Primary Psychiatry. 2007;14(3):31-33

Dr. Ginsberg is director of outpatient services in Tisch Hospital’s Department of Psychiatry at New York University Medical Center in New York City.

Disclosure: Dr. Ginsberg receives honoraria for lectures, papers, and/or teaching from AstraZeneca and GlaxoSmithKline; and receives research support from Cyberonics.

Atomoxetine-Induced Salivary Gland Stones

Atomoxetine is a norepinephrine reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adults. In randomized controlled trials, approximately 70% of children and adolescents with ADHD without comorbidity responded as measured by reduced scores on a variety of ADHD scales.^1,2 Prior to being studied in ADHD, atomoxetine was known as tomoxetine and studied as an antidepressant. In those trials,³ as well as in a recent case report,⁴ atomoxetine induced mania, a finding consistent with antidepressant activity. The following is the first published report of sialolithiasis in association with atomoxetine.⁵

A 36-year-old patient with adult ADHD was responding well to 16 weeks of treatment with dextroamphetamine spansules 20 mg/day. Due to wearing off of the effects too early in the day, atomoxetine 18 mg was added. The patient denied having any special diet or a personal or family history of gout or arthritis. Within 10 days of starting atomoxetine, he developed a painful pulsatile swelling below his jaw line, later confirmed by a computed tomography scan as a left submandibular sialolith in the salivary gland, which was extruded. A second sialolith developed after another 10 days of atomoxetine treatment. After atomoxetine was discontinued, the stone passed. Two weeks later, the patient restarted atomoxetine; within 4–5 days he experienced another recurrence. He again discontinued atomoxetine and repeated the cycle on three further occasions with shorter time intervals to stone recurrence upon each reexposure. Each time, he reexperienced pain and swelling of the gland. By massaging the gland digitally, he was able to pass the stones—numbering at least 10, described as off-white and bullet shaped—without assistance. At no time did the patient ever develop dry mouth with atomoxetine. Subsequently, he was advised by both his otolaryngologist and his psychiatrist to discontinue the atomoxetine altogether. Since then, he has had no further stones develop in 6 months of follow-up.

The temporal course of events described above is consistent with salivary gland stone formation due to exposure to atomoxetine. In general, sialolithiasis is a common cause of salivary dysfunction that typically involves the submandibular gland. The incidence of symptomatic stones is 27.5–59.0 cases per 1 million individuals. Factors which promote the formation of these calculi include increased salivary calcium, salivary stasis, calcification of organic material, and reduced dietary phytate, a crystallization inhibitor of calcium salts found in plant seeds.^6,7 The only known systemic cause of salivary stones is gout.⁸ According to the authors of this report, a search of the literature and contact with the manufacturer of atomoxetine failed to reveal any other cases of sialolithiasis in association with atomoxetine. Searches of reports of sialolithiasis with sympathomimetic drugs or with norepinephrine reuptake inhibitors were also negative. Interestingly, there are a few reports of salivary gland swelling associated with the norepinephrine reuptake inhibitor mianserin⁹ and with the b₂-adrenergic agonist ritodrine,^10,11 so noradrenergic activation may play a role here. Regardless of the presumed mechanism of action, clinicians who prescribe atomoxetine ought to be aware of the possibility of precipitating salivary gland stone formation in susceptible patients. PP

1. Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry. 2002;159(11):1896-1901.
2. Spencer T, Heiligenstein JH, Biederman J, et al. Results of 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2002;63(12):1140-1147.
3. Steinberg S, Chouinard G. A case of mania associated with tomoxetine. Am J Psychiatry. 1985;142(12):1517-1518.
4. Henderson TA. Mania induction associated with atomoxetine. J Clin Psychopharmacol. 2004;24(5):567-568.
5. Jerome L, Gardner D, Kutcher SP. First case of sialolithiasis associated with atomoxetine. J Clin Psychopharmacol. 2007;27(1):111-112.
6. Escudier MP, McGurk M. Symptomatic sialoadenitis and sialolithiasis in the English population, an estimate of the cost of hospital treatment. Br Dent J. 1999;186(9):463-466.
7. Baurmash HD. Submandibular salivary stones: current management modalities. J Oral Maxillofac Surg. 2004;62(3):369-378.
8. Grases F, Santiago C, Simonet BM, Costa-Bauza A. Sialolithiasis: mechanism of calculi formation and etiologic factors. Clin Chim Acta. 2003;334(1-2):131-136.
9. Gundert-Remy. Can salivary gland swelling, edema, and “direct” hyperbilirubinemia develop as sequelae of chronic administration of mianserin? [German] Internist (Berl). 1996;37(5):518-519.
10. Minakami H, Takahashi T, Izumi A, Itoi H, Tamada T. Enlargement of the salivary gland after ritodrine treatment in pregnant women. BMJ. 1992;304(6843):1668.
11. Marioni G, Marchese-Ragona R, Ottaviano G, Campobasso C, Staffieri A. Parotitis due to ritodrine tocolytic treatment for preterm labor. Otolaryngol Head Neck Surg. 2005;132(4):665-666.

