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Antipsychotic-Induced Obsessive-Compulsive Disorder

By: Cyril Collantes, PharmD Candidate c/o 2016

Obsessive-Compulsive Disorder (OCD) is characterized by two predominant psychiatric components: obsession and compulsion. Obsession refers to the uncontrolled and recurrent thoughts, impulses, or images that can provoke significant anxiety, whereas compulsions are repetitive behaviors or rituals in response to the obsessive thought(s). OCD is clinically significant if the obsessive-compulsive drive becomes time consuming (i.e. the patient is wasting about an hour a day with obsessive-compulsive thoughts). Unlike in schizophrenia, OCD patients have a relatively better insight into the nature of their obsessions and they are able to distinguish the obsessions / compulsions as unreasonable and excessive. However, the anxious feeling to succumb to the obsessive behavior may become unbearable until the patient replies with a compulsive action. One of the proposed mechanisms-of-disease includes the role of neurotransmitters (e.g. serotonin, dopamine). OCD is hypothesized to involve a dysfunction in the neuronal loop from the frontal cortex (which contains most of the dopamine-sensitive neurons) to the thalamus (involved in relaying sensory and motor signals) and back, thus inhibiting a sense of erroneous perception in a specific situation. In addition, serotonin agonists and dopamine antagonists have been hypothesized to exacerbate OCD symptom severity.1,2

OCD usually arises during childhood or teen years, and symptoms may be intermittent. Epidemiologic studies have estimated a prevalence of 2% in the general population, and some data suggests that OCD may be genetic.3,4 However, in a general psychiatric inpatient setting, up to 4% of patients exhibited obsessive-compulsive symptoms (OCS). Further evaluation implied that it might have been drug-induced, perhaps by antipsychotic medication.5

Antipsychotics are first-line agents for a variety of psychiatric disorders, including schizophrenia. As antipsychotic medications are primarily dopamine receptor antagonists, they may exacerbate OCD. Although typical (or first-generation) antipsychotics have higher dopamine receptor selectivity, antipsychotic-induced OCD is more commonly seen in patients taking atypical (second-generation) antipsychotics (e.g. clozapine, olanzapine, risperidone).2 In one study, clozapine-treated schizophrenia patients had an estimated de novo OCD incidence of 20 to 28% nationwide. Exacerbations of existing OCD symptoms occurred in 18% of the population.6 The prevalence of olanzapine-induced OCD ranged from 11 to 20%. Risperidone had a 3.4% de novo OCD prevalence; however, it accounted for about 33% of antipsychotic-induced OCD in a separate study.7 Studies of quetiapine, ziprasidone, and aripiprazole have yet to find a meaningful connection to OCD.2,8

Initially, OCS were difficult to differentiate from a patient’s positive schizophrenic symptoms (e.g. delusions). At times, as patients may exaggerate their need to comply with their compulsive response, it may be interpreted as responding to a delusional schizophrenic belief. As a result, OCD was neither screened for nor discovered in patients. Despite the similarities between schizophrenic delusions and obsessive-compulsive behaviors, they can be differentiated based on their degree of conviction, thought content, and perceived thought origin. Generally, patients with OCD have some insight into their obsessions and know that they have an internal issue. These patients are also more likely to admit that their thoughts are rather exaggerated (though realistic). However, delusional patients believe their impulses have an external origin, and these patients are highly convinced that their illness is not responsible for their bizarre thoughts.2 In DSM-IV, using a strict definition of OCD, there was an incidence of 3%, but when the criteria was relaxed to OCS, the incidence in patients with schizophrenia treated with atypical antipsychotics increased to about 21% (and 12.4% were considered antipsychotic-related).9,10

