Serotonin Reuptake Inhibitor Treatment of Obsessive-Compulsive Symptoms in Clozapine-Medicated Schizophrenia

Mr L, a 25-year-old man, was diagnosed with schizophrenia 4 years ago. After failing trials with different antipsychotic drugs, prescribed in adequate doses for adequate durations, he was started on clozapine treatment.

Mr L has now crossed a year of treatment with clozapine (400 mg/d), and the response to the drug has been good. However, there is a fresh clinical problem: he has repeated thoughts about making mistakes in his everyday routine, with resultant repetitive counting and checking behaviors. Mr L realizes that these thoughts and behaviors are not justifiable but does not make much effort to resist them. The symptoms are present for over an hour a day, on average, and they interfere with his activities of daily living. He cannot say for certain when the symptoms began, but it is clear that they attained their present degree of severity only during the past few months.

His psychiatrist is aware of the literature that associates obsessive-compulsive symptoms (OCS) in schizophrenia with atypical antipsychotic use. However, his psychiatrist is hesitant to switch him from clozapine to a typical antipsychotic, or even to reduce the dose of clozapine, because of the risk of loss of treatment efficacy. Rather, in consultation with Mr L, he prefers to continue clozapine treatment without change, along with a therapeutic trial of fluoxetine, fluvoxamine, or clomipramine, the efficacy of which is well established in obsessive-compulsive disorder (OCD). What might be the risks associated with the addition of any of these drugs to a prescription of clozapine?

Clinical Notes on the Comorbidity of Obsessive-Compulsive Disorder and Schizophrenia

Although psychosis and OCS were first described to coexist in the same patient as early as in the 19th century,1 OCS were considered rare and protective in schizophrenia.2 DSM-III did not allow the diagnosis of OCD if schizophrenia was present because schizophrenia was higher in the hierarchy of psychiatric illness.3 However, after Fenton and McGlashan4 showed a 13% prevalence of OCS in schizophrenia, with poorer outcome in schizo-obsessive patients, there was an explosion of research on the subject.

A recent meta-analysis of the prevalence of anxiety disorders in schizophrenia found that 12.1% of patients with schizophrenia also had OCD.5 OCD has been described in both adolescent6 and elderly7 patients with schizophrenia. Comparably high prevalences of OCS in schizophrenia have been described in ultra-high-risk patients; during the schizophrenia prodrome; in first-episode, drug-naive, or minimally drug-exposed patients; and in adults with schizophrenia, including those whose psychosis has responded to treatment.3,8,9

According to DSM-IV,10 patients must meet diagnostic thresholds for both disorders for Axis I comorbidity to be recorded. More specific criteria have, however, been proposed: obsessions/compulsions must be present for at least an hour a day, the symptoms should not be due to the content of current delusions or hallucinations, the symptoms should cause distress or interference independent of psychosis, the symptoms should not be due to drugs or organic factors, and the symptoms should have been present for a substantial period during the course of the illness.3

Evidence suggests that in most schizo-obsessive patients OCS precede psychotic symptoms or are coincidental in onset11,12; they are associated with fair to good insight, they exhibit symptom dimensions similar to those in pure OCD, and they are commonly moderate to severe.3,13 A meta-analysis found greater positive, negative, and global symptom burden in schizophrenia patients with OCS.14 Psychosocial impairment is greater in affected patients.15

Notes on the Management of Obsessive-Compulsive Symptoms in Schizophrenia

In general, atypical antipsychotic drugs alone do not suffice to contain OCS in schizophrenia.3 In fact, the inhibitory effect of these drugs on serotonin receptors has been suggested to be responsible for OCS in those patients whose OCS symptoms develop after the onset of psychosis.16,17 Favoring a causal effect with the atypicals is the observation that OCS have not been reported to arise after the initiation of neuroleptic drugs17 (but this may have been due to a lack of awareness or lack of reporting). Kwon et al18 even reported a possible linking of atypical antipsychotic-associated OCD to the glutamate transporter gene SKC1A1.

Against an etiologic role for the atypicals, however, is the consideration that, in about half of schizo-obsessive patients, OCS precede the onset of psychotic symptoms.12 The implication is that if there is a biological overlap between OCS and schizophrenia, OCS may well occur after the onset of psychosis in some patients. Therefore, in these patients, the introduction of atypical antipsychotic therapy may be coincidental rather than causal.