Quetiapine-Induced Erythema Multiforme Minor

Quetiapine is a second-generation antipsychotic (SGA) indicated for the treatment of schizophrenia; as monotherapy for the acute treatment of manic episodes, as well as an adjunct to treatment with lithium or divalproex for bipolar type I disorder; and for bipolar depression. Pharmacologically, it is an antagonist at serotonin (5-HT)_1A and 5-HT₂, dopamine (D)₁ and D₂, histamine-1, and adrenergic a₁ and a₂ receptors.¹

Erythema multiforme is an acute, self-limiting, inflammatory skin eruption. The rash is made of spots that are red welts, sometimes with purple or blistered areas in the center. Often it also affects the mouth, eyes, and other moist surfaces. Erythema multiforme has been so named because of the “multiple forms” it appears in; there is a large degree of variety in its clinical presentation. This variation has led to erythema multiforme being divided into two overlapping subgroups: erythema multiforme minor and Stevens-Johnson syndrome. These are different faces of the same disease.²

Erythema multiforme is a relatively common problem. Half the cases are in young people (under 20 years of age). It is rare both at <3 years of age and at >50 years of age. Males are slightly more affected than females and there is no racial predilection. One-third of erythema multiforme sufferers will have a recurrence of the disease. Seasonal epidemics are common.²

As its name suggests, erythema multiforme minor is the less severe of the two types and accounts for 80% of erythema multiforme. The rash appears over a few days. However, in some patients several crops follow each other during one attack. There may be minor burning or itch. It is most intense over the backs of the hands and feet. There are usually round “bulls eye” target-shaped rings on the palms. In severe cases, some blisters may be present both on the skin and lips. The rash lasts for 1–2 weeks and then recedes, leaving residual brown pigmentation.²

Typically, the main cause of erythema multiforme minor is the herpes virus, either as a cold sore, genital herpes, or a hidden infection. Other cases are due to other bacterial or viral infections or reactions to medications. If the infection returns at a later date, or the medication is taken again, the rash will soon follow. Medications that are most commonly associated with erythema multiforme include anticonvulsants, nonsteroidal anti-inflammatory drugs, allopurinol, penicillin, and sulfa-contained drugs such as sulfonamides and captopril. What follows is the first published case of erythema multiforme minor in association with the SGA quetiapine.³

A 21-year-old woman presented with “school refusal” and home withdrawal for 1 year. After receiving intervention through her guidance system at school, she was referred for clinical treatment and subsequently admitted to a Taiwanese Psychiatric Center in Taipei. Drug-naïve prior to admission, she was diagnosed with undifferentiated-type schizophrenia and started on quetiapine 100 mg/day. On the eleventh day, quetiapine was titrated up to 400 mg/day when erythematous, edematous papules were noted over the face. While not painful, the patient complained of the cosmetic effect of the papules. Her doctors prescribed antihistamines for what appeared to be a mild, transient drug eruption. Unfortunately, within the next 24 hours, the condition progressed to one manifested by edematous and swelling chins, painful tongue ulceration, and the extensive spread of lesions from the trunk to the extremities. Later, the patient complained of bilateral shoulder joint soreness. The skin lesions showed signs of erythematous, edematous change. There was no sign of further progressive desquamation. A comprehensive work-up consisting of complete blood count, hepatic and renal tests, rheumatoid markers such as C3/C4, erythrocyte sedimentation rate, and chest x-ray were all negative. After ruling out various infectious diseases such as herpes simplex virus and internal organ malignancy, a dermatologist consultant diagnosed drug-induced erythema multiforme minor. Topical steroids and oral antihistamines were administered followed by the discontinuation of quetiapine. As she remained paranoid and the eruptions rapidly resolved, the patient refused to undergo a biopsy or to allow blood samples to be drawn from her. Drug-free for the next 2 weeks, the patient accepted a trial of risperidone, which, although another atypical antipsychotic, has a distinct chemical structure and different pharmacologic profile from quetiapine. She improved significantly both behaviorally and cognitively, which resulted in her being discharged from the hospital 3 weeks later. No further drug reactions were noted.

The case described above is consistent with quetiapine-induced erythema multiforme minor. Based on experience with other medications associated with erythema multiforme, it is likely that the risk increases with rapid dose escalation. Individual genetic factors, as yet unidentified for most patient populations and drugs, also likely play a role.⁴ Querying patients about a past personal or family history of drug-associated rash may be useful for identifying those most at risk, in whom perhaps more gradual dosage titration ought to be considered. PP

1. Seroquel [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; October 2006.
2. American Osteopathic College of Dermatology. Erythema Multiforme. Available at: www.aocd.org/skin/dermatologic_diseases/erythema_multiform.html. Accessed February 5, 2007.
3. Lin GL, Chiu CH, Lin SK. Quetiapine-induced erythema multiforme minor: a case report. J Clin Psychopharmacol. 2006;26(6):668-669.
4. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486.

