This is the first time antipsychotic medications have been ranked according to these metabolic side effects. Clozapine and olanzapine were shown to have the worst side effect profiles, but the research also demonstrated that a high level of metabolic side effects was linked to an improvement in the symptoms of schizophrenia. Clozapine is the only drug recommended for use in those who do not respond to other antipsychotics i.e. treatment-resistant schizophrenia, so there may be no alternative for some patients.
Lead researcher, Dr Toby Pillinger from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, said: ‘Antipsychotic drugs all work on the same chemical system in the brain – dopamine – but they vary in their actions at other chemical systems, which may influence the risk of metabolic side effects. Our research showed a dramatic variation in metabolic side effects between different antipsychotics. Those with the worst side effects produced, in only a few weeks, metabolic changes within the blood that are associated with an increased risk in cardiovascular disease of up to 76%.'
Interestingly, we showed that these side effects appear to be linked to an improvement in symptoms of schizophrenia, so it may be that for some drugs to be effective, metabolic side effects are unavoidable. This complements previous research showing that people with schizophrenia treated with antipsychotics that have increased metabolic side effects paradoxically have better cardiovascular outcomes and live longer, possibly because improvements in their mental health from medication allows them to look after themselves and implement better self-care in the long-term.
– Lead researcher, Dr Toby Pillinger from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London
Antipsychotics form the mainstay of treatment for patients with schizophrenia, but some newer so-called second-generation drugs are associated with a range of side effects that are known to put individuals at risk of diabetes and cardiovascular disease. Compared with the general population, people with schizophrenia are twice as likely to have a diagnosis and die as a consequence of cardiovascular disease. This new study aimed to investigate the possible contribution of antipsychotics to the poorer physical health of these individuals.
By analysing 100 randomised controlled trials that examined antipsychotics and placebo in the short-term treatment of schizophrenia (on average 6 weeks) the study analysed the level of metabolic side effects and their relationship to changes in the symptoms of schizophrenia. The side effects that were studied were increases in weight and body mass index (BMI), and increases in levels of glucose, cholesterol and other fats in the blood. The research compared 18 antipsychotics and the 100 trials included over 25,000 patients.
There was a large variation in the level of metabolic side effects. Two antipsychotics in particular, clozapine and olanzapine, were shown to have a strong association with increases in body weight and BMI, and glucose and cholesterol levels. In contrast, some antipsychotics, such as lurasidone and cariprazine, were associated with improvements in glucose and cholesterol levels.
The research also investigated which patient characteristics might predict a high level of these metabolic side effects and indicated that being non-white, older and male were risk factors for developing a high level of these side effects when taking antipsychotic medication.
Senior researcher, Professor Oliver Howes, from the IoPPN, said: ‘Antipsychotics are widely used so it is important to understand their side effects and how they vary between different types of medication and different patients. This is the first time that research has systematically compared antipsychotics on their metabolic side effects and tried to identify which patients might be more at risk of developing them. The findings that there are significant differences in side effects between treatments have implications for the choice of antipsychotic, particularly for the at-risk groups we have identified. The side effects we examined may increase the risk of cardiovascular disease and diabetes.
‘We believe the results of the study should be reflected in treatment guidelines to help doctors and patients choose the best drug treatment. Drug choice should weigh up treatment benefits for symptoms against the risk of metabolic and other side effects.’
This is the first time that research has systematically compared antipsychotics on their metabolic side effects and tried to identify which patients might be more at risk of developing them. The findings that there are significant differences in side effects between treatments have implications for the choice of antipsychotic, particularly for the at-risk groups we have identified.– Senior researcher, Professor Oliver Howes, from the IoPPN
The research was published in The Lancet Psychiatry and was funded by the Medical Research Council, Wellcome and the NIHR Oxford Health Biomedical Research Centre.
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