Given the seriousness of schizophrenia, it is unlikely that discontinuation of atypical antipsychotic medication or reduction in antipsychotic dose would be clinically feasible in most schizo-obsessive patients whose psychotic symptoms have responded to medication. Given the absence of evidence in support, there does not appear to be a case for the substitution of atypical antipsychotic drugs with neuroleptic agents. Although aripiprazole monotherapy or augmentation therapy has been suggested for OCS in schizophrenia,19,20 the data are presently too weak to support recommendations. Adherence to cognitive-behavior therapy for OCS could prove challenging to most schizophrenia patients. Treatment therefore falls back on augmentation of antipsychotic medication with established anti-OCD agents, that is, the serotonin reuptake inhibitors (SRIs).3

Interactions Between Clozapine and Fluvoxamine or Fluoxetine

Mr L (whose case was described at the start of this article) is receiving clozapine, and add-on therapy with fluvoxamine, fluoxetine, or clomipramine is being considered. Is there a risk of drug interactions between clozapine and these SRIs?

Clozapine is mainly metabolized by the cytochrome P450 (CYP) enzyme CYP1A221-23; however, CYP2C19 and CYP3A4 also contribute to its metabolism, though to a smaller extent.21 Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C1924-26 and a weaker inhibitor of CYP3A4.27 Fluvoxamine could therefore increase the blood levels of clozapine several-fold,24,28 resulting in an increase in the adverse effects of clozapine. The most serious consequence would be an increased risk of seizures, a dose-dependent adverse effect of clozapine.29

Fluoxetine inhibits both CYP2C1930 and CYP3A4.27 Thus, fluoxetine is also likely to increase clozapine levels and hence the risk of dose-dependent adverse effects with clozapine, including the risk of seizures.31 However, the risk with fluoxetine will not be as high as that with fluvoxamine because fluoxetine does not inhibit CYP1A2 as does fluvoxamine.

The best way of anticipating the pharmacokinetic drug interaction between fluvoxamine or fluoxetine and clozapine would be to obtain blood levels of clozapine and its active metabolite, norclozapine, before and periodically after initiating add-on therapy with fluvoxamine or fluoxetine. The dose of clozapine can be adjusted on the basis of the blood level estimations.

CYP enzyme inhibition with a drug is immediate, and so blood levels of the substrate should immediately rise after the start of treatment with the enzyme inhibitor. It could be wise, therefore, to obtain blood levels and adjust clozapine doses every 2-3 days until the clozapine level stabilizes close to its initial value. If the enzyme inhibitor is discontinued, it would take about 5 half-lives for the inhibitor to be washed out of the body and up to a further week or two for sufficient quantities of new CYP enzyme to be synthesized, which is around when the dose of clozapine would need to be up-titrated back to its baseline value. Again, blood level estimations could guide the process.

Interactions Between Clozapine and Clomipramine

There is no evidence that clomipramine affects any of the CYP enzymes that metabolize clozapine; therefore, clomipramine probably has no effect on the pharmacokinetics of clozapine. However, clomipramine is associated with a dose-dependent increase in the risk of seizures,32 and it is therefore likely that the combination of clomipramine with clozapine would be pharmacodynamically additive or synergistic in increasing the seizure risk. Additionally, clomipramine is strongly anticholinergic and sedating32 and could increase the anticholinergic and sedating adverse effects of clozapine. Although clomipramine is associated with better anti-OCD outcomes than other selective serotonin reuptake inhibitor drugs,33-36 there is no simple solution to contain the adverse pharmacodynamic interactions between clomipramine and clozapine; the addition of an anticonvulsant such as valproate could reduce the risk of seizures but could introduce the risk of new adverse effects or new drug interactions.

Interactions Between Clozapine and Other Serotonin Reuptake Inhibitors

Although there is at least 1 report of paroxetine-related increase in blood clozapine levels,37 neither paroxetine nor sertraline affect the CYP enzymes that metabolize clozapine26; therefore, neither drug would be expected to pharmacokinetically interact with clozapine. Citalopram and escitalopram do not inhibit CYP enzymes to any appreciable extent.26 These drugs could therefore be safely administered along with clozapine. However, the evidence base for the use of these drugs in OCD is less strong than that for fluoxetine, fluvoxamine, and clomipramine.

Closing Questions

Does schizo-obsessive disorder merit independent nosologic status? How effective is SRI augmentation of antipsychotic medication in patients with comorbid schizophrenia and OCD? What are other possible interventions for such patients? The answers to these important questions should emerge in future research.

J Clin Psychiatry 2012;73(11):e1362-e1364 (doi:10.4088/JCP.12f08200)

© Copyright 2012 Physicians Postgraduate Press, Inc.

