Clozapine (multiple brands) reduces mortality and protects against self-harm in patients with treatment-resistant schizophrenia, new research shows.
Investigators at Aarhus University in Denmark found a nearly twofold higher mortality rate among patients with treatment-resistant schizophrenia who were not being treated with clozapine, compared with those treated with the drug. Additionally, their findings suggest a deleterious effect of other antipsychotics on self-harm compared to clozapine.
“The finding that treatment-resistant patients not treated with clozapine had higher rates of self-harm and death than those treated with clozapine corroborates previous research and was not surprising,” study investigator Theresa Wimberley, PhD, told Medscape Medical News.
“We found, though, for the first time, a relatively high rate of self-harm in nonclozapine antipsychotic users and an increased risk of death after clozapine discontinuation, and this needs more attention in future research,” she said.
The study was published online July 28 in the American Journal of Psychiatry.
Excess Early Mortality
Schizophrenia is associated with “an excess rate of early mortality” from both natural and unnatural causes, the authors note.
Some previous research showed significantly lower mortality rates among users of clozapine than among users of other antipsychotic drugs, including first-generation antipsychotics, as well as among patients who had not received antipsychotic drugs. However, these findings were not consistent across all studies.
In addition, previous observational studies have included individuals with schizophrenia or schizophrenia spectrum disorders who were not eligible to receive clozapine, “leading to the problem of confounding by indication,” because it was “not possible to distinguish whether the effect on mortality was due to clozapine treatment or to treatment-resistant schizophrenia in general,” the authors note.
“Several studies have demonstrated the beneficial effect of clozapine with regard to suicide prevention and early death, but in recent years there has been some controversy in the literature regarding the superiority of clozapine, which may lead to confusion among psychiatrists and patients, and this requiring more research,” Dr Wimberley said.
“The Danish registers offer a unique possibility to study outcomes such as death and self-harm in relation to antipsychotic treatment in the entire Danish population with long-term follow-up.”
The researchers state that the goal of their study “was to evaluate rates of all-cause (and cause-specific) mortality and self-harm in association with clozapine treatment and alternative antipsychotic treatment strategies among individuals with schizophrenia meeting criteria for treatment resistance.”
To investigate the question, the researchers utilized information from the Danish National Prescription Registry, the Danish National Patient Registry, and the Danish Psychiatric Central Research Register. They obtained causes of death from the Causes of Death Register. A unique personal identification number was used to link individual data across the national registration systems.
The cohort consisted of all individuals born in Denmark after January 1, 1955, who had received a first diagnosis of schizophrenia at age 18 years or older, as well as all individuals born after January 1, 1996, who met criteria for treatment resistance before June 1, 2013.
The researchers defined the cohort and start of follow-up on the basis of having either a clozapine prescription filled at a pharmacy or of undergoing a psychiatric hospitalization within 18 months during continued treatment with antipsychotics after at least 2 periods of monotherapy with different antipsychotics, each lasting ≥6 weeks.
They studied all-cause and cause-specific mortality as well as the first recorded episode of self-harm after the patient met one of the criteria for treatment resistance. Self-harm included suicide attempts as well as behaviors such as cutting and poisoning, excluding use of food, alcohol, and mild analgesics.
“Primary exposure” was defined as “time-varying treatment, classifying individual follow-up time into periods of clozapine treatment and no clozapine treatment.” The “no treatment” period was further subdivided into a period of nonclozapine antipsychotic treatment and a period in which no antipsychotic treatment was administered.
The researchers also defined secondary exposure measures. To account for periods of concomitant antipsychotic treatment, they further subcategorized treatment status as clozapine monotherapy (reference), treatment clozapine with other antipsychotics, treatment with nonclozapine antipsychotic polypharmacy, nonclozapine antipsychotic monotherapy, and no antipsychotic treatment.
To investigate the timing of all-cause mortality in relation to clozapine, the time-varying treatment was classified as periods of past treatment, no treatment, and current clozapine treatment.
The researchers adjusted for potential confounders such as sex, previous episodes of self-harm, comorbid substance abuse, comorbid somatic disorders, comorbid psychiatric diagnoses, living in the capital area, and cumulative clozapine treatment.
A total of 2370 individuals met the criteria for treatment-resistant schizophrenia. Of these, 45.8% were female. The median age of meeting criteria for treatment resistance was 30.1 years.
In total, 158 individuals (6.7%) died, and 602 (25.4%) had at least one episode of self-harm during follow-up (maximum of 17 years, median: 6.8 years; interquartile range [IQR], 3.2 – 10.6). The overall rates per 100 person-years were 0.9 (95% confidence inteval [CI], 0.8 – 1.1) for all-cause mortality and 4.6 (95% CI, 4.2 – 5.0) for self-harm.
During follow-up, 1372 individuals (58%) with treatment-resistant schizophrenia initiated clozapine treatment. The median number of clozapine treatments was three; the median duration of treatment was 10 months (IQR, 5 – 19 months) for a clozapine treatment period.
