J Gambl Stud DOI 10.1007/s10899-013-9360-2 ORIGINAL PAPER
Citalopram-Associated Gambling: A Case Report Ilaria Cuomo • Georgios D. Kotzalidis • Federica Caccia Emanuela Danese • Giovanni Manfredi • Paolo Girardi
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Ó Springer Science+Business Media New York 2013
Abstract Pathological gambling behaviour is a side effect of dopaminergic drugs used in Parkinson’s disease, but has seldom been reported with selective serotonin reuptake inhibitors. A 58-years-old woman with somatisation disorder since the age of 20 and recent-onset major depression (at 54 years) received 40 mg/day intravenous citalopram, thereafter switching to the same dose of oral citalopram to treat her comorbid psychiatric disorders after showing poor response to paroxetine for one year. Her anxious and depressive symptoms were moderately reduced after 7 months of oral citalopram, but simultaneously, the patient admitted gambling. We gradually discontinued citalopram and introduced pregabalin and alprazolam; this was followed by a reduction of gambling compulsions, but the somatisation and depressive symptoms did not further improve. Pathological gambling may be mediated by an interplay of 5-HT1A serotonergic and D2 dopaminergic mechanisms. Citalopram affects both these mechanisms in areas that were shown to be involved in gambling behaviour, but while dopaminergic effects of citalopram appear to be consistent with the induction of gambling, its serotonergic mechanisms are rather inconsistent. In our patient, mood destabilisation induced by citalopram may have contributed to the first onset of pathological gambling. Keywords Selective serotonin reuptake inhibitors Citalopram Pathological gambling Major depressive disorder Somatisation disorder
Introduction Pathological gambling (PG), a severely socially disruptive disorder (Marazziti et al. 2008; Grant and Kim 2005) affects 1–3.4 % of the adult US population. Patients with PG are highly comorbid with lifetime mood and anxiety disorders. Lifetime mood disorders in DSM-IV-TR PG amounted to 55.6 % in the National Comorbidity Survey Replication I. Cuomo (&) G. D. Kotzalidis F. Caccia E. Danese G. Manfredi P. Girardi NESMOS Department (Neurosciences, Mental Health, and Sensory Organs), Unit of Psychiatry, School of Medicine and Psychology, Sant’Andrea Hospital, Sapienza University, Via di Grottarossa 1035-1039, 00189 Rome, Italy e-mail:
[email protected]
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study (Kessler et al. 2008), with major depression and dysthymia accounting for 38.6 %, while lifetime anxiety disorders were 60.3 %. These findings differ somehow from those of a German study (Erbas and Buchner 2012), showing 63.1 % comorbidity with mood disorders and 37.1 % with anxiety disorders, with data in Canadian women approximating those of this study (Boughton and Falenchuk 2007). Many recent studies point to an important role for serotonin in pathological gambling and impulse dyscontrol. SSRIs have been used to treat PG, and some showed fair efficacy. A 12-week open escitalopram trial in 13 patients with comorbid anxiety reported some positive effects, but evidence was overall inconclusive (Grant and Potenza 2006). Another 10-week open-label flexible-dose escitalopram (10 mg/day titrated to maximum 30) trial in 19 patients with PG without depression showed improvements in 14 of the 16 completers (Black et al. 2007). In another 12-week open-label study of flexible-dose citalopram (20–60 mg/day, mean daily dose about 34 mg) in 15 patients with PG with or without major depressive disorder, all nine completers showed satisfactory improvement on the CGI, with no difference between patients with major depression and those without (Zimmerman et al. 2002). However, a double-blind multicentre trial of paroxetine in patients with PG (36 patients assigned to flexible-dose paroxetine [10 mg/day titrated to 20–60 mg/day] vs. 40 assigned to placebo) and no other DSM-IV axis I disorder other than specific phobia or nicotine dependence, showed no significant advantage of paroxetine over placebo. To date, few reports of SSRI-associated gambling have been published and none has proposed pathophysiological or neurochemical mechanisms to explain this phenomenon. We describe newly arising PG in a patient receiving 40 mg/day citalopram for her depression and somatisation disorder, providing a neurochemical hypothesis to explain the triggering of the impulse control disorder.
