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250 Current Drug Safety, 2012, 7, 250-253 Quetiapine Induced Hypomania: A Case Report and a Review of the Literature R. Bou Khalil* and C. Baddoura

Psychiatric Hospital of the Cross, Jalledib, Lebanon Saint Joseph University, Beirut, Lebanon

Abstract: Objectives: The 5-HT2 antagonistic action of quetiapine may disinhibit the dopaminergic system enhancing dopaminergic activity in the forebrain and influencing the mood state. Our objective is to investigate the possible induction of manic symptoms by quetiapine through a case report and a review of the literature. Method: We report the case of a 54 year old woman suffering from bipolar depression who developed hypomania seven weeks after the initiation of 300 mg/d of quetiapine. A literature review concerning the induction of hypomania or mania by quetiapine have retrieved the presence of seven similar case reports or series. Results: Available literature points toward an early induction of hypomania or mania with low dosage of quetiapine treatment (between 100 and 400 mg/day never exceeding 600 mg/day). Hypomania or mania are possible short term complications that can be present few days to few weeks of treatment initiation. The discontinuation of the drug or the increase of its dose seems to reverse the hypomanic or manic symptoms. Patients described in the literature suffer mostly from schizophrenia. Conclusion: The atypical antipsychotic drug quetiapine, which have antidepressant properties at low doses via its indirect dopamine enhancing activity due its serotoninergic antagonism, appears to be involved in the induction of rare hypomanic or manic state in patients suffering from bipolar disorders and to have mood stabilizing properties at higher doses when its dopamine antagonist activity becomes more prominent. Its manic/hypomanic induction properties should not prevent its administration to patients suffering from bipolar disorder. Keywords: Quetiapine, mood disorder, induced mania, induced hypomania, adverse drug reaction.

1. INTRODUCTION mania by quetiapine in patients suffering from mental disorders was made via MedLine, PsychINFO and Embase. The atypical antipsychotic, quetiapine, is characterized by a Terms used in the search were: “quetiapine”, “induced”, greater affinity to 5-HT2 receptors, compared to D2 receptors “mania” or “hypomania”. Only publications in English or in [1]. It is a dibenzothiazepine derivative with considerable French were included. No restrictions regarding the histamine receptor and
2-adrenoreceptor blockade [2]. At low publication date were considered. The search has retrieved doses (up to 300mg/day) it shows a consistently higher degree the presence of seven case reports or series describing ten of occupancy of 5-HT2A receptors than D2 receptors; the different patients. Every case report or series reporting a degree of occupancy of both receptors is dose-dependent [3]. patient(s) suffering from a severe mental disorder who has The 5-HT2 antagonistic action of quetiapine may disinhibit the (ve) developed a manic/hypomanic episode that has been dopaminergic system and enhance dopaminergic activity at the considered to be induced by quetiapine, was included in the level of forebrain and influences the mood state [4]. There are a review. limited number of cases which have suggested that quetiapine may induce hypomanic or manic symptoms in psychotic disorders [5]. We will report the first case of hypomania 3. RESULTS induced by quetiapine in a patient suffering from a mood 3.1. Case Report disorder and then expose available data from the literature. A 54 year old patient was admitted to our hospital suffering from depressive symptoms with suicidal ideation. 2. METHODS She was diagnosed, twenty five years ago, as having bipolar We report the case of a 54 year old woman suffering disorder type I. She has been receiving lithium treatment for from bipolar depression who developed hypomania seven many years. As she developed lithium induced weeks after the initiation of 300 mg/d of quetiapine. In the hypothyroidism and became resistant to the antimanic effect aim of performing a comprehensive literature review, a of lithium, her mood stabilizer was changed to valproic acid literature search concerning the induction of hypomania or (1000 mg/day) during the last 5 years. She did not manifest any manic or hypomanic episode while taking valproic acid

as a mood stabilizer. She received thyroid hormone *Address correspondence to this author at the psychiatric hospital of the Cross, supplements and was euthyroid at admission. Additionally, Jalledib, Lebanon; P.O box: 60096; Tel: 009614710224; she was chronically receiving chlorpromazine at 300mg/d, E-mail: [email protected]

