Apparent CYP 2D6 Interaction
with Amphetamine and Paroxetine
• Trichotillomania may present as an unusual iatrogenic condition secondary to specific drug-drug interactions.
• Depression and attention-deficit/hyperactivity disorder often present as comorbid conditions, and the medications used to treat those comorbid conditions may interact through the cytochrome P450 (CYP) 2D6 pathway.
• Understanding the pharmacology of this dramatic presentation of trichotillomania may alert the clinician to more subtle manifestations of this important CYP 2D6 interaction.
Although pharmacotherapy is intended to resolve clinically relevant symptoms, unpredictable side effects may occur, especially when polypharmacy is initiated. This report details a drug-drug interaction between paroxetine and mixed amphetamine salts that manifested as iatrogenic trichotillomania. Mild amphetamine toxicity may result in irritability, psychomotor agitation, restlessness, insomnia, tremor, hypervigilance, hal lucination, anxiety, and stereotypical repetitive motor activity. Trichotillomania, within the spectrum of anxiety disorders, may be described as having a repetitive motor com ponent of hair pulling, which serves as an anxiolytic to patients with trichotillomania. In this report, the onset of trichotillomania appears to have been initiated by long-term adjunctive treatment of amphetamine salts in a patient receiving paroxetine. Symptoms of trichotillomania in this patient abated with a reduction in the amphetamine salts and a discontinuation of paroxetine.
With the high comorbid incidence of attention-deficit/hyperactivity disorder (ADHD) and depression the poten tial for using antidepressants concur rently with stimulants is abundant and potentially problematic. Most relevant regarding the possibility of drug inter actions is the use of antidepressant medication that significantly inhibits cytochrome P450 (CYP) 2D6 while given simultaneously with stimulant medications that are substrates of CYP 2D6. This case report demonstrates an unusual but graphic patient reaction, in the form of trichotillomania, to such a CYP 2D6 interaction between parox etine and mixed amphetamine salts.
Noteworthy with similar CYP 2D6 interactions and important to take into account is the length of time necessary for this type of interaction to appear, sometimes presenting clinically up to ≥3 months after starting the two inter active medications. Noting that the CYP 2D6 inhibition is often not abso lute and therefore not complete, these interactions take some time to appear and are often overlooked in their more clinically subtle manifestations.
Ms. A is a single 19-year-old female with dysthymic disorder and ADHD, inattentive type. She has no history of tic disorder or other significant medical his tory. Two years prior to her recent presen tation she began taking mixed amphet amine salts 20 mg QAM for ADHD and, at the same time, paroxetine 20 mg QAM for comorbid anxiety and depression. Ms. A reported taking her medication as prescribed with no self regulation of her dosage. The combination of medications was initially effective for both conditions, but the patient began noticing difficulty sleeping, agitation, and anxiety. After 6 months the patient began to report sores on her scalp and was seen by a number of dermatologists who were unable to diagnose the lesions (Figure). Some dos age adjustments of mixed amphetamine salts were made with no clear response. Approximately 6 months ago her cur rent dermatologist ultimately diagnosed the loss of hair as trichotillomania and referred the patient to our office for a second psychiatric opinion. Her dose of mixed amphetamine salts was immedi ately reduced while slowly and simultaneously she was titrated off of paroxetine and venlafaxine extended release 150 mg QAM was added. On 21-day follow-up, the patient reported feeling “much better,” had improved sleeping patterns, and had significant hair re-growth.