Case Report A 58-year-old Caucasian housewife consulted our outpatient facility for an exacerbation of her recurrent major depressive disorder and somatisation disorder. The first of six siblings, she had a negative family psychiatric history, except for past heroin use disorder in one of her brothers, and generalised anxiety disorder in her only son. She married at age 18 and delivered uneventfully at age 25. She denied any peri-partum mood disorder, but traces back the onset of her psychiatric symptoms to age 20, mainly consisting of somatisation symptoms for which she sought no psychiatric help. Her first psychiatric contact occurred at age 28, when she reported difficulties with caring for her 3-year-old son and an exacerbation of somatisations (colitis and dizziness). She was prescribed imipramine, which benefitted her little, and referred for psychoanalytic psychotherapy. She carried on her psychoanalytic therapy for 6 years, but meanwhile she visited various psychiatrists complaining about her increasingly worsening mood. From 2006 to 2008, she took oral 20 mg/ day paroxetine improving only transiently, but felt worse when discontinuing. She referred to our psychiatric centre in July 2008, 4 months after having voluntarily discontinued paroxetine. She complained anxiety and depressed mood, morning mood worsening, inner tension, and hypochondriac thinking. During this period she entered a research protocol and underwent a PET scan, which showed lower neuronal glucose metabolism in the left parietal-temporal region. We used the SCID-I and SCID-II diagnostic interviews to diagnose her with DSM-IV-TR (American Psychiatric Association 2000) Recurrent Major Depressive Disorder, and Somatization Disorder and prescribed paroxetine 20 mg/day, and olanzapine 5 mg/day for almost 1 year. Treatment was followed by no improvement of
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depression and by worsening of anxiety and somatisations. As a result, she was admitted in August 2009 to our psychiatric day hospital. During hospitalisation was diagnosed with autoimmune thyroiditis, with high anti TPO antibody levels, and prescribed 50 mcg/day levothyroxine. On admission she scored 30 on the Hamilton Depression Rating Scale (HAM-D) and 39 on the Hamilton Anxiety Rating Scale (HAM-A). We treated her for 2 weeks with intravenous citalopram titrated up to 40 mg/day, thereafter switching to the oral formulation (40 mg/day). Four months later she was discharged. Her HAM-D and HAM-A scores had dropped to 17 and 21, respectively, which were still clinically significant. The patient missed her scheduled psychiatric visits for the following 3 months because she was hospitalised for a bone fracture secondary to a traffic accident. By the time she had returned to her scheduled visits, her mood symptoms were moderately improved and her sleep-wake cycle normalised, while her anxiety symptoms had only mildly improved. Given her improvement, we decided to gradually reduce citalopram to 20 mg/day. Four months later, the patient complained of disabling inner tremor, dizziness, soaring hypochondriac thoughts, and worsening of anxiety and somatisation. The patient admitted gambling addiction concurrently with this relapse, which she referred to have never experienced before. She traced back the initiation of this behaviour to the period of her psychiatric discharge and the exacerbation of such behaviour to the period she was hospitalised at the orthopedic ward. She reportedly passed from sporadic purchase of lottery scratching-off tickets during day hospital visits, to regular and increasing purchase, culminating during the rehabilitation programme for her femoral fracture. Asked for her mood state at the beginning of gambling, she reported feeling somewhat alone, but quite self-confident, and did not report any mood alteration. In November 2010, she became addicted to poker machines, which led her to lose more than €1,000 per month and to lie to her family members and doctors. The patient reported no prior financial mismanagement. She did not meet criteria for mania or hypomania on the Structured Clinical Interview for the DSM-IV-TR (SCID-I). Among criteria for hypomania (four out of seven symptoms required), she only satisfied three, i.e., irritable mood, more talkativeness than usual, and excessive involvement in pleasurable activities with high potential of painful consequences. Furthermore, her