2212-3911/12 $58.00+.00 © 2012 Bentham Science Publishers Quetiapine Induced Hypomania Current Drug Safety, 2012, Vol. 7, No. 3 251 zolpidem at 10mg/d and bromazepam at 3mg/d. Two weeks week. The diagnosis of hypomania was established. The before her admission, she started developing a depressed management of this hypomanic episode relied on what was mood, along with anhedonia, insomnia, decreased appetite described in the literature regarding the management of and suicidal ideation. Because of her bipolar disorder, she quetiapine induced hypomania. Because six out of nine cases did not receive any antidepressant drug but she was switched (see Table 1) have been successfully treated with quetiapine from chlorpromazine to a rapidly escalated dose of 300 mg/d discontinuation the drug was stopped and replaced with the of quetiapine in order to improve her sleep and to control her same dose of chlorpromazine the patient used to take. One mood symptoms. All her biological parameters were within week after the discontinuation of quetiapine the patient the normal ranges including her thyroid function and her became normothymic. The episode was considered to be blood valproic acid dosage (65 mg/dl). She was discharged probably induced by quetiapine. one week after her admission after noticing an important improvement in her depressive symptoms especially concerning her suicidal ideation and sleep. Seven weeks 3.2. Comprehensive Literature Review after, while she was adherent to her psychotropic medication, Seven published case reports or case series between 2001 she consulted for suffering from pressured speech, insomnia, and 2010 were considered to be directly linked to the search inflated mood, and grandiosity that appeared during the last

Table 1. Summary of Case Reports in the Literature Describing Quetiapine Induced Hypomanic/Manic Symptoms

Personal or Highest Dose of Onset of Hypomanic/ Family Quetiapine Reached Authors and Age Sex of Axis I DSM-IV Manic Symptoms Management of History of Before Onset of Reference of Patients Patients Diagnosis After Quetiapine Hypomanic/Manic Symptoms Bipolar Hypomanic/Manic Treatment Disorder Symptoms