When the researchers used a Cox regression model with time-varying clozapine treatment, they found that the absence of clozapine treatment was associated with an elevated rate of all-cause mortality (hazard ratio [HR], 1.88; 95% CI, 1.16 – 3.05), compared with clozapine treatment in adjusted models.
Self-harm, Mortality Data
They found “substantially higher” estimates for no antipsychotic treatment (HR, 2.50; 95% CI, 1.50 – 4.17) and “somewhat higher” estimates for nonclozapine antipsychotic treatment (HR, 1.45; 95% CI, 0.86 – 2.45) than for clozapine treatment.
The highest rates of all-cause mortality were found after clozapine discontinuation, particularly within the first year, when compared with rates during clozapine treatment.
Compared with current clozapine treatment, the 1-year mortality HRs, when adjusted for sex, age, calendar year, psychiatric hospitalization, and comorbid somatic diseases, were 1.41 (95% CI, 0.63 – 3.13) in periods of no past or current clozapine treatment and 2.65 (95% CI, 1.47 – 4.78) in periods after clozapine discontinuation.
The researchers analyzed cause-specific mortality in 2141 patients, of whom 125 (5.8%) died during follow-up. They found that, using clozapine treatment used as reference, the estimated adjusted HRs for nonclozapine antipsychotic treatment or no antipsychotic-based treatment were 1.74 (95% CI, 0.59 – 5.12) for suicide, 1.41 (95% CI, 0.80 – 2.49) for deaths from other diseases or medical conditions, and 0.77 (95% CI, 0.31 – 1.89) for deaths from other external causes.
Nonclozapine antipsychotic treatment was associated with an increased rate of self-harm (HR, 1.36; 95% CI, 1.04 – 1.78), compared with clozapine, in adjusted models. However, the researchers did not find an association when they compared no antipsychotic treatment with clozapine treatment (HR, 1.15; 95% CI, 0.86 – 1.53).
The estimated rates of self-harm were lowest for clozapine (monotherapy or polypharmacy) and highest for nonclozapine antipsychotic polypharmacy. No significant differences were found across treatment strategies in any of the models.
The effect sizes, although slightly decreased, remained unaltered in all models, even when the researchers excluded periods of hospitalization lasting longer than 1 month.
“This study demonstrated that clozapine treatment in treatment-resistant schizophrenia was associated with a substantially lower rate of all-cause mortality compared with no antipsychotic treatment and there was an increase in mortality after clozapine discontinuation,” the authors write.
“Moreover, we found a significantly lower rate of self-harm during clozapine treatment compared with nonclozapine antipsychotic treatment in treatment-resistant schizophrenia.”
There are immediately clinically applicable take-home messages. “We observed a 2.5-fold increased rate of death among treatment-resistant patients not treated with any antipsychotics, compared with treatment-resistant patients treated with clozapine.
“This indicates a need for optimized care and treatment in treatment-resistant patients who discontinue antipsychotic treatment, and particularly in those who discontinue treatment with clozapine,” said Dr Wimberley.
Additionally, “to prevent self-harm in patients with treatment-resistant schizophrenia, the results of the current study indicate that especially patients on nonclozapine antipsychotics treatment may need more attention.”
“Real-World” Study
Commenting on the study for Medscape Medical News, Gary Remington, MD, PhD, professor of psychiatry, and schizophrenia lead, Division of Brain and Therapeutics, University of Toronto, Canada, stated that this population-based cohort study represented “real-world” patients without inclusion and exclusion criteria “that restrict the generalizability of results.”
He noted that the results of the study were “not surprising and fit with our own work as well as clinical experience.
“The study makes an important contribution to the field because clozapine is a very important drug in treatment-resistant schizophrenia” and is “the only antipsychotic with established efficacy in this population and, accordingly, is positioned as the treatment of choice in published algorithms and guidelines.”
However, “for various reasons, clozapine is markedly underutilized, with many of the concerns centered around its safety,” he pointed out. “The findings here argue strongly against its underuse based on such concerns.”
He emphasized that the study provides “yet further evidence that calls for increased use of clozapine in treatment-resistant schizophrenia, with benefits certainly outweighing risk.”
Dr Wimberley agreed. “Clozapine is the gold standard treatment, but it is underused in most countries, mainly due to the fear of severe side effects.”
She added that patients with treatment-resistant schizophrenia “need specialized and individualized treatment. Not all patients will benefit from clozapine, but several studies indicate that many patients not receiving clozapine might benefit from it.”
She urged psychiatrists to “continue to follow the treatment guidelines as closely as possible. The current study indicates that close monitoring of the patient is important, not only at clozapine initiation and during clozapine treatment but also particularly before and after clozapine discontinuation.”
The study was funded by the CRESTAR study, under the European Community’s Seventh Framework Programme. One coauthor’s salary was partly funded by the National Institute for Health Research Biomedical Research Center at South London and Maudsley National Health Service (Foundation Trust and King’s College London). Another coauthor received an unrestricted research grant from Eli Lilly and was in research collaboration with LA-SER Analytica. Dr Wimberley and Dr Remington have disclosed no relevant financial relationships.
Am J Psychiatry. Published online July 28, 2017. Abstract
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