A study was conducted to compare antipsychotic-induced OCS in schizophrenia and OCD symptoms. Drug-induced OCS patients (n=51) were compared with OCD patients (n=130) for symptom frequencies for the 13 non-miscellaneous OCD symptoms of the Yale-Brown Obsessive-Compulsive Scale Symptom Checklist (Y-BOCS). The symptom categories accounted for 70.7% of the total variance in symptom structure between drug-induced and not drug-induced OCS. The most commonly seen factors were those of “forbidden thoughts” (e.g. aggression, sexual, religious, somatic obsessions; checking compulsions), which accounted for most of the variance (19.4%) and demonstrated statistical significance (in terms of intra-class correlation). Symptom prevalence of sexual thoughts, cleaning, and hoarding were most similar between the two groups. The need for symmetry, ordering, repeating, and counting was also rather common between the two groups. The similar symptomatic frequencies between antipsychotic-induced OCD and OCS suggested that the two diseases had a very similar, if not identical, underlying pathological mechanism.11

A possible mechanism of clozapine-induced OCD has been proposed, linking the second-generation antipsychotic’s activity on dopamine and serotonin receptors to the onset of OCD. MacCabe et al. suggested that the high serotonin (5-HT2A) and dopamine (D2) receptor affinities of second-generation antipsychotics alter the balance between dopaminergic activation and serotonergic inhibition.12 Normally, serotonergic neurons (mediated by 5-HT2A receptors) inhibit the firing of dopaminergic neurons. If this serotonin-induced inhibition of dopamine becomes overactive, then OCS may arise. Theoretically, dopamine-selective first-generation antipsychotics would have higher potential for drug-induced OCD, but the authors proposed that patients who take first-generation antipsychotics might have relatively higher dopamine receptor upregulation.12

As serotonin agonists and dopamine antagonists may exacerbate OCS, treatment would involve removing (or at least tapering down) the dopamine antagonist. This theory is supported by data suggesting a relationship between antipsychotic dose and OCD incidence. Case reports and series from 1990 to 2002 found a de novo incidence of OCS in 76.7% of patients who received clozapine and 69.2% in those who received risperidone. Clozapine-induced OCD has occurred with doses ranging from 125 to 800 mg/day, with slightly higher rates as the dose increased. Only eight patients in the study were taking olanzapine, but OCS were exacerbated at doses as low as 5 mg/day in a 42-year-old male patient with a prior history of OCD.13 In six cases involving risperidone, symptoms emerged shortly after initiation of 3 mg/day or higher dosing, but the issues faded as doses were lowered or discontinued.14 In all cases where the offending antipsychotic was removed or the dose was reduced, patients experienced a gradual remission of OCS. Other suggested solutions involved switching to an antipsychotic unassociated with OCS, but there was a lack of data to support the use of specific drugs (aside from using second-generation antipsychotics with lower incidences of OCS).2,13 A 40-year-old female who developed de novo symptoms of OCS was switched from risperidone to olanzapine, but she did not have any symptomatic improvement until sertraline 100 mg/day was added to her regimen.14

Alternative OCD management is to lower intracellular serotonin concentration with an antidepressant (an established first-line treatment for OCD). Commonly used antidepressants include selective serotonin reuptake inhibitors (SSRIs; e.g. fluoxetine, sertraline, paroxetine, fluvoxamine) and tricyclic antidepressants (e.g. clomipramine). Fluoxetine was the most studied drug with mostly positive outcomes, but there are a few cases where it  lacked effectiveness until the antipsychotic was discontinued.13,17 Paroxetine showed little promise; when it was used in paranoid schizophrenic patients with olanzapine-induced OCS, obsessive-compulsive behaviors persisted despite paroxetine treatment.18 Studies of various doses of sertraline showed preferable outcomes of OCS reduction in clozapine-, risperidone-, and olanzapine-induced OCD.2,13,16

As with several other psychiatric disorders, cognitive behavioral therapy (CBT) is recommended at every level of OCD therapy, either alone or as adjunct to pharmacotherapy. Benefits of CBT were first explored in a 50-year-old male who developed de novo OCD about one year after clozapine initiation. The behavioral therapy helped to attenuate the patient’s symptoms over four months and it continued to maintain symptom repression at an 11-month follow-up. In another trial, six patients were initiated on CBT as an adjunct to SSRIs and all of them improved on every measure of the Y-BOCS.15,16 Despite the small sample sizes of the studies evaluating CBT, the therapy is inexpensive with “virtually no downsides.”