symptomatology seemed to be strictly related to antidepressant treatment. We tapered-off citalopram over 2 months and introduced pregabalin, titrated to 225 mg/ day, and the triazolobenzodiazepine alprazolam 0.5 mg b.i.d. This was followed by remarkable improvement of anxiety and somatisations. There was a gradual reduction of slot machine gambling, with persistence of the ‘impulse to play’, and lack of insight. We referred her to a self-help group, Gamblers Anonymous, which she finally accepted to join during June 2011. Two weeks after joining the self-help group, she had quitted gambling. She had two isolated relapses during summer, which she read as ‘putting herself to test’, after which she overcame the impulse to gamble. Currently, she still abstains from gambling, but a recent worsening of anxiety and somatisations (inner tension and tremor, and dizziness), and sleep disorder, prompted the patient to visit the emergency room. Neurological examination showed no strength or sensory deficits, nor dysmetria or ataxia; we added olanzapine, 5 mg/day, and increased the dose of alprazolam to 1.5 mg/day. In July 2012, the patient was hospitalised for 2 months due to worsening of somatisations and recurrence of tremor which were concurrent with severe life stress. We rated gambling behaviour on the Naranjo ADR Probability Scale (Naranjo et al. 1981) and attributed a score of 8, compatible with probable relation to citalopram. The
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patient provided free-informed consent for all treatments received and for the publication of her case.
Discussion The time sequence of psychopathological events occurring in our patient point to a relationship between the administration of citalopram and gambling behaviour, which she had never displayed in the past. She had undergone various antidepressant trials in her history, including the SSRI paroxetine; in no case did she show gambling behaviour. Treatment with citalopram overlapped temporally with the onset of PG behaviour. Furthermore, improvement of gambling addiction paralleled the tapering-off of citalopram. The onset of PG coincided with full-dose citalopram, and not with dose reduction. The mechanism by which citalopram could have triggered gambling behaviour is unclear. Its role in 5-HT1A serotonin receptor function, which was found to be related to gambling in a rat analogue (Zeeb et al. 2009), is controversial (Moulin-Sallanon et al. 2009; Ceglia et al. 2004; Bobula et al. 2003). However, all SSRIs increase central serotonin function, which may sustain rather than inhibit loss chasing in the context of gambling (Campbell-Meiklejohn et al. 2011). Serotonin appears to have a role in the response to high-risk related large wins in the amygdala, while leaving the dorsomedial prefrontal cortex unaffected, with citalopram activating neural transmission and acute tryptophan depletion, which depresses serotonergic function having the opposite effect (Macoveanu et al. 2012). Increased serotonergic function elicited by repeated/(sub)chronic citalopram administration in the rat reinforces win-stay behaviour, i.e., reward (Bari et al. 2010); hence, it is possible that after 4 months of treatment, our patient’s brain serotonin tone had increased to mediate positive reward, provided that similar mechanism operate in both humans and rodents. Another mechanism could be an action related to dopamine. Animal data point to suppressed dopaminergic firing in the ventral tegmental area (Prisco and Esposito 1995) and increased dopamine activity in cortex and limbic system after chronic citalopram (Sekine et al. 2007; Pozzi et al. 1999; Weikop et al. 2007; Bijak and Smiałowski 1988; Maj et al. 1998; Rogoz and Dziedzicka-Wasylewska 1999; Arnt et al. 1984), which may promote gambling behaviour (Zeeb et al. 2009). Before developing PG, our patient underwent a PET scan, showing lower neuronal glucose metabolism in the left parietal-temporal region. This matches findings in depressive disorders (Hosokawa et al. 2009), but not PG, where baseline glucose metabolic rate is lower in the ventral striatum, higher in the dorsal striatum (Pallanti et al. 2010), and higher in the orbitofrontal and medial cortices (Hollander et al. 2008), compared to healthy controls. Gambling behaviour has been taken to represent an equivalent of substance abuse (van Holst et al. 2010a, b). However, when pathological gamblers were compared