Reinitiation of 100 mg/d of chlorpromazine and Benazzi 2001 Not Schizoaffective 43 yr woman 300 mg/d 4 weeks discontinuation of quetiapine: [6] determined disorder disappearance of hypomanic symptoms after week. Reduction of quetiapine dose to Atmaca et al. Paranoid 33 yr woman No 400mg/d 2 weeks 100 mg/d: remission of 2002 [7] schizophrenia symptoms after five days. Discontinuation of quetiapine and Biancosino Schizophrenia administration of zuclopenthixol 23 yr woman No 400 mg/d 4 weeks et al. [8] form disorder and lorazepam. Resolution of symptoms in 10 days. Discontinuation of quetiapine. Pacchiarotti Paranoid Association to haloperidol and et al. 2003 21 yr man No 300 mg/d 2 weeks schizophrenia chlorpromazine, clozapine and [9] Valproic acid. quetiapine’s dose escalation to Lykouras 600 mg/d worsened the clinical Paranoid et al. 2003 26 yr man No 100 mg/d One day picture. quetiapine schizophrenia [10] discontinuation led to symptom’s resolution the next day. Discontinuation of quetiapine. Mishra et al. Initiation of lithium then valproic 40 yr man No Schizophrenia 500 mg/d Few months 2004 [11] acid treatment. Resolution of manic symptoms after 4 weeks. Efficient increase in quetiapine Mishra et al. Not Paranoid Not determined man No 400mg/d dose to 6oomg/d, then to 800 2004 [11] determined schizophrenia (probably six weeks) mg/d Monosymptomati Discontinuation of quetiapine. Mishra et al. Not c delusion v/s 1000 mg/d of valproic acid and 27 yr man 600 mg/d Not determined 2004 [11] determined schizophreniform clozapine were efficiently disorder introduced. Discontinuation of quetiapine and Erberk-Ozen Paranoid introduction of chlorpromazine et al. 2008 29 yr man No 100 mg/d 4 days schizophrenia and clonazepam resolved manic [12] symptoms after ten days. Discontinuation of quetiapine and Erberk-Ozen Not Paranoid introduction of chlorpromazine et al. 2008 44 yr man 100 mg/d 5 days determined schizophrenia and clonazepam resolved manic [12] symptoms 252 Current Drug Safety, 2012, Vol. 7, No. 3 Bou Khalil and Baddoura subject (see Table 1). Patients described in the literature are stabilizing properties, they won’t benefit from its effect aged between 21 and 44 years old. They are predominantly unless higher doses than usual were attained [13]. of male gender (7 out of 10). The majority of these patients However, we do not deny the presence of other factors were diagnosed as suffering from paranoid schizophrenia that could have played a role in the induction of the according to DSM-IV (6 out of 10). The majority of these hypomanic state in our patient. For example, the occurrence patients did not present a family history of mood disorders (7 of her hypomanic symptoms might be simply explained by out of 10). The majority of patients described were men (7 the natural course of her bipolar disorder but the fact that she out of 10). Additionnally, the majority of these cases has been free of any manic/hypomanic manifestations for the received low doses of quetiapine (between 100-400mg/day last five years renders more eligible the hypothesis of never exceeding 600 mg/day) and had the onset of their quetiapine induction of the current manic episode. manic/hypomanic symptoms a few days to a few weeks after (from as short as one day after quetiapine initiation to as Although the delay between the introduction of long as four to six weeks afterwards). In only one case quetiapine and the onset of hypomanic symptoms is report, the delay between the initiation of quetiapine and the relatively long (seven weeks as compared to a few days or onset of manic symptoms exceeded the typical delay of few weeks in other case reports in the literature), one can always days to few weeks in a way that renders the incrimination of incriminate quetiapine for many reasons: First, because quetiapine in the induction of manic symptoms questionable similar but slightly shorter delays (4-6 weeks) has already [11]. Finally, the management of patients suffering from been considered to be compatible with the incrimination of quetiapine induced hypomania was predominantly the quetiapine in manic symptoms induction [6, 11]. Second, discontinuation of quetiapine with or without an introduction because all other case reports concern patients suffering from of another mood stabilizing drug (7 out of 10) but in some schizophrenia who received quetiapine while they were cases an increase in quetiapine dose to more than 600 normothymic. Accordingly, the shift into mania might mg/day was also effective in resolving the manic/hypomanic happen in a shorter period than when it occurs to a bipolar episode. patient who received the drug when she was in a depressed mood state. 4. DISCUSSION There are a few reports describing hypomania or mania We report the first case in the literature describing a induction by quetiapine. The available literature points toward an early induction of hypomania or mania with low bipolar patient who developed hypomania seven weeks after dosage of quetiapine treatment (probably not higher than 300 she received 300 mg/d of quetiapine. The temporal mg/d). Hypomania or mania are possible short term relationship between quetiapine initiation and the complications of quetiapine administration that can be development of a hypomanic state as well as the reversibility present from as soon as few days to few weeks after the of this state with the drug discontinuation are suggestive of the possible incrimination of quetiapine in the induction of treatment initiation. The discontinuation of the drug seems to reverse the hypomanic or manic symptoms. Patients the hypomanic episode. The mechanism explaining this side described in the literature suffer mostly from schizophrenia. effect of the drug could be its dose-dependent higher degree Male gender appears to be more frequently represented in the of occupancy of 5-HT2A receptors than D2 receptors. Its 5- cases reported in the literature or it could be a predisposing HT2A antagonism may disinhibit the dopaminergic system factor for the occurrence of quetiapine-induced enhancing dopaminergic activity at the level of forebrain and elevating the mood level. On the other hand, quetiapine has mania/hypomania. This finding needs to be further evaluated. Finally, family history of mood disorder is not a relatively low D2 antagonism which may reflect its capacity predictive factor for hypomania or mania induction since this to bind loosely to the D2 receptor and to dissociate fast from parameter was negative in most of the cases described. it, allowing attenuated physiological dopamine transmission to continue, despite the