Serotonin Syndrome Due to Drug Interactions

Over the past 25 years, drug companies have released so-called “serotonergic drugs” that increase the amount of serotonin — a neurotransmitter that regulates mood, sleep, body temperature and aggression — in the body. Many anti-depressants are serotonergic, but so are certain herbal supplements, painkillers and antibiotics.

If a patient is given too much of these drugs or supplements, or if they are taken in combination with other serotonergic products, a side effect known as “serotonin syndrome” or “serotonin toxicity” may occur. Serotonin syndrome happens when there are excessive serotonin concentrations in the central nervous system. Because serotonin syndrome can progress rapidly and can be life-threatening in severe cases, it is important that patients and health professionals be aware of this condition and the drugs that can cause it.

Is serotonin syndrome difficult to diagnose?
Serotonin syndrome can be difficult to diagnose because many of the symptoms — such as agitation, fast heart rate, fever, sweating, flushing and the like — are nonspecific.

The good news is that newer diagnostic techniques improve physicians’ ability to diagnose serotonin syndrome by focusing on the more important and specific symptoms, which mainly involve the nerves and muscles, according to the New England Journal of Medicine and the Medical Journal of Australia. For example, patients with serotonin syndrome often experience muscle jerks (called myoclonus) especially in the legs, and this symptom by itself may be enough to make the diagnosis. Other neuromuscular effects of serotonin syndrome include muscle rigidity, overactive reflexes and tremors.

Importantly, in order for a doctor to diagnose serotonin syndrome, there must be a recent change in the patient’s drug therapy. Any of the following are possibilities:

1. The recent addition of a serotonergic drug to a patient’s medication regimen;
2. An increase in the dose of a serotonergic drug;
3. The simultaneous use of two or more drugs that interact to increase the blood levels of a serotonergic drug.

Not all physicians are aware of serotonin syndrome. A paper published in 1999 found that 85 percent of physicians were not aware of serotonin syndrome, although that percentage may have since increased.

Is serotonin syndrome a newly discovered side effect?
Actually, the scientific community has known about serotonin syndrome caused by drug interactions for about half a century. In the 1960s, physicians tried to treat depressed patients with drugs called MAO inhibitors in combination with tricyclic antidepressants such as imipramine (TOFRANIL, TOFRANIL PM). Both MAO inhibitors and tricyclic antidepressants are serotonergic drugs. The use of these products concurrently led to several deaths. Consequently, the Food and Drug Administration (FDA) specifically recommended against using these drugs in combination.

Reports of serotonin syndrome have increased dramatically over the past two decades due mainly to the marked increase in the use of selective serotonin reuptake inhibitors (SSRIs), a class of drugs that acts specifically to increase serotonin levels.

What drugs have been associated with serotonin syndrome?
A large number of drugs have serotonergic effects (the most commonly used are listed in the accompanying table). Any combination of two or more of these drugs may increase the risk of serotonin syndrome.

Note that some herbal and dietary supplements may have serotonergic effects, such as St. John’s wort, ginseng and tryptophan (tryptophan is a building block of serotonin in the body). The serotonergic effect of these products is not as well established as the effects of other medications in the table.

However, these and other herbal products should be avoided in general because there is not sufficient evidence that they are safe, effective or properly manufactured.

The serotonergic effect of some of the drugs in the table may last for a long time. For example, fluoxetine (PROZAC, SERAFEM) can continue to interact with other drugs for up to five weeks after a patient stops using the drug. The MAO inhibitors mentioned in the table can last for two or more weeks after they are discontinued.

Generally, it is a good idea to check with a physician or pharmacist for advice on how long to wait between stopping one drug and beginning another.

How is serotonin syndrome treated?
Prompt treatment is important. Serotonin syndrome often has a very rapid onset, and symptoms can occur soon after the interacting drug is added to the therapy. The most important step in managing serotonin syndrome is stopping the use of serotonergic drugs in consultation with your physician. If the drugs are not stopped, serotonin syndrome may progress to more serious forms.

Mild cases of serotonin syndrome produce symptoms that are merely annoying and may not require treatment beyond stopping the drugs. Moderate cases require treatment but are not life-threatening.

However, severe cases of serotonin syndrome can be fatal. They are a medical emergency and require immediate and vigorous treatment. The treatment is primarily supportive: fluids, anti-anxiety agents such as diazepam (VALIUM) and treatment for blood pressure changes. (Some of these might be required for moderate cases as well.) In severe cases, patients may have a very high fever due to the excessive muscle contractions. In these cases, it may actually be necessary to paralyze the muscles and place the patient on a ventilator in order to relieve the fever that results from the muscle contractions. Large doses of serotonin antagonists such as cyproheptadine (PERIACTIN) have been used with good results in some cases, but more information is needed to establish the effectiveness of this drug.

How can the risk of serotonin syndrome be reduced?
First, avoid taking serotonergic drugs that are “Do Not Use” in Worst Pills, Best Pills, some of which are associated with serotonin syndrome. Dextromethorphan (DELSYM), for example, is relatively ineffective as a cough suppressant and may cause serious toxicity if combined with certain other drugs.

Second, patients taking any of the drugs listed in the accompanying table should check to make sure any other drugs they are taking do not interact to increase the risk of serotonin syndrome.

Third, patients taking any of the drugs listed in the accompanying table should talk to a physician and/or pharmacist about serotonin syndrome to make sure they are aware of the problem.

Fourth, patients taking serotonergic drugs should seek immediate medical help if any of the key symptoms of serotonin syndrome occur: muscle jerking, rigid muscles or tremor (especially if accompanied by less specific symptoms such as fever, sweating and agitation).