with cocaine addicts and their respective controls, they showed a differential pattern of lack of activation of the parietal lobule in response to their respective cues, i.e., gambling-related versus substance use-related cues, i.e., gamblers showed unchanged activity in the inferior parietal lobe, whereas their controls showed increased activity upon exposure to gambling cues; cocaine users showed unchanged activity in the same area, whereas their controls showed decreased activity when exposed to cocaine use-related cues (Potenza 2008). Interestingly, our patient had low inferior parietal lobule (IPC) baseline activation, a fact that may be linked to gambling behaviour and impulse dyscontrol, since the parietal lobule is one of the sites involved in executive inhibition (Swick et al. 2011; Hu and Li 2012). However,
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citalopram was shown not to affect prepotent response inhibition in a Go-No go task, but impaired probabilistic learning in human volunteers (Chamberlain et al. 2006), which in turn is important in gambling behaviour (Vaidya et al. 2012). During hospitalisation, our patient was diagnosed with autoimmune thyroiditis. In literature there is evidence of significantly lower serum levels of free triiodothyronine in pathological male gamblers than in healthy male controls, while thyroid stimulating hormone and free thyroxine did not differ (Nordin and Sjo¨din 2005). These findings may suggest a link between thyroid function and gambling behaviour, the mechanism of which is still obscure. However, serum levels of all thyroid-related hormones in our patient were in the normal range at discharge and at all subsequent evaluations (every 6 months). In conclusion, the sudden, unexpected onset of PG in our patient may find its basis in multiple inter-correlated factors, i.e., genetic, neuroendocrine, pharmacological, and neurobiological. Citalopram treatment, and not dose reduction seems to have triggered PG; despite no frank hypomanic symptoms or mood alteration, it is possible that it induced subthreshold hypomanic-like symptoms, thus acting as a long-term mood destabiliser (Ghaemi 2008); one aspect of this mood symptomatology might be represented by PG. Clinicians should be aware that PG could be associated with antidepressant drug treatment and subtle changes in mind state, and should question their patients about pathological gambling behaviour. Acknowledgments We gratefully acknowledge the contribution of the Librarians of the School of Medicine and Psychology of Sapienza University, Ms. Mimma Ariano, Ms. Felicia Proietti and the late Ms. Tiziana Mattei, in helping us localising relevant literature. Conflict of interest Paolo Girardi in the past 12 months has participated in Advisory Boards for Springer Healthcare and received grants and payment for writing a manuscript from Springer Healthcare, Milan; Georgios D. Kotzalidis is the recipient of an Italian Ministry of Education Ph.D. Grant for Early Intervention in the Psychoses.
All other authors of this paper have no relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
References American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders, 4th edition-text revision (DSM-IV-TR). Washington, D.C.: American Psychiatric Association. Arnt, J., Overø, K. F., Hyttel, J., & Olsen, R. (1984). Changes in rat dopamine- and serotonin function in vivo after prolonged administration of the specific 5-HT uptake inhibitor, citalopram. Psychopharmacology (Berlin), 84(4), 457–465. Bari, A., Theobald, D. E., Caprioli, D., Mar, A. C., Aidoo-Micah, A., Dalley, J. W., et al. (2010). Serotonin modulates sensitivity to reward and negative feedback in a probabilistic reversal learning task in rats. Neuropsychopharmacology, 35(6), 1290–1301. Bijak, M., & Smiałowski, A. (1988). The effect of acute and prolonged treatment with citalopram on the action of dopamine and SKF 38393 in rat hippocampal slices. European Journal of Pharmacology, 149(1–2), 41–47. Black, D. W., Shaw, M., Forbush, K. T., & Allen, J. (2007). An open-label trial of escitalopram in the treatment of pathological gambling. Clinical Neuropharmacology, 30(4), 206–212. Bobula, B., Tokarski, K., Zahorodna, A., & Hess, G. (2003). Adaptive changes in the reactivity of 5-HT1A and 5-HT2 receptors induced in rat frontal cortex by repeated imipramine and citalopram. NaunynSchmiedeberg’s Archives of Pharmacology, 367(5), 444–450.
