Quetiapine (OCS):
and obsessive-compulsive symptoms case report and review of atypical
antipsychotic-induced
OCS
Atul Khullar, MD; Pierre Chue, MB BCh; Phillip Tibbo, MD Khullar, Tibbo Edmonton, Alta.
University of Alberta, Edmonton, Alta; Chue
University of Alberta Hospital and Alberta Hospital,
The atypical antipsychotics have advanced the treatment of schizophrenia and have proved to be effective agents in treating other disorders with or without psychotic features. We review the literature concerning an increasingly reported and interesting adverse effect, atypical antipsychotic-induced obsessive-compulsive symptoms (OCS). The first known report of quetiapine exacerbating OCS in a 43-year-old man with obsessive-compulsive disorder (OCD), trichotillomania, delusional disorder and bipolar 11 disorder is presented. Mechanisms, including 5-HT,, and 5-HT2c antagonism, serotonergic regulation of dopamine systems and putative dopaminergic subtypes of OCS and OCD, are discussed. Given the paradoxical efficacy of the atypical antipsychotics in pure OCD, the neurobiology and comorbidity of OCD and schizophrenia, as well as the increasing use of atypical antipsychotics, a cautious and rational pharmacotherapeutic treatment approach is recommended. Les neuroleptiques atypiques ont fait progresser le traitement de la schizophrenie et se sont reveles effidans le traitement d'autres troubles comportant ou non des caracteristiques psychotiques. Nous passons en revue les documents publies sur un effet indesirable de plus en plus signale et interessant, soit les sympt6mes obsessionnels compulsifs (SOC) provoques par les neuroleptiques atypiques. Nous presentons le premier compte rendu connu de SOC exacerbes par la quetiapine chez un homme de 43 ans atteint de trouble obsessionnel compulsif (TOC), de trichotillomanie, de trouble delirant et de trouble bipolaire 11. On discute des mecanismes, y compris de I'antagonisme 5-HT2A et 5HT2C, de la regulation serotoninergique des systemes de la dopamine et des sous-types dopaminergiques hypothetiques du SOC et du TOC. Etant donne l'efficacite paradoxale des neuroleptiques atypiques dans les cas de TOC pur, la neurobiologie et la comorbidit6 du TOC et de la schizophrenie, ainsi que l'utilisation accrue des neuroleptiques atypiques, on recommande une d6marche prudente et rationnelle dans le traitement pharmacotherapeutique. caces
Correspondence to: Dr. Pierre Chue, Psychopharmacology Research Unit, 10-126 Clinical Sciences Bldg., 8440-112 St., Edmonton AB T6G 2B7; fax 780 407-3329;
[email protected] Medical subject headings: antipsychotic schizophrenia; serotonin J
agents;
clozapine; dopamine; haloperidol; obsessive-compulsive disorder;
receptors,
serotonin; risperidone;
Psychiatry Neurosci 2001;26(I):55-9.
Submitted Oct. 18, 1999 Revised Jun. 12, 2000 Accepted Jul. 27, 2000 2001 Canadian Medical Association
Vol. 26, ~noQxx no .1I, 20 2001 s1. 2,
of Psychiatry Journal chia, 100*4..O(f
0 & Neuroscience
4 Nootosexence
55
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The worsening or production de novo of obsessivecompulsive symptoms (OCS) with atypical antipsychotics has been documented in numerous case reports.' In terms of frequency, most cases involve the use of clozapine, followed by risperidone and olanzapine, which has been reported in 3 recent cases.2' Clothiapine, an antipsychotic related to clozapine, has also been reported to cause OCS.5 Larger trials have shown mixed results, with both negative,6 and more recently, positive correlations with clozapine,7 as well as a negative correlation with olanzapine.8 Most of the cases of atypical antipsychotic-induced OCS have involved patients with chronic schizophrenia; other primary diagnoses have included a psychotic element - psychosis not yet diagnosed,9 delusional disorder,'0 major depressive episodes with psychotic features,3'6 and obsessive-compulsive disorder (OCD).6"' We present a case report of a patient who had a clear increase in OCS over his baseline OCD on separate trials of low-dose quetiapine. The patient also had comorbid diagnoses of trichotillomania, bipolar II disorder and delusional disorder, persecutory type. To our knowledge, this is the first reported case of increased OCS with quetiapine administration and only the sixth report of atypical antipsychotics worsening OCS in a patient without a primary diagnosis of schizophrenia.
