Serotonin syndrome with a combination of aripiprazole and fluoxetine: a case report

Introduction

Serotonin syndrome (SS) is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. SS is characterized by a triad of altered mental status, autonomic dysfunction, and neuromuscular abnormalities [Boyer and Shannon, 2005]. The syndrome is, for some authors, a loose term to define the clinical picture at the moderate to severe end of a spectrum of serotonin toxicity, mild symptoms of which include tremor, hyperreflexia, and occasional myoclonus [Gillman and Whyte, 2004]. In the severe forms of toxicity, generalized myoclonus, sustained ankle clonus, and hyperreflexia may occur along with hyperthermia, which is associated with increased mortality [Gillman, 2013]. SS is classically associated with the high doses of a single selective serotonin reuptake ınhibitor (SSRI) use, or with a combination of two or more serotonergic agents [Mason et al. 2000].

Fluoxetine is metabolized in the liver by the isoenzymes of the cytochrome P450 system, including CYP2D6 [Blazquez et al. 2012]. The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is a great genetic variability in the function of this enzyme [Gaedigk, 2013].

Aripiprazole, an atypical antipsychotic, which is a partial agonist at the 5-HT1A receptors, is equally metabolized via both CYP3A4 and CYP2D6 isoenzymes [Molden et al. 2006]. Therefore, coadministration with fluoxetine (a potent inhibitor of CYP450 2D6) may significantly increase the plasma concentrations of aripiprazole. On the other hand, aripiprazole has no known effect on fluoxetine metabolism [Boulton et al. 2010].

Here, we describe a case in which increased plasma concentration of aripiprazole due to a drug interaction with fluoxetine led to SS.

Case report

A previously healthy 20-year-old woman with a diagnosis of autism spectrum disorder was admitted to the emergency room (ER) with rigidity and muscle pain. According to the medical history obtained, she had been using sertraline 50–100 mg/day for the last 6 years for her depressive symptoms. Two years ago, risperidone was initiated for irritability. It was discontinued 2 months ago due to sedation and weight gain, and aripiprazole 10 mg/day was initiated. Within 2 months of aripiprazole and sertraline combination, the patient complained of hair loss and sertraline was gradually tapered to 12.5 mg and fluoxetine 20 mg was initiated. After 2 days of simultaneous use, sertraline was ceased. On the seventh week of aripiprazole treatment and 4 days after the initiation of fluoxetine (2 days after the cessation of sertraline), she started to experience muscle pain, tremor, rigidity, akathisia, ataxia, agitation, sweating, and tachycardia. Her parents, who were physicians themselves, stopped fluoxetine immediately and aripiprazole 3 days later. At 10 days after the emergence of the first symptoms, the patient was admitted to the ER. She presented with all of the symptoms mentioned above, except ataxia and sweating, which had remitted during this time course. At the first physical examination, she was cooperative and oriented to person, place, and time. She was mildly agitated. Vital signs were as follows: blood pressure 140/90 mmHg, heart rate 120 beats/min, respiratory rate 24 breaths/min, temperature 36.7 °C, oxygen saturation 98% in room air. Initial physical examination revealed: dilated but reactive pupils, ocular clonus; rigidity in her upper and lower extremities; hyperreflexia; inducible clonus; hand tremor and bilateral extensor plantar responses. Bowel sounds were normal and mild nausea was noted. Electrocardiogram demonstrated sinus tachycardia. Initial laboratory findings revealed normal liver (liver function test [LFT]) and renal functions (renal function test [RFT]). Serum electrolytes and complete blood count (CBC) were normal. Erythrocyte sedimentation rate was 23 mm/h, total creatine phosphokinase (CPK) was 118 U/L. She was given intravenous fluids and 1 mg clonazepam by mouth. After 10 h, repeat LFT, RFT, and CBC were normal; CPK was 103 U/L. Rigidity improved. Vital signs were normal. As a result of the rapid improvement of symptoms, the patient was discharged with clonazepam 2 × 1 mg and paracetamol 4 × 500 mg by mouth. All symptoms resolved within 1 week.

Discussion

The patient was diagnosed with SS, according to the Hunter toxicity criteria, as she displayed concurrent tremor, hyperreflexia, hypertonia, and ocular, ankle and knee clonus [Dunkley et al. 2003]. Since there are symptomatic similarities between SS and neuroleptic malignant syndrome (NMS), and the patient had been using an antipsychotic medication, a differential diagnosis was made between the two conditions. Along with rigidity, NMS is associated with bradyreflexia, while SS is characterized by hyperreflexia, myoclonus, and tremors, which we had observed in our patient. In fact, variable rigidity and, in some cases, rhabdomyolysis, were also reported, albeit to a lesser degree in SS [Keck, 2003]. Dilated pupils are rare in NMS [Boyer, 2013]. Temperature over 38 °C is observed in almost 90% of NMS patients, therefore the lack of pyrexia in our patient also favored the diagnosis of SS [Wijdicks, 2014]. Indeed, hyperthermia is less frequently observed in SS [Mason et al. 2000]. In addition, CPK levels, which are usually expected to rise during the course of NMS, were within normal range in both assessments. There was no known medical illness and no signs of acute infection were observed during her examination in the ER. Akathisia and rigidity were not isolated but together with the symptoms related to autonomic and neuromuscular activity. Thus, overall, the occurrence of tremor, rigidity, hyperreflexia, sustained clonus, and autonomic hyperactivity in our patient suggested a diagnosis of significant SS.

The clearance of aripiprazole is principally determined by the functional activity of the cytochrome P450 enzymes CYP2D6 and CYP3A3/4, with the former usually being somewhat more important in most people [Preskorn, 2003]. Fluoxetine is a substantial inhibitor of several CYP enzymes including CYP450 2D6 [Hiemke and Hartter, 2000]. The SS in this case seemed to develop due to an interaction between fluoxetine and aripiprazole. After initiation of fluoxetine, the serum level of aripiprazole could have been elevated because of the decreased metabolism of the latter. Aripiprazole has partial agonist activity at the 5-HT1A receptors [Stark et al. 2007], and an increase in its plasma concentration could overstimulate the 5-HT1A receptors along with fluoxetine leading to SS. The elimination half-life of fluoxetine (and its metabolite norfluoxetine) may extend for up to 20 days, therefore explaining the enduring symptoms despite the immediate cessation of fluoxetine after the symptoms emerged [Zahajszky et al. 2009]. As the patient had been on sertraline for the last 7 years, we do not think that fluoxetine 20 mg/day alone was responsible for the emergence of SS, since sertraline inhibits serotonin reuptake transport more potently than fluoxetine in vitro [Bolden-Watson and Richelson, 1993].

To our knowledge, there is only one other report of SS on the aripiprazole–fluoxetine combination. This report describes a 64-year-old male patient who had been using citalopram 60 mg for many years with no adverse events, who developed SS after the addition of a single dose of aripiprazole 5 mg [Primeau et al. 2012]. In that case, in contrast to our patient, the SSRI dose was relatively high. Since serotonin toxicity is generally related to the use of high doses of serotonergic drugs, the development of SS in our patient is rather unusual. However, SS cases associated with relatively low doses of serotonergic drugs were also reported [Pan and Shen, 2003; Turedi et al. 2007].

Reports, including ours, on aripiprazole’s potential serotonergic side effects should be kept in mind when combination treatments of this antipsychotic with other serotonergic agents, especially those which also affect the metabolism of the former, are to be considered.