Aspirin, ibuprofen (Advil, Motrin), and naproxen (Alleve) are the best-known examples of non-steroidal anti-inflammatory medications (NSAIDs). There are more than 20 different NSAID medications that can be used in clinical practice. NSAIDs are also widely prescribed, accounting for
five to ten percent of all drug prescriptions in the U.S. They are usually prescribed as pain relievers.
As clinicians and researchers further understand the role that inflammation plays in various psychiatric conditions, NSAIDs are increasingly investigated as therapeutics to be used in combination with other treatments for several psychiatric illnesses, such as schizophrenia.
Like any drug, the NSAIDs come with side effects. This article will focus on one of their rare but important side effects—psychosis.
Benefits of NSAIDs in psychiatric treatment
Several studies have shown that adding an NSAID to the medications usually prescribed for depression or schizophrenia can further reduce symptoms—at least for some patients.
Other studies have shown elevated levels of inflammation in patients with schizophrenia, and that elevated measures of inflammation during adolescence are associated with increased psychosis risks later in life. It’s also been observed that a history of being prescribed an NSAID is associated
with an almost 60% reduction of schizophrenia risk in men.
However, psychosis is caused by many different pathways, and we cannot assume that these findings apply to all patients. While NSAIDs can have many benefits for the majority of patients, they can cause adverse effects for others. It is important to look at this population that experiences adverse effects and understand the cause.
Adverse effects of NSAIDs
In the 1990s, NSAIDs accounted for
nearly one quarter (21-25%) of adverse events in the UK and the U.S., and they were the
third most common type of adverse event reported in New Zealand and Spain. Rare but consistent adverse events include depression, hallucination, paranoia, sleepiness, and increased anxiety. These adverse events tend to onset fairly quickly after the patient takes an NSAID and go away fairly quickly upon stopping use of the medication.
Why do NSAIDs cause side effects in some patients?
NSAIDs inhibit the production of prostaglandin signaling molecules, which regulate dopamine release in the brain. For some people, it seems, NSAID medications may function as pro-dopamine drugs, which may explain some of the psychiatric adverse effects that NSAIDs seem to cause in some people.
To look at this pathway more closely, phospholipase causes arachidonic acid to be released from the phospholipid membrane of a person’s cells. Then, cyclooxygenase (COX 1/2) turns arachidonic acid into prostaglandin. However, NSAIDs block COX 1/2 and therefore block arachidonic acid from being converted into prostaglandin, causing a prostaglandin deficiency.
Prostaglandin regulates blood flow in the brain, providing on-demand oxygen to active parts of the brain and facilitating important facets of brain function. High doses of prostaglandin suppress the release of dopamine, whereas inhibiting prostaglandin can cause a surge of dopamine to the brain. Surges of dopamine are a cause for psychosis. Therefore, NSAID use can inhibit prostaglandin, cause a surge of dopamine, and therefore cause psychosis in some people.
The prostaglandin hypothesis and schizophrenia
The
prostaglandin hypothesis proposes that overactive phospholipase depletes the cell membrane’s stores of arachidonic acid, thus contributes to a prostaglandin deficiency which may contribute to the symptoms of schizophrenia. The prostaglandin hypothesis is supported by evidence like: people with schizophrenia tend to have unusually high pain tolerance, extremely low rates of rheumatoid arthritis, and remission of psychosis symptoms during fever. It has not been well studied, but a few small ‘proof of concept’ clinical trials have shown a reduction in symptoms for people with schizophrenia who were given treatments that increase prostaglandin signaling.
Even though there is some evidence that at least some cases of schizophrenia may be caused or worsened by prostaglandin deficiency, there is also apparently contradictory evidence that inhibiting prostaglandin formation (by adding NSAIDs to existing medication) can alleviate symptoms for some people with schizophrenia but that it can have negative effects for others. These apparently opposite findings probably indicate that schizophrenia is not a single disease but rather is caused by multiple pathways. It’s important to evaluate each patient individually.
When evaluating patients with seemingly inexplicable episodes of psychosis or surges of exacerbated symptoms, it is therefore worthwhile to consider the potential role that NSAID use may be playing in causing the symptoms.
Learn more:
You can find a video lecture with more information on gluten sensitivity, celiac disease, and psychosis on my YouTube channel,
15-Minute Pharmacology. The lecture was given at the January 5, 2021 meeting of the
SZconsult learning community.
Disclaimers
This article summarizes the results and conclusions of articles published in the medical literature. It is for general information. It is not a substitute for medical advice, and readers are admonished not to enact or change treatments based on this article. Always seek the advice of your doctor before starting or changing treatment.
The thoughts, views, and opinions expressed in this article are my own and do not reflect or represent the policy or position of Northeast Ohio Medical University.