Case report Mr. A is a 43-year-old male who has suffered from OCD since he was 10 years of age and trichotillomania since he was 14. Since his mid-20s, he has also suffered from a bipolar II disorder and a comorbid delusional disorder, persecutory type. He believed that he gave off a peculiar odour, strangers stared at him and neighbours harassed him. All diagnoses were made using Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria.'2 Central to Mr. A's OCD were hoarding behaviours and elaborate organizational and cleaning rituals (e.g., washing his hands or arranging items numerous times until he reached a "magic number" of repetitions). His OCD had not responded to cognitive-behavioral strategies in conjunction with trials of selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), venlafaxine, bupropion, moclobemide or mirtazapine, either as monotherapy or in combination. The OCD followed a chronic waxing and waning pattern in which Mr. A would spend 4-8 h/day on his ritualistic behaviours. He consistently scored
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tLIAIII.
around 25 on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Overall, moclobemide was the besttolerated antidepressant, and in conjunction with diltiazem and triidothyronine, the bipolar disorder stabilized. Although loxapine (25 mg/day) had been effective in controlling the delusional disorder to a degree, attempts at further improvement with a 1-month trial of risperidone in 1998 and a subsequent 1-month trial of olanzapine, were both unsuccessful. No change in his OCD with these 2 agents was noted. After a 2-day washout period from the olanzapine, quetiapine (50 mg every night) was added to his regimen of moclobemide (150 mg twice daily), triiodothyronine (0.05 mg every morning), cetirizine (15 mg every night) and diltiazem (180 mg every morning). Three weeks later, Mr. A's community psychiatric nurse reported that he was unable to leave his house. His "magic number" had increased from a baseline level in the low 20s to well into the hundreds; Mr. A therefore spent up to 14 h/day on his rituals. Mr. A reported that this was the worst his OCD had ever been, and he scored 32 on the Y-BOCS (with good insight). His hoarding behaviours had also increased, but his mood, sleep and energy were stable. There were no contributory stressors identified. Mr. A felt his paranoia was diminished on the quetiapine, but he was unable to enjoy the improvement because of the increased time devoted to his rituals. Quetiapine was discontinued, and 2 weeks later he returned to his previous baseline level of OCD, scoring 26 on the Y-BOCS. The paranoia increased again, and loxapine (25 mg every night) was recommenced. The community nurse, who was in semiweekly contact with Mr. A, corroborated the timeline of events.
Discussion Of Mr. A's concomitant medications, diltiazem inhibits the cytochrome P450 isoenzyme CYP3A4, which metabolizes quetiapine.'3 The resulting possible increase in quetiapine levels, however, has never been demonstrated in vivo and would likely have been of questionable clinical significance because quetiapine's normal therapeutic dose range is between 200 mg and 750 mg.'3 The paucity of reports of quetiapine-induced OCS in the literature may stem from its recent introduction, but it is interesting to note that it possesses much lower 5-HT2A and 5-HT2c receptor binding affinities than clozapine, olanzapine or risperidone (Table 1).14
-antisychotc-induced OCS Atypica-l The serotonergic (5-HT) system is known to play a major role in OCD, and SSRIs are effective agents in the treatment of OCD. Both 5-HT,," and 5-HT2c16 receptor antagonism have been postulated to play a role in the generation of OCS in patients with a comorbid psychotic disorder. 5-HT2c receptors have been implicated because of the greater number of such receptors in the basal ganglia,17 an area that has been linked to UCD in many imaging studies.'8 The finding that long-
blocks 5-HT2c receptors led to the hypothesis that supersensitivity of the 5-HT2c receptor may lead to clozapine-induced OCS.16 A dose-response relationship has been suggested on the basis of case studies of children,'9 and most cases of clozapineinduced OCS have occurred after months of clozapine therapy. Quetapine's weak antagonism compared with the other atypical antipsychotics at the 5-HT2, and 5-HT2A receptor sites and its relative apparent lack of OCS production may be related. Given the complexity of the numerous 5-HT receptor systems, it is unlikely that 5-HT2 receptor antagonism alone accounts for antipsychotic-induced OCS, since, for example, more cases of olanzapine-induced OCS would be expected on the basis of its receptor profile. Furthermore, SSRIs are the treatment of choice in OCD, and their anti-OCS effects are thought to be related to an increase in serotonin, yet 40%/6-60% of OCD patients have only a partial or no response to SSRIs alone.20 Conventional antipsychotics such as haloperidol, pimozide term clozapine
use
and loxapine possess some 5-HT2A antagonism,'6 and there are no reports of increased OCS with these agents. Risperidone, with its strong 5-HT, binding,'42' has also had some success as a treatment adjunct for OCD,2 and it is theorized that this may be because of its greater antagonism at a number of serotonergic receptor sub-
types.2324 All of the atypical antipsychotics have been
Receptor, binding affinity (K), nmol/L
Drug Haloperidol Quetiapine Olanzapine Risperidone Clozapine
5-HT2
5-HT2c
D2
(human cloned receptors)
(pig choroid
(human cloned receptors)
200 96 2.5
0.52 9.6
plexus) > 5000 3820
2.2 700 31 5.6 190
7.1 63 13
Adapted from Schotte et al.I4 with permission.
