Ms. G, age 28, presents to a tertiary care hospital with altered mental status. Six weeks ago she started taking phentermine, 37.5 mg/d, to lose weight. Her body mass index is 24 kg/m2 (normal range), and she obtained the stimulant agent via the Internet. Her family reports Ms. G was very busy in the past week, staying up until 2 AM cleaning. They say she also was irritable with her 5-year-old son.
Two days ago, Ms. G complained of fatigue and nausea without emesis. She went to bed early and did not awaken the next morning. Her sister found her in bed, minimally responsive to verbal stimuli, and brought her to the hospital.
Patients have used phentermine as a weight-reducing agent since the FDA approved this amphetamine-like compound in 1960.1 Phentermine’s mechanism of action is thought to involve dopaminergic, noradrenergic, and serotonergic effects.2 Stimulation of norepinephrine (NE) release is its most potent effect, followed by NE reuptake inhibition, stimulation of dopamine (DA) release, DA reuptake inhibition, stimulation of serotonin (5-HT) release, and 5-HT reuptake inhibition (weak).3
Because phentermine could in theory cause serotonin syndrome,4 its use is contraindicated with monoamine oxidase inhibitors (MAOIs) and not recommended with selective serotonin reuptake inhibitors (SSRIs).5 One case report describes an interaction between fluoxetine and phentermine that appears consistent with serotonin syndrome.6 We are aware of no case reports of serotonin syndrome caused by phentermine alone.
This article reports the case of Ms. G, who presented with probable serotonin syndrome associated with phentermine use and subsequently developed a rapid-onset, superimposed neuroleptic malignant syndrome (NMS). We hypothesize that phentermine use may increase NMS risk through adverse drug events and discuss potential pathophysiologic mechanisms and treatment implications.
Serotonin syndrome vs NMS
Serotonin syndrome is an infrequent and potentially life-threatening adverse drug reaction that presumably results from excess serotonin activity (Box 1).7-10 NMS also is an infrequent and potentially life-threatening neurologic emergency (Box 2).11-18 Similarities between disorders of increased serotonergic activity and disorders of low dopaminergic activity (Table 1) suggest both may result from an imbalance between the serotonergic and dopaminergic systems, which have reciprocal relationships in the CNS.19
Differentiating between serotonin syndrome and NMS is further complicated when both antipsychotics and serotonergic agents may be implicated.20 Clinical trials are not feasible because NMS and serotonin syndrome rarely occur.
Serotonin syndrome: Excessive serotonin activity
Box 2Sternbach7 first summarized serotonin syndrome’s clinical presentation in a review of 38 cases. The most frequent clinical features include changes in mental status, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, and tremor (Table 1).
The clinical syndrome varies in scope and intensity. Animal models suggest the pathophysiologic mechanism involves brainstem and spinal cord inundation with serotonin, acting on 5-HT1A and 5-HT2A receptors. Recent evidence supports a greater role for 5-HT2A receptors.8
Primary treatment calls for discontinuing the suspected serotonergic agent and instituting supportive measures. Case reports also suggest using serotonin receptor antagonists—such as cyproheptadine, methysergide, chlorpromazine, or propranolol—to clinically manage serotonin syndrome, although empiric support is limited.9
The syndrome often improves within 24 hours of primary treatment, although confusion sometimes last for days and death has been reported.10
NMS: Disorder of low dopaminergic activity
Table 1NMS—characterized by fever, extrapyramidal rigidity, and disturbances of autonomic function and consciousness—was first described with the use of haloperidol.11 Risk factors include catatonia, disorganized presentation, and dehydration.12 NMS is thought to result from deficient compensatory mechanisms following blockade of dopaminergic regulation of muscle tone and autonomic function.13
Although possibly idiosyncratic, the reaction has been associated with:
- intramuscular, higher total dose, or abruptly increasing doses of antipsychotics14
- withdrawal of dopaminergic agents, such as those used to treat Parkinson’s disease.15
Akin to serotonin syndrome, managing NMS focuses on removing the offending agent(s) and providing supportive care. Severe cases require intensive monitoring, aggressive IV hydration, and respiratory support. Dopaminergics such as bromocriptine16 and skeletal muscle relaxants such as dantrolene17 also have been used to manage NMS.
Unlike serotonin syndrome, NMS often resolves slowly (typically >1 week). NMS’ mortality rate of 11% to 38% appears to be declining in recent years, perhaps because it is being recognized more rapidly.18
Signs and symptoms of NMS vs serotonin syndrome
| NMS | Serotonin syndrome | |
|---|---|---|
| Onset | Insidious, days to weeks | Acute (minutes to hours) |
| Resolution | Slow, often >1 week | Improvement or resolution often within 24 hours |
| Autonomic | Fever, tachycardia, diaphoresis, elevated or labile blood pressure, sialorrhea, tachypnea, incontinence | Diaphoresis, shivering, fever, tachycardia, hypertension, mydriasis |
| Gastrointestinal | Dysphagia, elevated transaminases | Diarrhea, nausea, vomiting, elevated ammonia and transaminases |
| Neuromuscular | Rigidity, bradykinesia, dysarthria, dyskinesias, coarse tremor, ataxia, opisthotonos, oculogyric crisis, rhabdomyolysis | Clonus, myoclonus, hyperreflexia, ataxia, incoordination, rigidity, tremor |
| Psychiatric | Altered mental status, stupor, somnolence, mutism | Altered mental status, agitation, hypomania, hyperactivity, restlessness, somnolence (less common) |
| Other | Leukocytosis, elevated creatine kinase (significant), elevated serum creatinine, proteinuria, renal failure, disseminated intravascular coagulation | Leukocytosis (rarely >20K cells/mm3), elevated creatine kinase (less common), disseminated intravascular coagulation, metabolic acidosis |
| NMS: neuroleptic malignant syndrome | ||
| Note: Classically reported symptoms are italicized | ||