A large study has raised concerns about using newer antipsychotic medicines as an added treatment for depression.
Researchers from Rutgers University and Columbia University found that working-age adults who added an antipsychotic after antidepressant treatment had a higher risk of death than people who added a second antidepressant instead.
The research was published in PLOS ONE. It does not prove that antipsychotic medicines directly caused the additional deaths, but the findings suggest doctors should carefully weigh their possible benefits against their risks.
Depression is one of the most common mental health conditions and can affect sleep, appetite, concentration, motivation and the ability to enjoy everyday life. Antidepressants are often one of the treatments offered when symptoms are moderate or severe.
However, the first antidepressant does not work well enough for everyone. When symptoms continue, doctors have several choices, including changing the antidepressant, adding another antidepressant or adding a medicine from another drug class.
One option is a newer, or second-generation, antipsychotic. Medicines such as aripiprazole, quetiapine and olanzapine were developed mainly for conditions such as schizophrenia and bipolar disorder, but some are also used alongside antidepressants for difficult-to-treat depression.
These medicines can help some patients, but they can also cause significant side effects. Depending on the drug, these may include sleepiness, weight gain and changes in blood sugar and cholesterol, which can affect long-term physical health.
Previous research has also raised concerns about mortality in some groups taking antipsychotics. The risk is particularly well recognized among older people with dementia, although that population is very different from the younger and middle-aged adults examined in this study.
For the new analysis, researchers studied Medicaid records from 39,582 adults between the ages of 25 and 64. The records covered the years 2001 through 2010 and were linked with information from the National Death Index.
All of the patients had already been treated with one antidepressant and then started an additional medicine. The researchers compared people who added a newer antipsychotic with those who added a second antidepressant.
The antipsychotic group had a 45% higher relative risk of death during the study period. The researchers estimated that the difference was equal to approximately one additional death for every 265 people treated with an antipsychotic for one year.
That number needs to be interpreted carefully. A 45% relative increase can sound very large, but the absolute increase in risk was much smaller, and an observational study cannot establish cause and effect.
People who receive antipsychotics may differ from those given another antidepressant in ways that are difficult to measure. For example, they may have more severe depression, different medical problems or other factors that independently affect mortality.
The researchers used statistical methods to make the groups more comparable, but such adjustments cannot remove every possible difference. A large randomized clinical trial would provide stronger evidence about whether the medicines themselves are responsible for the higher mortality.
The study also raised questions about how quickly some patients move to additional treatment. Antidepressants usually need several weeks before their full effect can be judged, although the exact timing depends on the medicine, symptoms and individual response.
Researchers noted that some patients may begin antipsychotic treatment before an adequate antidepressant trial has been completed. If a lower-risk option has not yet been fully tested, adding a medicine with more serious potential side effects may expose patients to unnecessary risk.
At the same time, the findings do not mean that people taking an antipsychotic for depression should suddenly stop it. Abruptly stopping psychiatric medication can cause withdrawal effects or a return or worsening of symptoms.
For some people with severe or persistent depression, adding an antipsychotic can provide meaningful improvement when other treatments have failed. Treatment decisions therefore need to consider the person’s symptoms, previous treatments, physical health and individual risks.
The study is best viewed as a warning about careful prescribing rather than proof that antipsychotics should never be used for depression. Its large number of patients and mortality data are important strengths, while its observational design remains a major limitation.
Future randomized studies could help determine whether particular antipsychotic drugs, doses or patient groups carry greater risks. They could also clarify how those risks compare with the improvement in depression that some patients experience.
For patients, the practical message is to discuss the reasons for adding a new medicine, its expected benefits, possible side effects and available alternatives with a healthcare professional. Medication choices for depression are rarely one-size-fits-all, and both mental and physical health need to be considered.
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