Antipsychotics and Reduction in Mortality in Schizophrenia

Patients with schizophrenia have a life expectancy about 15-20 years shorter than the general population. Various studies have linked this to generally unhealthy lifestyles, such as smoking, sedentary habits with little or no physical activity, and an inadequate diet. These factors increase the risk of cardiovascular diseases and, consequently, associated conditions that shorten their lives, such as hypertension, obesity, hypercholesterolemia, and diabetes.

Furthermore, for years, there has been controversy over whether the increased mortality rate in patients with schizophrenia is also due to the side effects of the medications they take for their mental illness, as some of these medications do increase appetite, the risk of diabetes, or dyslipidemia, to name a few examples.

Over time, new antipsychotic medications with fewer side effects and cleaner metabolic profiles, and thus less harmful to patients, have emerged. More convenient formulations have also appeared, such as long-acting injectables (administered every 15 days, monthly, or even quarterly). One immediate advantage of injectables is the higher treatment adherence, as patients must go to their healthcare facility to receive their injection, which reduces the number of relapses and hospitalizations. Other advantages related to a better side effect profile could also be expected. However, there were no major studies that proved the presumed benefits of these drugs.

A recent publication in the journal “Schizophrenia Research,” based on a staggering 29,823 patients with schizophrenia followed for nearly 6 years, concludes that in patients with schizophrenia, the use of long-acting treatments (the famous injectables) is associated with a roughly 30% reduction in the risk of death compared to oral antipsychotics. Xeplion®, Abilify Maintena®, and Abilify oral® are associated with lower mortality compared to others. This may suggest that uninterrupted treatment of schizophrenia with these medications is the most suitable option to protect patients from neuronal damage (neurotoxicity) that occurs during psychotic relapses, clinical deterioration, and the high mortality associated with untreated psychosis or psychosis treated with first-generation antipsychotics.

Building upon this study and others, one year later, Dr. Henry A. Nasrallah of Saint Louis University in Missouri (USA) drew a series of conclusions, which he published in the same journal in 2018.

In these conclusions, he emphasizes the importance of treating patients with second-generation antipsychotics (as mentioned earlier) from the beginning for the following reasons:

• With psychotic relapses, brain structures suffer damage (brain atrophy due to destruction of neuronal neuropil).
• While first-generation antipsychotics (older drugs like haloperidol) cause neurotoxicity, destroying neurons, second-generation drugs have shown neuroprotective effects (they protect the brain).
• Injectable drugs ensure adherence, thus reducing the risk of relapses. In other words, if we prescribe an oral medication, we don’t know if the patient will take it, whereas with injectable administration, patients must attend their healthcare facility to receive it, ensuring that they do.

For more advanced readers in this field, the neuroprotective effects of second-generation antipsychotics that have been studied and described to dateinclude the following:

• Increase neurotrophic factors (NGF and BDNF), which decrease in psychosis.
• Promote neurogenesis.
• Protect cortical neurons from glutamate-induced toxicity.
• Reverse the reduction in glutathione concentration induced by PCP.
• Protect cortical brain neurons from dizocilpine-induced injury.
• Protect against cell death induced by beta-amyloid and hydrogen peroxide.
• Have an anti-inflammatory effect.
• Reverse the loss of dendritic spines in the prefrontal cortex induced by decreased dopamine.
• Prevent damage to oligodendroglia caused by microglia activated by interferon-gamma.
• Prevent loss of dendritic spines caused by PCP if used prophylactically (not with haloperidol).
• Reverse gene expression induced by PCP.

Of course, there is still much to learn about a complex condition like schizophrenia, but I hope these findings shed more light on the controversies and help improve patients’ quality of life. We have come a long way, but there is still much more to discover.