123
J Gambl Stud Boughton, R., & Falenchuk, O. (2007). Vulnerability and comorbidity factors of female problem gambling. Journal of Gambling Studies, 23(3), 323–334. Campbell-Meiklejohn, D., Wakeley, J., Herbert, V., Cook, J., Scollo, P., Ray, M. K., et al. (2011). Serotonin and dopamine play complementary roles in gambling to recover losses. Neuropsychopharmacology, 36(2), 402–410. Ceglia, I., Acconcia, S., Fracasso, C., Colovic, M., Caccia, S., & Invernizzi, R. W. (2004). Effects of chronic treatment with escitalopram or citalopram on extracellular 5-HT in the prefrontal cortex of rats: Role of 5-HT1A receptors. British Journal of Pharmacology, 142(3), 469–478. Chamberlain, S. R., Mu¨ller, U., Blackwell, A. D., Clark, L., Robbins, T. W., & Sahakian, B. J. (2006). Neurochemical modulation of response inhibition and probabilistic learning in humans. Science, 311(5762), 861–863. Erbas, B., & Buchner, U. G. (2012). Pathological gambling: Prevalence, diagnosis, comorbidity, and intervention in Germany. Deutsches A¨rzteblatt International, 109(10), 173–179. Ghaemi, S. N. (2008). Treatment of rapid-cycling bipolar disorder: Are antidepressants mood destabilizers? American Journal of Psychiatry, 165(3), 300–302. Grant, J. E., & Kim, S. W. (2005). Quality of life in kleptomania and pathological gambling. Comprehensive Psychiatry, 46(1), 34–37. Grant, J. E., & Potenza, M. N. (2006). Escitalopram treatment of pathological gambling with co-occurring anxiety: An open-label pilot study with double-blind discontinuation. International Clinical Psychopharmacology, 21(4), 203–209. Hollander, E., Buchsbaum, M. S., Haznedar, M. M., Berenguer, J., Berlin, H. A., Chaplin, W., et al. (2008). FDG-PET study in pathological gamblers. 1. Lithium increases orbitofrontal, dorsolateral and cingulate metabolism. Neuropsychobiology, 58(1), 37–47. Hosokawa, T., Momose, T., & Kasai, K. (2009). Brain glucose metabolism difference between bipolar and unipolar mood disorders in depressed and euthymic states. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33(2), 243–250. Hu, S., & Li, C. S. (2012). Neural processes of preparatory control for stop signal inhibition. Human Brain Mapping, 33, 2785–2796. Kessler, R. C., Hwang, I., LaBrie, R., Petukhova, M., Sampson, N. A., Winters, K. C., et al. (2008). DSM-IV pathological gambling in the National Comorbidity Survey Replication. Psychological Medicine, 38(9), 1351–1360. Macoveanu, J., Rowe, J.B., Hornboll, B., Elliott, R., Paulson, O.B., Knudsen, G.M., & Siebner, H.R. (2012). Playing it safe but losing anyway–Serotonergic signaling of negative outcomes in dorsomedial prefrontal cortex in the context of risk-aversion. European Neuropsychopharmacology, 2012 Oct 7. doi: 10.1016/j.euroneuro.2012.09.006. Maj, J., Dziedzicka-Wasylewska, M., Rogoz, R., & Rogo´z, Z. (1998). Effect of antidepressant drugs administered repeatedly on the dopamine D3 receptors in the rat brain. European Journal of Pharmacology, 351(1), 31–37. Marazziti, D., Golia, F., Picchetti, M., Pioli, E., Mannari, P., Lenzi, F., et al. (2008). Decreased density of the platelet serotonin transporter in pathological gamblers. Neuropsychobiology, 57(1–2), 38–43. Moulin-Sallanon, M., Charnay, Y., Ginovart, N., Perret, P., Lanfumey, L., Hamon, M., et al. (2009). Acute and chronic effects of citalopram on 5-HT1A receptor-labeling by [18F] MPPF and—coupling to receptors-G proteins. Synapse (New