Trazodone Side Effects Can Include Mania or Psychosis

Trazodone can be a very helpful medication for many people. But, like any medication, it has potential side effects. This article will focus on some rare but possibly serious trazodone side effects: mania or psychosis.

What is trazodone?

Today trazodone is one of the most commonly prescribed treatments for insomnia. It was originally developed as a treatment for depression. As medical professionals learned that it has a sedative side effect, doctors started prescribing trazodone as a sleep aid. Now, it is the 30th most prescribed medication in the U.S. and one of the top three medications prescribed for insomnia. Trazodone is an inexpensive generic medicine that has been on the market for 40 years. Unlike many other medications that can be used for insomnia, trazodone is not a controlled substance. These factors have helped make trazodone a very popular insomnia treatment. In many cases, people also report significant reductions in anxiety while taking trazodone.

Trazodone and psychosis

However, every medication comes with some side effects for some people, and trazodone is no different. Two very uncommon but potentially serious side effects from trazodone are mania and psychosis. It’s important to know that trazodone has the potential to cause these types of side effects so that if these side effects ever develop, the doctor and patient can come up with a correct diagnosis—trazodone side effect—instead of concluding that a new condition has developed which requires additional medicine. It’s also important to be aware of trazodone’s potential for serious psychiatric side effects because insomnia can be a sign of mental illness. And having a mental illness might make a person more vulnerable to psychiatric side effects from medications.

Trazodone and psychosis case study

I first learned about the potential for trazodone to cause psychosis while I was doing consultations at a residential care facility. The staff had asked me to see a patient who had been living there for a couple of years and had never had any particularly notable difficulties. Seemingly all of a sudden, he started to talk about robotic insects that would hide under his bed and crawl up and down his body all day and night. I approached this consultation question by first constructing a detailed timeline of medication administration and clinical observations recorded by the staff in his medical record. This approach is great because you can sometimes allow one to catch unexpected side effects from medications or medication interactions. Here is what I found:

This timeline shows very clearly that hallucinations did not start until shortly after trazodone was added. It also shows that the hallucinations went away entirely after trazodone was discontinued. This was surprising to me at the time. I always say that anybody can get any side effects from any medicine. But I had never heard of anyone developing hallucinations as a side effect from a relatively low dose of trazodone. There are a couple of other very noteworthy observations from this timeline. First, notice how sleep quality seems to get worse after fluoxetine (Prozac) was increased. Anti-depressant medications can often disrupt sleep quality. However, it could also be that the sleep problems or a primary manifestation of what appears to be a worsening depression that caused the doctor to increase the dose of Prozac in the first place. The other thing this timeline shows is that by not realizing that the hallucinations were a side effect of trazodone, this patient wound up getting a higher dose of the antipsychotic medication risperidone. Staff observations about him appearing uncomfortable or agitated could reflect the possibility that he was experiencing side effects from the increased dose of risperidone. And this could have potentially been avoided if the cause of the problem had been identified earlier.

Why can trazodone produce mania or psychosis?

Trazodone is a serotonin antagonist and reuptake inhibitor, or SARI-type medication. Lower doses of trazodone block the 2A subtype of the serotonin receptor (5HT_2A) and result in sedation, therefore making it easier to fall asleep. Higher doses of trazodone block serotonin reuptake and can have SSRI-like action. High doses of trazodone may therefore lead to SSRI overstimulation and be a cause for why we sometimes see mania or psychosis as a side effect. The exact reason why trazodone can produce mania or psychosis is not known for certain. However, it is worth noting that trazodone is converted within the body to a chemical called meta-chlorophenylpiperazine, or m-CPP. Up to one-tenth of the trazodone dose will be converted into m-CPP. Some people report that m-CPP effects are pleasant, and it is a drug of abuse. However, in many people, m-CPP can cause or worsen a lot of psychiatric symptoms and is known to provoke anxiety, panic attacks, dysphoria, and agitation. Many people also report that m-CPP can cause headaches, confusion, and depressed mood. Furthermore, in human laboratory studies, m-CPP was found to exacerbate symptoms of OCD. Therefore, m-CPP might be responsible for trazodone’s negative psychiatric side effects.

Some other medicines might increase the risk from trazodone’s unwanted breakdown product

m-CPP is metabolized in the body by 2D6. 2D6 is strongly inhibited by some other common psychiatric drugs, including Wellbutrin, Prozac, and Paxil. People taking any of these drugs along with trazodone may have m-CPP in their system for longer periods and therefore be at higher risk for mania, psychosis, or other negative side effects from trazodone.

Key takeaways

• Mania, psychosis, and other psychiatric side effects from trazodone are very uncommon—however, with a drug as commonly prescribed as trazodone, there are probably some people experiencing these side effects (and who might not realize what is causing them).
• The exact mechanism of mania or psychosis side effects from trazodone is yet to be determined. However, m-CPP can serve as an anti-therapy metabolite for many people.
• While not formally written about yet, we should be cautious of co-prescribing trazodone with medications like fluoxetine (Prozac), paroxetine (Paxil), or bupropion (Wellbutrin) that can inhibit m-CPP elimination.

Learn more:

You can find a video lecture with more information on trazodone and psychosis on my YouTube channel, 15-Minute Pharmacology. The lecture was given at the January 19, 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.