Initiation of Illusions After Combination of Zolpidem and Paroxetine in a Young Woman: A Case Report
To the Editor: We report a case of possible interaction between the non-benzodiazepine hypnotic zolpidem and the selective serotonin reuptake inhibitor (SSRI) paroxetine in a young woman diagnosed with panic disorder and then summarize the current relevant literature as identified via PubMed, EMBASE, and PsycINFO as well as reference sections of selected articles.
Case report. Ms A, a 24-year-old woman, visited the outpatient clinic in a state of crisis and reported experiencing illusions after the addition of zolpidem to her daily paroxetine regimen.
She had been diagnosed with panic disorder, per DSM-IV-TR criteria, 2 years earlier and was stabilized on a dosage of oral paroxetine 30 mg daily. The results of all necessary blood tests, including complete blood cell count, biochemical analysis, and thyroid function tests, were unremarkable at that time. Recently, during her regular follow-up visit to the outpatient psychiatric department, she complained of insomnia consisting of difficulties in the initiation of sleep with additional nighttime awakenings mainly during the first half of the night. After discussion of her problem with her psychiatrist, she was given detailed advice on how to improve her sleep. Despite following sleep hygiene advice, she returned, continuing to complain of disordered sleep. The clinician prescribed zolpidem 10 mg at bedtime.
After the first dose of zolpidem, she experienced disturbance of perception, specifically an illusional state, when watching herself in the mirror (an illusion is a temporary distortion or misinterpretation of a real perception, in contrast to a hallucination, which is a perception in the absence of a real stimulus). In this case, the illusions took the form of a frightening distortion of her perceived appearance that triggered a panic attack in the patient. When levels of anxiety decreased, she understood that this phenomenon was not real, but the symptom did not fully resolve until after approximately 1 hour.
Paroxetine is an SSRI, a drug category that is believed to act through the blocking of the serotonin reuptake transporter; paroxetine additionally desensitizes serotonin (5-HT1A) autoreceptors, resulting in the disinhibition of the serotonergic neuron, increase of serotonin release, and increase of neuronal impulse flow. Panic disorder is characterized by overactivation of amygdala-centered circuits,1 and SSRIs are thought to act therapeutically by increasing serotoninergic inhibitory input to the amygdala from incoming serotonergic neurons from the raphe nuclei area.2 Also, paroxetine is thought to have mild noradrenergic as well as mild anticholinergic action. Paroxetine is commonly prescribed for the treatment of panic disorder.3-6 Zolpidem is a commonly prescribed non-benzodiazepine hypnotic sleep medication, a drug category that is believed to act through binding in the α1 isoform of the benzodiazepine receptor, consequently enhancing chloride conductance through the γ-aminobutyric acid (GABA) ion channel, leading to increased inhibitory GABA action in brain sleep centers.
To the knowledge of the authors this is the first reported case of a patient with panic disorder stabilized and symptomless with paroxetine that destabilized by the experiencing of fear after the addition of zolpidem. Some authors have reported development of hallucinations in a patient treated with zolpidem7-12 or with the combination of zolpidem and SSRIs,13-15 including the combination of zolpidem and paroxetine16 specifically. Other authors found the combination of zolpidem and SSRIs to be generally effective and safe.17,18 There is no obvious pharmacokinetic mechanism responsible for this interaction, as paroxetine is thought to be an inhibitor of the cytochrome P450 (CYP) isoenzyme CYP2D6,19 whereas zolpidem is converted to hydroxylated metabolites principally by the CYP3A4 isoenzyme, with minor contributions of 1A2 and 2C9 isoforms.20 A pharmacodynamic interaction mechanism has been suggested,16 based on the fact that both drugs are highly protein bound and could interact through competitive binding with consequent toxic increase of serum zolpidem levels causing symptoms of delirium such as illusions and hallucinations. We suggest that physicians use this 2-drug combination with caution as well as under close supervision in a clinical setting similar to the one described.