Antipsychotic-induced OCD is a rising concern with atypical antipsychotics. OCS can negatively affect a patient’s recovery by compromising benefits, affecting compliance, and diminishing clinical prognosis overall. Although these symptoms can be reversed by lowering the dose or removing the antipsychotic, this is not always possible, as the patient’s underlying psychiatric problem will reemerge without treatment. In select cases, it may be appropriate to add SSRIs to alleviate OCS. Sertraline has the most success in drug-induced OCD, albeit small sample sizes were studied. In addition, CBT is appropriate at all stages to maximize benefit and repress obsessive-compulsive urges.



  1. Aouizerate B, Guehl D, Cuny E, et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog Neurobiol. 2004;72(3):195-221.
  2. Fonseka TM, Richter MA, Müller DJ. Second-generation antipsychotic-induced obsessive-compulsive symptoms in schizophrenia: a review of the experimental literature. Curr Psychiatry Rep. 2014;16(11):510.
  3. Pauls DL. The genetics of obsessive-compulsive disorder: a review. Dialogues Clin Neurosci. 2010;12(2):149-63.
  4. Swedo SE, Rapoport JL, Leonard H, Lenane M, Cheslow D. Obsessive-compulsive disorder in children and adolescents. Clinical phenomenology of 70 consecutive cases. Arch Gen Psychiatry. 1989;46(4):335-41.
  5. Rasmussen SA, Eisen JL. The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry. 1994;55 Suppl:5-10.
  6. Ertugrul A, Anil yagcioglu AE, Eni N, Yazici KM. Obsessive-compulsive symptoms in clozapine-treated schizophrenic patients. Psychiatry Clin Neurosci. 2005;59(2):219-22.
  7. Van Nimwegen L, de Haan L, van Beveren N, Laan W, van den Brink W, Linszen D. Obsessive-compulsive symptoms in a randomized, double-blind study with olanzapine or risperidone in young patients with early psychosis. J Clin Psychopharmacol. 2008;28(2):214–8.
  8. Lim M, Park DY, Kwon JS, Joo YH, Hong KS. Prevalence and clinical characteristics of obsessive-compulsive symptoms associated with atypical antipsychotics. J Clin Psychopharmacol. 2007;27(6):712-3.
  9. Poyurovsky M. Schizo-Obsessive Disorder. Cambridge: Cambridge University Press, 2013. Textbook; 12:213-22
  10. American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders: DSM-4 (4th ed.). Arlington, VA: American Psychiatric Publishing.
  11. Kim JH, Ryu S, Nam HJ, et al. Symptom structure of antipsychotic-induced obsessive compulsive symptoms in schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39(1):75-9.
  12. Maccabe JH, Travis M. Clozapine-induced obsessive-compulsive symptoms. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(7):1209.
  13. Lykouras L, Alevizos B, Michalopoulou P, Rabavilas A. Obsessive-compulsive symptoms induced by atypical antipsychotics. A review of the reported cases. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(3):333-46.
  14. Alevizos B, Lykouras L, Zervas IM, Christodoulou GN. Risperidone-induced obsessive-compulsive symptoms: a series of six cases. J Clin Psychopharmacol. 2002;22(5):461-7.
  15. Maccabe JH, Marks IM, Murray RM. Behavior therapy attenuates clozapine-induced obsessions and compulsions. J Clin Psychiatry. 2002;63(12):1179-80.
  16. Simpson HB, Gorfinkle KS, Liebowitz MR. Cognitive-behavioral therapy as an adjunct to serotonin reuptake inhibitors in obsessive-compulsive disorder: an open trial. J Clin Psychiatry. 1999;60(9):584-90.
  17. Eales and Layeni, 1994 M.J. Eales, A.O. Layeni. Exacerbation of obsessive–compulsive symptoms associated with clozapine (letter). Br. J. Psychiatry, 164 (1994), pp. 687–688
  18. Lykouras et al., 2000 O.L. Lykouras, I.M. Zervas, R. Gournellis, M. Malliori, A. Rabavilas. Olanzapine and obsessive–compulsive symptoms. Eur. Neuropsychopharmacol., 10 (2000), pp. 385–387
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