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Did Internet-purchased diet pills cause serotonin syndrome?

Current Psychiatry. 2008 July;07(07):67-78
July 1, 2008|Current Psychiatry
Kyoung Bin Im, MD;Jess G. Fiedorowicz, MD
Author and Disclosure Information

Kyoung Bin Im, MD
Chief resident, internal medicine and psychiatry combined residency program, departments of internal medicine and psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City

Jess G. Fiedorowicz, MD
Associate in psychiatry, department of psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City

Phentermine also may have increased patient’s neuroleptic malignant syndrome risk.

Evidence for serotonin syndrome

This case involves a young woman with a several-week history of phentermine use for weight reduction who presented with confusion, sedation, mutism, and nausea. She was initially found to have an abnormal EEG, for which she was loaded with the anticonvulsant phenytoin. However, she continued to exhibit altered mental status, myoclonus, and hyperreflexia along with autonomic dysregulation—such as urinary retention and tachycardia—despite a negative EEG on continuous monitoring.

On retrospective review, we believe she likely was experiencing serotonin toxicity from phentermine. She later developed NMS within several hours of receiving the antipsychotic haloperidol.

Clinical Point

Phentermine increases serotonin efflux in the rat hypothalamus to a greater degree than fluoxetine

Seizure has been reported with Fen-Phen (fenfluramine and phentermine),21 but not to date with phentermine monotherapy. On the other hand, seizure—often generalized, tonic-clonic in nature—has been reported with serotonin syndrome.22 Partial seizures might explain Ms. G’s initial confusion. However, neuromuscular abnormalities persisted after a normalized EEG, further supporting the diagnosis of serotonin syndrome.

Even though phentermine is thought to have a relatively weak serotonergic effect,3 it has been shown to markedly increase serotonin efflux in the rat hypothalamus (to a greater degree than the SSRI fluoxetine).23 Although Ms. G did not report having consumed foods or supplements that could have interfered with phentermine’s metabolism, such use could have contributed to or prolonged a serotonin syndrome.20 Phentermine misuse also cannot be ruled out.

Excess phentermine or concomitant use of other serotonergic agents may have precipitated serotonin syndrome. Ms. G’s hyperactivity a few days before she complained of fatigue and somnolence may represent:

  • a sign of phentermine intoxication or overuse
  • a harbinger of serotonin syndrome, because these symptoms were followed by overt serotonin syndrome signs such as confusion, disorientation, myoclonus, and autonomic dysfunction.
Features such as slow progression to the full-blown signs and unclear medication history may obscure the clinical picture at presentation in this and similar cases.24

Evidence for NMS

Ms. G received haloperidol because her agitation obstructed urgent evaluation. After several doses, she rapidly developed signs and symptoms highly consistent with NMS. Onset was rapid compared with the typically described, more insidious NMS evolution of 24 to 72 hours, however.25 Rapid NMS onset may have been precipitated in 2 ways:

  • dopaminergic (phentermine) withdrawal combined with dopamine antagonist challenge (haloperidol)25,26
  • background serotonin syndrome caused by amphetamine (phentermine) predisposing the patient to develop NMS.27
For the first possibility, 1 case report has described a narcolepsy patient developing NMS after discontinuing dextroamphetamine, which he had been taking for 16 years.28 NMS also has been observed during withdrawal of dopaminergic medications used in Parkinson’s disease.29 For the second possibility, Kline et al30 reported a similar case of a 45-year-old woman with probable serotonin syndrome who developed NMS after a single neuroleptic dose.
Clinical Point

Sympathetic hyperactivity from phentermine or serotonin syndrome may increase the risk of developing NMS

Although phentermine-induced sympathetic hyperactivity also could have predisposed Ms. G to NMS,31 we think this is unlikely because phentermine was discontinued 3 to 4 days before she developed NMS. Nonetheless, sympathetic hyperactivity secondary to phentermine or serotonin syndrome may increase the risk of developing NMS.

Treatment strategy

Because serotonin syndrome and NMS share many clinical findings, differentiating between the 2 syndromes may be difficult, especially when the patient’s medication history does not implicate a specific agent. A detailed history and physical may help distinguish the syndromes. Clonus may be particularly specific and is important in the diagnosis of serotonin syndrome.32 If you are unable to differentiate between serotonin syndrome and NMS in a patient with this acute neurotoxic abnormal behavior syndrome,33 consider a common treatment strategy (Table 2).19,25

In Ms. G’s case, she probably should not have received bromocriptine for NMS,20 given the potential role of serotonin syndrome in precipitating her symptoms.

Case reports support our hypotheses of an increased predilection for NMS with dopaminergic withdrawal or serotonin syndrome. Growing evidence supports the use of chlorpromazine for serotonin syndrome,34 but consider its use contraindicated in patients with NMS.

Table 2

Serotonin syndrome or NMS?
When in doubt, follow 4 management principles

Avoid serotonin agonists and dopamine antagonists when a patient presents with features of serotonin syndrome or neuroleptic malignant syndrome (NMS) and the diagnosis is unclear20
Provide supportive care with monitoring, cooling blankets as needed, and hydration
Avoid using antipsychotics for agitation, when possible; benzodiazepines may be preferable, although their use in NMS is controversial25
Avoid using bromocriptine, given its contraindication in serotonin syndrome, but consider cyproheptadine for the serotonin syndrome component and dantrolene for skeletal muscle rigidity20

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