References
1. Gorman JM, Kent JM, Sullivan GM, et al. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry. 2000;157(4):493-505. PubMed
2. Coplan JD, Lydiard RB. Brain circuits in panic disorder. Biol Psychiatry. 1998;44(12):1264-1276. PubMed doi:10.1016/S0006-3223(98)00300-X
3. Pollack M, Mangano R, Entsuah R, et al. A randomized controlled trial of venlafaxine ER and paroxetine in the treatment of outpatients with panic disorder. Psychopharmacology (Berl). 2007;194(2):233-242. PubMed doi:10.1007/s00213-007-0821-0
4. Sheehan DV, Burnham DB, Iyengar MK, et al; Paxil CR Panic Disorder Study Group. Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder. J Clin Psychiatry. 2005;66(1):34-40. PubMed doi:10.4088/JCP.v66n0105
5. Pollack MH, Simon NM, Worthington JJ, et al. Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder. J Psychopharmacol. 2003;17(3):276-282. PubMed doi:10.1177/02698811030173009
6. Ballenger JC, Wheadon DE, Steiner M, et al. Double-blind, fixed-dose, placebo-controlled study of paroxetine in the treatment of panic disorder. Am J Psychiatry. 1998;155(1):36-42. PubMed
7. Elko CJ, Burgess JL, Robertson WO. Zolpidem-associated hallucinations and serotonin reuptake inhibition: a possible interaction. J Toxicol Clin Toxicol. 1998;36(3):195-203. PubMed doi:10.3109/15563659809028939
8. Markowitz JS, Rames LJ, Reeves N, et al. Zolpidem and hallucinations. Ann Emerg Med. 1997;29(2):300-301. PubMed doi:10.1016/S0196-0644(97)70291-9
9. Mignot G, Chichmanian RM, Jean-Girard C. [Zolpidem and hypnotic hallucinations]. Therapie. 1990;45(5):439. PubMed
10. Toner LC, Tsambiras BM, Catalano G, et al. Central nervous system side effects associated with zolpidem treatment. Clin Neuropharmacol. 2000;23(1):54-58. PubMed doi:10.1097/00002826-200001000-00011
11. Tsai MJ, Huang YB, Wu PC. A novel clinical pattern of visual hallucination after zolpidem use. J Toxicol Clin Toxicol. 2003;41(6):869-872. PubMed doi:10.1081/CLT-120025354
12. van Puijenbroek EP, Egberts AC, Krom HJ. Visual hallucinations and amnesia associated with the use of zolpidem. Int J Clin Pharmacol Ther. 1996;34(7):318. PubMed
13. Coleman DE, Ota K. Hallucinations with zolpidem and fluoxetine in an impaired driver. J Forensic Sci. 2004;49(2):392-393. PubMed doi:10.1520/JFS2003171
14. Kito S, Koga Y. Visual hallucinations and amnesia associated with zolpidem triggered by fluvoxamine: a possible interaction. Int Psychogeriatr. 2006;18(4):749-751. PubMed doi:10.1017/S1041610206214418
15. Andrade C. Zolpidem, vascular headache, and hallucinations in an adolescent. Aust N Z J Psychiatry. 2002;36(3):425-426. PubMed doi:10.1046/j.1440-1614.2001.t01-2-01030.x
16. Katz SE. Possible paroxetine-zolpidem interaction. Am J Psychiatry. 1995;152(11):1689. PubMed
17. Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry. 1999;60(10):668-676. PubMed doi:10.4088/JCP.v60n1005
18. Piergies AA, Sweet J, Johnson M, et al. The effect of co-administration of zolpidem with fluoxetine: pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther. 1996;34(4):178-183. PubMed
19. Bourin M, Chue P, Guillon Y. Paroxetine: a review. CNS Drug Rev. 2001;7(1):25-47. PubMed doi:10.1111/j.1527-3458.2001.tb00189.x
20. Holm KJ, Goa KL. Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs. 2000;59(4):865-889. PubMed doi:10.2165/00003495-200059040-00014
Author affiliations: Department of Psychiatry, Nicosia Mental Health Services, Nicosia, Cyprus.
Potential conflicts of interest: None reported.
Funding/support: None reported.
Published online: July 19, 2012.
Prim Care Companion CNS Disord 2012:14(4):doi:10.4088/PCC.12l01361
© Copyright 2012 Physicians Postgraduate Press, Inc.