: Cw0.iE ........... ,2004 ::VVoL26,no T.6L Ef no ..|1,2.001 ..E ,
used as treatment adjuncts in pure OCD without comorbid psychosis,' without any report of a consistent worsening of OCS. It would appear that the primary syndrome is a key determinant in whether atypicalinduced OCS occurs, suggesting that pure OCD and OCD comorbid with a psychotic disorder represent very different disorders in terms of neurobiology. Risperidone demonstrates greater binding affinity and antagonism for the dopamine D2 receptor site than most of the other atypical antipsychotics.'4'2' This has been postulated as a reason for its effect in OCD and OCS treatment.22 Given this and the efficacy in controlled trials of haloperidol, a conventional highpotency D2-blocking antipsychotic, as a treatment adjunct for OCD,5 it is possible that dopamine plays some role in the iatrogenic production of OCS in susceptible patients, as well as in OCD in general. Dopamine may play a more significant role in a subtype of OCS, since OCD spectrum disorders such as Tourette's syndrome, tic disorders and trichotillomania have also responded well to D2-blocking agents.2 When potent D2-blocking drugs such as haloperidol, pimozide and risperidone are added to patients with SSRI-refractory OCD, individuals with a personal or family history of tics improve more than patients without such a history.2526 A role for dopamine in obsessions and compulsions has been discussed extensively in the literature,2728 and the large number of treatment-resistant OCD cases may be further indicative of other primarily dopaminergic subtypes of OCD. Since Mr. A had delusional disorder, trichotillomania and OCD, it is possible that he may have had a pattern of comorbidity or a particular subtype of OCD that was more influenced by dopaminergic changes. However, given quetiapine's weak direct dopaminergic effect compared with other antipsychotics (Table 1), it is unlikely that this was the principal mechanism operating in this case. A recent positron-emission tomography (PET) study with primates has shown that citalopram, an SSRI, inhibits dopamine release in the midbrain and cortex. Altanserin, a 5-HT2 antagonist, disinhibits the dopamine system29 and ritanserin, a related 5-HT, and 5-HT2c antagonist, has also been shown in a controlled trial to improve negative symptoms of schizophrenia.This type of serotonergic disinhibition of dopamine is postulated to be a mechanism by which the atypical antipsychotics reduce the extrapyramidal side effects of dopamine blockade,3' as well as mediate their own antipsychotic effects.32 Perhaps it is this difference in
Journal of Psychiatry . Nturnseieace ,
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57
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the modulation of dopaminergic systems by serotonin that plays a key role in the generation of OCS and OCD with the atypical antipsychotics. Given the number of serotonin receptors and their subtypes, this is a simplistic model; newer technologies such as receptor cloning and PET scanning may offer further clarification of the mechanisms in the future. Obsessive-compulsive symptoms are known to occur in the natural history of schizophrenia33 and may possibly be a late feature of the disease.34 In almost all cases reported of atypical antipsychotic-induced OCS, there has been a comorbid psychotic disorder,7 as with Mr. A. A number of theories have been suggested to explain the relationship in this subtype of patients the overt psychosis may mask the OCS, the obsessions represent a residual form of psychosis, OCS and psychosis are 2 discrete phenomena, or the obsessions may be transient adverse effects. Given the low dose of quetiapine and Mr. A's complex pathology and history of treatment response, it could be argued that the OCS observed was a reflection of an atypical neurobiological substrate in this individual. The natural fluctuations in the course of OCD may have also caused Mr. A's increased symptoms, but the quantitative intensity of the change and temporal relation to quetiapine makes this unlikely. The phenomenon of atypical antipsychoticinduced OCS further suggests that the interplay of serotonin and dopamine is substantially different in pure OCD versus OCD and comorbid psychotic disorder. Given that the atypical antipsychotics are now being used frequently in the treatment of many nonpsychotic disorders,' this case and the burgeoning literature indicate that atypical antipsychotic-induced OCS are rare, but the potential side effects of treatment warrant further study, not only in the relationship between OCD and other disorders, but also in the early identification of OCS with current and future atypical antipsychotic treatments.
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CANADIAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY COLLEGE CANADIEN DE NEUROPSYCHOPHARMACOLOGIE
Jock Cleghom Prize This prize, which will consist of a suitably engraved plaque and a cheque for $500, will be awarded by the CCNP for the best poster presentation by a research trainee (graduate student or clinical resident) at the Annual Meeting of the CCNP. Candidates wishing to have their poster presentation considered should send a covering letter and a copy of their submitted abstract to Dr. Andrew J. Greenshaw at the address below. Those already applying for travel bursaries will automatically be considered for the Jock Cleghom Prize. All others can contact Dr. Greenshaw. The poster presentations will be judged at the Annual Meeting by a committee consisting of at least 3 members of the Awards Committee (or substitute judges to be chosen by the Council from the CCNP membership if Awards Committee members are unable to attend the Annual Meeting). Topics on either basic or clinical aspects of neuropsychopharmacology will be considered. The poster should represent research in which the graduate student or resident is the primary investigator, and (s)he should be the first author of the submitted abstract. The winner of the award will be announced in the first Newsletter following the Annual Meeting. Research trainees should send a copy of the abstract they are submitting to the 2001 meeting of the CCNP along with a covering letter stating that they wish to have their presentation considered for the prize to: Dr. Andrew Greenshaw Dept. of Psychiatry University of Alberta 1E1.01, 8440-112 St. Edmonton, AB T6G 2B7 or by fax 780 492-6841 or e-mail:
[email protected] The deadlinefor submissions is March 31, 2001.
59EA o f tl;0; Nemosciee no0 I 200100 joum P~cIitr Vo 26.