occupancy of D2 receptors. Despite that worsening of manic symptoms has already Quetiapine is also a partial agonist of the 5HT-1A receptors. been described in a patient suffering from bipolar disorder Accordingly, the enhancement of frontal dopamine release in receiving quetiapine, no case report exists concerning the the case of quetiapine could be attributed– at least partly–to induction or a switch of mood in patients suffering from the 5HT-1A receptor activation, which is produced by bipolar disorder maybe because manic or hypomanic simultaneous blockade of 5HT-2A/D2 receptors and the episodes in patients suffering from mood disorders are rarely 5HT-1A agonist property of quetiapine itself [12]. Another attributed to drugs supposed to have mood stabilizing effect possible explanation for the manic/hypomanic induction such as quetiapine [14]. In many randomized placebo- potency of quetiapine exists. Patients suffering from controlled studies, it has been shown that patients suffering quetiapine induced mania/hypomania might be slow from mood disorders such as bipolar I and II disorders metabolisers of CYP450. The metabolising activity of treated with quetiapine for a bipolar depressive episode may CYP450 enzyme varies between individuals. Poor rarely manifest a manic/hypomanic switch in a frequency metabolisers of CYP450 have slight or no activity in any that is comparable to that of the groups of patients who sub-group of this enzyme. Since quetiapine is extensively received placebo (according to one study: 3.2% in the metabolised by the CYP450-3A4 isoenzyme, the manic quetiapine group vs 3.9% in the placebo group [15]) [15-17]. symptoms related to quetiapine treatment in those patients In a recent literature review of all case reports concerning could be explained by the fact that these patients may have atypical antipsychotic drugs induced mania/hypomania, 5 poor metaboliser phenotypes for CYP450-3A4. Accordingly, out of 28 cases published between 2004 and 2010 were when they receive the antipsychotic drug having mood found to be induced by quetiapine [18]. Authors of this literature review found that the induction of Quetiapine Induced Hypomania Current Drug Safety, 2012, Vol. 7, No. 3 253 mania/hypomania by atypical antipsychotic drugs is a [3] Gefvert O, Lundberg T, Wieselgren IM, et al. D (2) and 5HT(2A) marginal phenomena, especially when one no well-designed receptor occupancy of different doses of quetiapine in schizophrenia: a PET study. Eur Neuropsychopharmacol 2001; 11: clinical trial confirms the superiority of any atypical 105-10. antipsychotic drug tested (including quetiapine) in terms of [4] Lykouras L, Oulis P, Hatzimanolis J. Manic symptoms associated induction of a manic/hypomanic episode over placebo [18]. with quetiapine treatment. Eur Neuropsychopharmacol 2003; 13: 13513-6. [5] Michalopoulou PG, Lykouras L. Manic/hypomanic symptoms 5. CONCLUSION induced by atypical antipsychotics: a review of the reported cases. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 549-64. In conclusion, case reports regarding quetiapine-induced [6] Benazzi F. Quetiapine-associated hypomania in a woman with manic/hypomanic symptoms concern patients suffering from schizoaffective disorder. Can J Psychiatry 2001; 46: 182-3. schizophrenia. The current case report shows that patients [7] Atmaca M, Kuloglu M, Buyukbayram A, Tezcan E. Quetiapine- suffering from bipolar disorder could also present this drug associated and dose-related hypomania in a woman with schizophrenia. Eur Psychiatry 2002; 17: 292-3. adverse event. The comprehensive literature review [8] Biancosino B, Marmai L, Facchi A, Rossi E, Grassi L. Quetiapine concerning cases of patients with mental disorders may induce mania: a case report. Can J Psychiatry 2003; 48: 349- presenting quetiapine-induced mania/hypomania is in 50. concordance with the available data in other literature [9] Pacchiarotti I, Manfredi G, Kotzalidis GD, Ruberto A, Tatarelli R, reviews [12, 18]. The atypical antipsychotic drug quetiapine, Girardi P. Quetiapine-induced mania. Aust N Z J Psychiatry 2003; 37: 626. which have antidepressant properties at low doses via its [10] Mishra A, Moore PB, Hobbs R. Does quetiapine have mood indirect dopamine enhancing activity due its serotoninergic altering properties? J Psychopharmacol 2004; 18: 281-4. antagonism, appears to be involved in the induction of rare [11] Erberk-Ozen N. Manic symptoms probably associated with short- hypomanic or manic state in patients suffering from bipolar term low-dose quetiapine use. Adv Ther 2008; 25: 53-8. [12] Michalopoulou PG, Lykouras L. Manic/hypomanic symptoms disorders and to have mood stabilizing properties at higher induced by atypical antipsychotics: a review of the reported cases. doses when its dopamine antagonist activity becomes more Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 549-64. prominent. Its manic/hypomanic induction properties should [13] Strakowski SM, Keck PE Jr, Wong YW, Thyrum PT, Yeh C. The not prevent its administration to patients suffering from effect of multiple doses of cimetidine on the steady-state bipolar disorder. pharmacokinetics of quetiapine in men with selected psychotic disorders. J Clin Psychopharmacol 2002; 22: 201-5. [14] Cordoba S, de Asis J, Kotbi N, Mahgoub N. Worsening mania CONFLICT OF INTEREST associated with slow increase of quetiapine dose. J Neuropsychiatry Clin Neurosci 2011; 23:E5-6. The authors confirm that this article content has no [15] Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, conflict of interest. double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005; 162: 1351-60. [16] Vieta E, Calabrese JR, Goikolea JM, Raines S, Macfadden W; ACKNOWLEDGEMENTS BOLDER Study Group. Quetiapine monotherapy in the treatment of patients with bipolar I or II depression and a rapid-cycling None declared. disease course: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2007; 9: 413-25. [17] McElroy SL, Weisler RH, Chang W, et al. A double-blind, REFERENCES placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J [1] Saller CF, Salama AI. Seroquel: biochemical profile of a potential Clin Psychiatry 2010; 71: 163-74. atypical antipsychotic. Psychopharmacology (Berl) 1993; 112: 285- [18] Benyamina A, Samalin L. Atypical antipsychotic-induced 292. mania/hypomania: a review of recent case reports and clinical [2] Arnt J, Skarsfeldt T. Do novel antipsychotics have similar studies. Int J Psychiatry Clin Pract 2012; 16: 2-7. pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 1998; 18: 63-101.

Received: May 23, 2012 Revised: July 19, 2012 Accepted: August 1, 2012