicide and cardiovascular mortality.

What I do now

Based upon these studies, I find the evidence compelling that benzodiazepines are contraindicated for long-term use in people with schizophrenia. When appropriate, I continue to use lorazepam for acute agitation amongst other reasons, I also educate patients about the risk of long-term use, including dependence and cognitive impairment in addition to mortality.To raise awareness of this issue among my colleagues, I mention the rationale and include recommendations for tapering benzodiazepines in consultation reports and discharge summaries.

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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.

References

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.