Each month in his online column, Dr Andrade considers theoretical and practical ideas in clinical psychopharmacology with a view to update the knowledge and skills of medical practitioners who treat patients with psychiatric conditions.

Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore, India (candrade@psychiatrist.com).

Financial disclosure and more about Dr Andrade.

REFERENCES

1. Bottas A, Cooke RG, Richter MA. Comorbidity and pathophysiology of obsessive-compulsive disorder in schizophrenia: is there evidence for a schizo-obsessive subtype of schizophrenia? J Psychiatry Neurosci. 2005;30(3):187-193. PubMed

2. Rosen I. The clinical significance of obsessions in schizophrenia. J Ment Sci. 1957;103(433):773-785. PubMed

3. Poyurovsky M, Zohar J, Glick I, et al. Obsessive-compulsive symptoms in schizophrenia: implications for future psychiatric classifications. Compr Psychiatry. 2012;53(5):480-483. PubMed doi:10.1016/j.comppsych.2011.08.009

4. Fenton WS, McGlashan TH. The prognostic significance of obsessive-compulsive symptoms in schizophrenia. Am J Psychiatry. 1986;143(4):437-441. PubMed

5. Achim AM, Maziade M, Raymond E, et al. How prevalent are anxiety disorders in schizophrenia? a meta-analysis and critical review on a significant association. Schizophr Bull. 2011;37(4):811-821. PubMed doi:10.1093/schbul/sbp148

6. Nechmad A, Ratzoni G, Poyurovsky M, et al. Obsessive-compulsive disorder in adolescent schizophrenia patients. Am J Psychiatry. 2003;160(5):1002-1004. PubMed doi:10.1176/appi.ajp.160.5.1002

7. Poyurovsky M, Bergman J, Weizman R. Obsessive-compulsive disorder in elderly schizophrenia patients. J Psychiatr Res. 2006;40(3):189-191. PubMed doi:10.1016/j.jpsychires.2005.03.009

8. Poyurovsky M, Fuchs C, Weizman A. Obsessive-compulsive disorder in patients with first-episode schizophrenia. Am J Psychiatry. 1999;156(12):1998-2000. PubMed

9. Niendam TA, Berzak J, Cannon TD, et al. Obsessive compulsive symptoms in the psychosis prodrome: correlates of clinical and functional outcome. Schizophr Res. 2009;108(1-3):170-175. PubMed doi:10.1016/j.schres.2008.11.023

10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.

11. Devulapalli KK, Welge JA, Nasrallah HA. Temporal sequence of clinical manifestation in schizophrenia with co-morbid OCD: review and meta-analysis. Psychiatry Res. 2008;161(1):105-108. PubMed doi:10.1016/j.psychres.2008.01.013

12. Faragian S, Fuchs C, Pashinian A, et al. Age-of-onset of schizophrenic and obsessive-compulsive symptoms in patients with schizo-obsessive disorder. Psychiatry Res. 2012;197(1-2):19-22. PubMed doi:10.1016/j.psychres.2012.02.024

13. Faragian S, Pashinian A, Fuchs C, et al. Obsessive-compulsive symptom dimensions in schizophrenia patients with comorbid obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(6):1009-1012. PubMed doi:10.1016/j.pnpbp.2009.05.008

14. Cunill R, Castells X, Simeon D. Relationships between obsessive-compulsive symptomatology and severity of psychosis in schizophrenia: a systematic review and meta-analysis. J Clin Psychiatry. 2009;70(1):70-82. PubMed doi:10.4088/JCP.07r03618

15. Lysaker PH, Whitney KA. Obsessive-compulsive symptoms in schizophrenia: prevalence, correlates and treatment. Expert Rev Neurother. 2009;9(1):99-107. PubMed doi:10.1586/14737175.9.1.99

16. Lykouras L, Alevizos B, Michalopoulou P, et al. Obsessive-compulsive symptoms induced by atypical antipsychotics: a review of the reported cases. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(3):333-346. PubMed doi:10.1016/S0278-5846(03)00039-3

17. Schirmbeck F, Zink M. Clozapine-induced obsessive-compulsive symptoms in schizophrenia: a critical review. Curr Neuropharmacol. 2012;10(1):88-95. PubMed doi:10.2174/157015912799362724

18. Kwon JS, Joo YH, Nam HJ, et al. Association of the glutamate transporter gene SLC1A1 with atypical antipsychotics-induced obsessive-compulsive symptoms. Arch Gen Psychiatry. 2009;66(11):1233-1241. PubMed doi:10.1001/archgenpsychiatry.2009.155

