SS is caused largely by drug–drug interactions, although occasional cases have been reported following the use of single serotonergic drugs. Unfortunately, there is still some confusion and controversy about SS.
Misdiagnosis in Case Reports
A large number of cases of SS have been reported in the literature and to the FDA over the past few decades. Unfortunately, many of these cases probably do not represent actual SS.
More than 20 years ago, psychiatrist Harvey Sternbach proposed a set of diagnostic features of SS known as Sternbach’s criteria.
While useful and sometimes still used today, these criteria included some relatively nonspecific symptoms, such as agitation, confusion, diarrhea, fever, and sweating. This resulted in misdiagnosis of SS in many patients and sometimes, paradoxically, failure to identify mild forms of the disorder. There is now general agreement that the Hunter criteria—which focus more on the neuromuscular findings of clonus, muscle rigidity, tremor, and hyperreflexia—are more reliable for diagnosing SS
Errors Regarding Which Drugs Can Cause SS
Two primary misunderstandings are responsible for the erroneous listing of various drugs as causes of SS.
First, drugs capable of exerting serotonergic effects differ widely in their likelihood of causing SS. Just combining 2 serotonergic drugs does not necessarily increase the risk for SS. There are many different serotonin receptors, and only some of them appear to be involved in the etiology of SS.
Second, very few drugs (mainly the monoamine oxidase inhibitors) are capable of producing severe SS, while a much greater number of drugs can cause mild to moderate SS.
SS is a drug-induced phenomenon and usually results from the combined effects of 2 or more drugs.
The diagnosis is now made primarily on the basis of adverse neuromuscular effects as found in the Hunter criteria.
Many published purported cases of SS do not represent actual SS, and this has resulted in much misinformation in computerized drug interaction detection systems.