Long-term medication for schizophrenia is safe

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A Karolinska Institutet data analysis suggests that long‐term antipsychotic use does not increase severe physical morbidity leading to hospitalisation, and is associated with substantially decreased mortality, especially among patients treated with clozapine.

People with schizophrenia have an average life expectancy ten to twenty years below the norm, and there has long been concern that one of the causes is the long-term use of antipsychotic drugs. Earlier compilations (meta-analyses) of results from randomised studies, however, indicated that the mortality rate for people with schizophrenia on antipsychotic medication was 30% to 50% lower than those who have received placebo.

However, most of the studies done have been shorter than six months, which does not reflect the reality of treatment often being life-long. Researchers from Karolinska Institutet and their international colleagues have now done a long-term follow-up, substantiating previous results and demonstrating that antipsychotic drugs are not associated with increased risk of co-morbid complications, such as cardiovascular disease. The study is the largest conducted in the field to date.

"It's difficult to make comparisons between people on permanent medication and those who aren't, as these groups differ in many ways," says Heidi Taipale, assistant professor at the department of clinical neuroscience at Karolinska Institutet. "One common method of dealing with this has been to try to take account of such differences when making comparisons. However, we chose another method, in which each person was their own control, making it possible for us to make individual comparisons of hospitalisation during periods of antipsychotic medication and periods of no treatment."

The researchers monitored just over 62,000 Finns who had received a schizophrenia diagnosis at some time between 1972 and 2014. This they did by accessing various Finnish registries up until 2015, giving an average follow-up period of over 14 years. They found that the likelihood of being hospitalised for a somatic disease was just as high during the periods when the patients were on antipsychotic drugs as when they were not. The differences in mortality, however, were noticeable. The cumulative mortality rate in the follow-up period at periods of medication and non-medication was 26% and 46% respectively.

The researchers believe that there is overwhelming support for continual antipsychotic treatment for schizophrenia being a safer option than no medication. At the same time, treatment brings the risk of adverse reactions, such as an increase in weight, which can raise the risk of cardiovascular disease. The finding that treatment with antipsychotic drugs does not increase the likelihood of hospitalisation for cardiovascular disease may be attributable, argue the researchers, to the fact that the drugs can also have an antihypertensive effect and can reduce anxiety and the risk of substance abuse.

Antipsychotic treatment may also help patients adopt a healthier lifestyle and make them more likely to seek care when needed.

"Antipsychotics get something of a bad press, which can make it difficult to reach out to the patient group with information on how important they are," says Jari Tiihonen, professor of psychiatry at the department of clinical neuroscience, Karolinska Institutet.

"We know from previous studies that only half of those who have been discharged from hospital after their first psychotic episode with a schizophrenia diagnosis take antipsychotic drugs. Besides, there are many people with schizophrenia who are on long-term benzodiazepine medication, which is in breach of existing guidelines and is associated with increased mortality risk. Building trust and understanding towards the efficacy and safety of antipsychotic drugs is important, and we hope that this study can contribute to this end."

The study was conducted with researchers from Finland, the US and Germany and financed with grants from the Finnish Ministry of Social Affairs and Health via a development fund for Niuvanniemi Hospital. Heidi Taipele has received financial support from the Academy of Finland.

Antipsychotics are effective in preventing relapses of schizophrenia, but it is generally believed that their long‐term use is harmful for patients’ physical well‐being. However, there are no long‐term studies which have verified this view. This nationwide, register‐based cohort study aimed to assess the risk of hospitalization due to physical health problems, as a marker for severe physical morbidity, and the risk of all‐cause mortality, as well as of cardiovascular and suicidal death, associated with antipsychotic use in all patients treated for schizophrenia in inpatient care between 1972 and 2014 in Finland (N=62,250), with up to 20 years of follow‐up (median: 14.1 years). The use of antipsychotic drugs (i.e., use of any antipsychotic compared with non‐use) and the use of specific antipsychotics were investigated, and outcomes were somatic and cardiovascular hospitalization, and all‐cause, cardiovascular and suicide death. Hospitalization‐based outcomes were analyzed by a within‐individual design to eliminate selection bias, comparing use and non‐use periods in the same individual by stratified Cox model. Mortality outcomes were assessed by traditional between‐individual Cox multivariate models. The adjusted hazard ratios (aHRs) for any somatic hospitalization and cardiovascular hospitalization were 1.00 (95% CI: 0.98‐1.03) and 1.00 (95% CI: 0.92‐1.07) during use of any antipsychotic compared to non‐exposure periods within the same individual. The aHRs were 0.48 (95% CI: 0.46‐0.51) for all‐cause mortality, 0.62 (95% CI: 0.57‐0.67) for cardiovascular mortality, and 0.52 (95% CI: 0.43‐0.62) for suicide mortality during use vs. non‐use of any antipsychotic. The most beneficial mortality outcome was associated with use of clozapine in terms of all‐cause (aHR=0.39, 95% CI: 0.36‐0.43), cardiovascular (aHR=0.55, 95% CI: 0.47‐0.64) and suicide mortality (aHR=0.21, 95% CI: 0.15‐0.29). The cumulative mortality rates during maximum follow‐up of 20 years were 46.2% for no antipsychotic use, 25.7% for any antipsychotic use, and 15.6% for clozapine use. These data suggest that long‐term antipsychotic use does not increase severe physical morbidity leading to hospitalization, and is associated with substantially decreased mortality, especially among patients treated with clozapine.

Heidi Taipale, Antti Tanskanen, Juha Mehtälä, Pia Vattulainen, Christoph U. Correll and Jari Tiihonen

Karolinska Institutet material

World Psychiatry abstract

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