Metabolically, paroxetine is a CYP 2D6 substrate and potently inhibits CYP 2D6, even in extensive metabolizers.1 Using the popular technique of measuring blood levels of desipramine (a CYP 2D6 substrate) metabolites, patients showed a 3-fold increase in desipramine levels when administered with paroxetine.2 Regarding the metabolism of the mixed amphetamine salts, there is no evidence that amphetamines cause CYP 2D6 inhibition.3 A literature review of amphetamine metabolism describes a complex process where a portion of the oral dose is renally excreted by “oxidative deamination forming the inactive metabolites benzoic acid and hippuric acid.”4 The remaining amphetamine is converted by aromatic hydroxylation via 2D6 to three active metabolites: p-hydroxyamphetamine, phenylpropanolamine and p-hydroxynorephedrine.5-7
Additional studies used a potent CYP 2D6 inhibitor, quinidine, on rat CYP 2D1, (rat CYP 2D1 is equivalent to human CYP 2D6) which resulted in a decrease in the amount of active metabolite p-hydroxyamphetamine that was excreted.8 Other research demonstrated a 2-fold increase in plasma concentration of amphetamine in rats treated with quinidine.9
Further rat studies reported increased amphetamine concentrations in the brains of rats treated with similar potent CYP 2D6 inhibitor, fluoxetine.10,11 Based on well-documented research of rat metabolism of amphetamines on CYP 2D1, and on this clinical presentation, one is lead to the conclusion that amphetamine salts are metabolized to some extent by CYP 2D6. This report demonstrates what appears to be a significant drugdrug interaction due to enzymatic inhibition of metabolic clearance by paroxetine, which caused a relative accumulation of amphetamines and resulted in trichotillomania. A resolution of symptoms was seen when an antidepressant that does not significantly inhibit CYP 2D6 was combined with a lower dose of mixed amphetamine salts. The duration of use of the two interacting medications and the presence or absence of medication self-regulation are important factors to consider in the clinical setting when evaluating whether pharmacokinetic interactions are taking place.
This unusual case is only one example of a drug-drug interaction with amphetamines based upon the described CYP 2D6 interaction. This report illuminates a metabolic pathway along CYP 2D6 for amphetamines, one of the oldest psychiatric medications, and warrants ongoing clinical vigilance when administering amphetamines with medications that inhibit CYP 2D6. PP
1. Hardman JG, Limbird LE, Gilman AG, Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill Professional; 2001.
2. Alderman J, Preskorn SH, Greenblatt DJ, et al. Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. J Clin Psychopharmacol. 1997;17(4):284-291.
3. Markowitz JS, Morrison SD, DeVane CL. Drug interactions with psychostimulants. Int Clin Psychopharmacol. 1999;14(1):1-18.
4. Dring LG, Smith RL, Williams RT. The metabolic fate of amphetamine in man and other species. Biochem J. 1970;116(3):425-435.
5. Patrick KS, Straughn AB, Jarvi EJ, Breese GR, Meyer MC. The absorption of sustainedrelease methylphenidate formulations compared to an immediate-release formulation. Biopharm Drug Dispos. 1989;10(2):165-171.
6. Bach MV, Coutts RT, Baker GB. Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives. Xenobiotica. 1999;29(7):719-732.
7. Wu D, Otton SV, Inaba T, Kalow W, Sellers EM. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol. 1997;53(11):1605-1612.
8. Moody DE, Ruangyuttikarn W, Law MY. Quinidine inhibits in vivo metabolism of amphetamine in rats: impact upon correlation between GC/MS and immunoassay findings in rat urine. J Anal Toxicol. 1990;14(5):311-317.
9. Tomkins DM, Otton SV, Joharchi N, et al. Effect of CYP2D1 inhibition on the behavioural effects of d-amphetamine. Behav Pharmacol. 1997;8(2-3):223-235.
10. Sills TL, Greenshaw AJ, Baker GB, Fletcher PJ. Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction. Psychopharmacology (Berl). 1999;141(4):421-427.
11. Sills TL, Greenshaw AJ, Baker GB, Fletcher PJ. Subchronic fluoxetine treatment induces a transient potentiation of amphetamineinduced hyperlocomotion: possible pharmacokinetic interaction. Behav Pharmacol. 2000;11(2):109-116.
Mr. N.W. Parker is a fourth year medical student at Eastern Virginia Medical School.
Mr. C.E. Parker is chief psychiatrist of Amen Clinic in Washington, DC.
Disclosure: Mr. N.W. Parker reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Mr. C.E. Parker is on the speaker’s bureaus of Sanofi-Aventis, Shire, and Wyeth.
Please direct all correspondence to: Nathaniel W. Parker, BA, 545 Warren Crescent #9, Norfolk, VA 23507; Tel: 757-285-5467; Fax: 757-473-3768; email@example.com.