Serotonin Syndrome Due to Duloxetine-Cyclobenzaprine Combination

Serotonin syndrome results from excessive serotonin stimulation and is characterized by the triad of mental status changes, neurologic abnormalities, and autonomic instability.¹ Symptoms may include confusion, restlessness, diarrhea, tremor, diaphoresis, myoclonus, and hyperreflexia.² Severe cases may result in seizures, coma, or death. Medications with serotonergic activity such as serotonin reuptake inhibitors (SRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), L-tryptophan, amphetamines, and lithium have the potential for causing this condition, especially when used in combination or taken as an overdose.³ Other medications associated with serotonin syndrome include opiates, antiemetics such as ondansetron and metoclopramide, antimicrobials including linezolid and ritonavir, triptans, and dextromethorphan.⁴

Cyclobenzaprine, marketed under the name Flexeril, is a tricyclic amine salt indicated for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Its chemical structure resembles that of TCAs. Pharmacologically, cyclobenzaprine exhibits reserpine antagonism, norepinephrine potentiation, and strong central and peripheral anticholinergic effects.⁵ It also likely augments central serotonin transmission. Previous “Psychopharmacology Reviews” have reported on episodes of paranoid psychosis associated with cyclobenzaprine use.^6,7 The following is a report of serotonin syndrome resulting from an interaction between cyclobenzaprine and the serotonin norepinephrine reuptake inhibitor duloxetine.⁸

A 53-year-old man with a history of multiple low-back surgeries was admitted for the removal of infected spinal hardware. He had a history of chronic pain and depression, for which he was receiving duloxetine 60 mg/day, pregabalin 75 mg BID, bupropion 300 mg/day, and oxycodone or hydromorphone as needed for pain. The patient underwent uneventful removal of his spinal hardware under general endotracheal anesthesia. Postoperative pain was managed with opiates; his infection was treated with vancomycin. Two days after the surgery, the patient developed worsening confusion with hallucinations. On the fifth postoperative day, over the course of a few hours, he became very diaphoretic, tachycardic, and markedly agitated. Pronounced tremors, spontaneous sustained clonus, and multifocal myoclonus were noted. Laboratory studies revealed hypernatremia (154 mEq/L) and lactic acidosis (arterial pH 7.27, anion gap 20, lactate level 10.1 mmol/L). There was only mild hyperthermia and no significant increase of his creatine kinase concentration (highest 265 U/L). Because of the extreme severity of his agitation, the patient’s trachea was intubated after administration of propofol and vecuronium. He was then sedated with a continuous infusion of propofol and scheduled intravenous lorazepam. To allow for serial neurologic examinations, sedation was withheld at prearranged intervals. The patient was rehydrated, with a b-blocker used to ameliorate the tachycardia.

In reviewing the case, the treating physicians recognized that the patient had been given cyclobenzaprine 10 mg TID very shortly before the onset of his confusion. His medication regimen also included duloxetine 60 mg/day, which the patient had been taking for the previous 4 months, and oxycodone 5 mg every 6 hours as needed for pain, which he had also been using for several weeks before the current hospital admission. Bupropion had not been administered for more than 60 hours. Cyclobenzaprine and duloxetine were stopped. The serotonin antagonist cyproheptadine 8 mg via nasogastric tube every 6 hours was administered for 72 hours. Over the next few days, the patient’s clinical status improved steadily. Two days later, he was tracheally extubated and recovered without sequelae.

The temporal sequence of events described above is consistent with serotonin syndrome resulting principally from an interaction between cyclobenzaprine and duloxetine. A contributing role in precipitating serotonin syndrome from the opiates oxycodone and hydromorphone, as well as from use of the norepinephrine dopamine reuptake inhibitor bupropion, cannot be excluded. The package insert for cyclobenzaprine warns against its use in conjunction with MAOIs but not with SRIs. Given the seriousness of serotonin syndrome, clinicians ought to be aware of the potential for duloxetine, as well as likely other SRIs, to result in this condition when used in combination with cyclobenzaprine. PP

1. Lavery S, Ravi H, McDaniel WW, Pushkin YR. Linezolid and serotonin syndrome. Psychosomatics. 2001;42(5):432-434.
2. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148(6):705-713.
3. Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: a brief review. CMAJ. 2003;168(11):1439-1442.
4. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
5. Flexeril [package insert]. Whitehouse Station, NJ: Merck & Co; 1998.
6. Beeber AR, Manring JM Jr. Psychosis following cyclobenzaprine use. J Clin Psychiatry. 1983;44(4):151-152.
7. O’Neil BA, Knudson GA, Bhaskara SM. First episode psychosis following cyclobenzaprine use. Can J Psychiatry. 2000;45(8):763-764.
8. Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the interaction of cyclobenzaprine with other serotonergic drugs. Anesth Analg. 2006;103(6):1466-1468.