York, N. Y.), 63(2), 106–116. Naranjo, C. A., Busto, U., Sellers, E. M., Sandor, P., Ruiz, I., Roberts, E. A., et al. (1981). A method for estimating the probability of adverse drug reactions. Clinical Pharmacology and Therapeutics, 30(2), 239–245. Nordin, C., & Sjo¨din, I. (2005). Reduced free tri-iodothyronine serum levels are lower in pathological male gamblers than in healthy male controls. Journal of Psychiatric Research, 39(4), 449. Pallanti, S., Haznedar, M. M., Hollander, E., Licalzi, E. M., Bernardi, S., Newmark, R., et al. (2010). Basal ganglia activity in pathological gambling: A fluorodeoxyglucose-positron emission tomography study. Neuropsychobiology, 62(2), 132–138. Potenza, M. N. (2008). Review. The neurobiology of pathological gambling and drug addiction: An overview and new findings. Philosophical Transactions of the Royal Society London B. Biological Sciences, 363(1507), 3181–3189. Pozzi, L., Invernizzi, R., Garavaglia, C., & Samanin, R. (1999). Fluoxetine increases extracellular dopamine in the prefrontal cortex by a mechanism not dependent on serotonin: A comparison with citalopram. Journal of Neurochemistry, 73(3), 1051–1057. Prisco, S., & Esposito, E. (1995). Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area. British Journal of Pharmacology, 116(2), 1923–1931.
123
J Gambl Stud Rogoz, R., & Dziedzicka-Wasylewska, M. (1999). Effects of antidepressant drugs on the dopamine D2/D3 receptors in the rat brain differentiated by agonist and antagonist binding—an autoradiographic analysis. Naunyn-Schmiedeberg’s Archives of Pharmacology, 359(3), 178–186. Sekine, Y., Suzuki, K., Ramachandran, P. V., Blackburn, T. P., & Ashby, C. R., Jr. (2007). Acute and repeated administration of fluoxetine, citalopram, and paroxetine significantly alters the activity of midbrain dopamine neurons in rats: An in vivo electrophysiological study. Synapse (New York, N. Y.), 61(2), 72–77. Swick, D., Ashley, V., & Turken, U. (2011). Are the neural correlates of stopping and not going identical? Quantitative meta-analysis of two response inhibition tasks. Neuroimage, 56(3), 1655–1665. Vaidya, J. G., Block, R. I., O’Leary, D. S., Ponto, L. B., Ghoneim, M. M., & Bechara, A. (2012). Effects of chronic marijuana use on brain activity during monetary decision-making. Neuropsychopharmacology, 37(3), 618–629. van Holst, R. J., van den Brink, W., Veltman, D. J., & Goudriaan, A. E. (2010a). Brain imaging studies in pathological gambling. Current Psychiatry Reports, 12(5), 418–425. van Holst, R. J., van den Brink, W., Veltman, D. J., & Goudriaan, A. E. (2010b). Why gamblers fail to win: A review of cognitive and neuroimaging findings in pathological gambling. Neuroscience and Biobehavioral Reviews, 34(1), 87–107. Weikop, P., Yoshitake, T., & Kehr, J. (2007). Differential effects of adjunctive methylphenidate and citalopram on extracellular levels of serotonin, noradrenaline and dopamine in the rat brain. European Neuropsychopharmacology, 17(10), 658–671. Zeeb, F. D., Robbins, T. W., & Winstanley, C. A. (2009). Serotonergic and dopaminergic modulation of gambling behavior as assessed using a novel rat gambling task. Neuropsychopharmacology, 34(10), 2329–2343. Zimmerman, M., Breen, R. B., & Posternak, M. A. (2002). An open-label study of citalopram in the treatment of pathological gambling. Journal of Clinical Psychiatry, 63(1), 44–48.
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