19. Glick ID, Poyurovsky M, Ivanova O, et al. Aripiprazole in schizophrenia patients with comorbid obsessive-compulsive symptoms: an open-label study of 15 patients. J Clin Psychiatry. 2008;69(12):1856-1859. PubMed doi:10.4088/JCP.v69n1202

20. Schönfelder S, Schirmbeck F, Waltereit R, et al. Aripiprazole improves olanzapine-associated obsessive compulsive symptoms in schizophrenia. Clin Neuropharmacol. 2011;34(6):256-257. PubMed doi:10.1097/WNF.0b013e31823429bd

21. Jaquenoud Sirot E, Knezevic B, Morena GP, et al. ABCB1 and cytochrome P450 polymorphisms: clinical pharmacogenetics of clozapine. J Clin Psychopharmacol. 2009;29(4):319-326. PubMed doi:10.1097/JCP.0b013e3181acc372

22. Andrade C. Schizophrenia and smoking. J Clin Psychiatry. 2012;73(6):e725-e727. PubMed doi:10.4088/JCP.12f07732

23. Ferrari M, Bolla E, Bortolaso P, et al. Association between CYP1A2 polymorphisms and clozapine-induced adverse reactions in patients with schizophrenia [published online ahead of print August 16, 2012]. Psychiatry Res. PubMed doi:10.1016/j.psychres.2012.07.002

24. Olesen OV, Linnet K. Fluvoxamine-clozapine drug interaction: inhibition in vitro of five cytochrome P450 isoforms involved in clozapine metabolism. J Clin Psychopharmacol. 2000;20(1):35-42. PubMed doi:10.1097/00004714-200002000-00007

25. Christensen M, Tybring G, Mihara K, et al. Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Clin Pharmacol Ther. 2002;71(3):141-152. PubMed doi:10.1067/mcp.2002.121788

26. Spina E, Santoro V, D’ Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008;30(7):1206-1227. PubMed doi:10.1016/S0149-2918(08)80047-1

27. Zhou SF, Xue CC, Yu XQ, et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007;29(6):687-710. PubMed doi:10.1097/FTD.0b013e31815c16f5

28. Heeringa M, Beurskens R, Schouten W, et al. Elevated plasma levels of clozapine after concomitant use of fluvoxamine. Pharm World Sci. 1999;21(5):243-244. PubMed doi:10.1023/A:1008748110692

29. Wong J, Delva N. Clozapine-induced seizures: recognition and treatment. Can J Psychiatry. 2007;52(7):457-463. PubMed

30. Harvey AT, Preskorn SH. Fluoxetine pharmacokinetics and effect on CYP2C19 in young and elderly volunteers. J Clin Psychopharmacol. 2001;21(2):161-166. PubMed doi:10.1097/00004714-200104000-00007

31. Ferslew KE, Hagardorn AN, Harlan GC, et al. A fatal drug interaction between clozapine and fluoxetine. J Forensic Sci. 1998;43(5):1082-1085. PubMed

32. McTavish D, Benfield P. Clomipramine: an overview of its pharmacological properties and a review of its therapeutic use in obsessive compulsive disorder and panic disorder. Drugs. 1990;39(1):136-153. PubMed doi:10.2165/00003495-199039010-00010

33. Piccinelli M, Pini S, Bellantuono C, et al. Efficacy of drug treatment in obsessive-compulsive disorder: a meta-analytic review. Br J Psychiatry. 1995;166(4):424-443. PubMed doi:10.1192/bjp.166.4.424

34. Stein DJ, Spadaccini E, Hollander E. Meta-analysis of pharmacotherapy trials for obsessive-compulsive disorder. Int Clin Psychopharmacol. 1995;10(1):11-18. PubMed doi:10.1097/00004850-199503000-00002

35. Ackerman DL, Greenland S. Multivariate meta-analysis of controlled drug studies for obsessive-compulsive disorder. J Clin Psychopharmacol. 2002;22(3):309-317. PubMed doi:10.1097/00004714-200206000-00012

36. Geller DA, Biederman J, Stewart SE, et al. Which SSRI? a meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder. Am J Psychiatry. 2003;160(11):1919-1928. PubMed doi:10.1176/appi.ajp.160.11.1919

37. Joos AA, König F, Frank UG, et al. Dose-dependent pharmacokinetic interaction of clozapine and paroxetine in an extensive metabolizer. Pharmacopsychiatry. 1997;30(6):266-270. PubMed doi:10.1055/s-2007-979505