Unexpected resolution of clozapine-induced obsessive–compulsive symptoms with cariprazine augmentation: a case report

Abstract

Introduction

The management of obsessive–compulsive symptoms (OCS) in patients with schizophrenia is challenging, as many antipsychotics can induce OCS. Increasing evidence supports the use of partial agonists in managing these cases. This case report describes a patient with treatment-resistant schizophrenia and clozapine-induced obsessive–compulsive symptoms who underwent multiple antipsychotic regimens without significant improvement.

The patient’s main concerns and important clinical findings

The patient's symptoms progressed gradually, and their condition was managed entirely on an outpatient basis. Despite multiple adjustments to antipsychotic medications (risperidone, then haloperidol, then aripiprazole), the patient showed only a partial response to treatment, leading to their classification as treatment-resistant.

The primary diagnoses, interventions, and outcomes

Due to the lack of adequate response, the medical team decided to prescribe clozapine. However, at a dose of 350 mg, clozapine triggered compulsive checking and washing behaviors. Consequently, the team initiated treatment with a third-generation antipsychotic, cariprazine, at a dose of 6 mg, combined with sertraline at 100 mg while gradually reducing clozapine. Unexpectedly, there was a significant improvement in both psychotic symptoms and OCS.

Conclusion

The combination of cariprazine, as a D3 partial agonist, with clozapine may be an effective approach for managing challenging cases of treatment-resistant schizophrenia associated with de novo OCS.

Introduction

Patients with schizophrenia have a lifetime risk of approximately 25% for developing comorbid obsessive–compulsive symptoms (OCS), whereas the prevalence of obsessive–compulsive disorder (OCD) in the general population is significantly lower, ranging from 1 to 2% [25]. Despite this high comorbidity, few studies have investigated the temporal relationship between schizophrenia and OCS using a longitudinal approach. Research indicates that OCS precede psychotic symptoms in 40% of cases, emerge during the course of schizophrenia in another 40%, and occur simultaneously with psychotic symptoms in 20% of cases [23]. The most common obsessive themes in this comorbidity include contamination and aggression [22], accompanied by washing and counting compulsions (Singh et al., 2019).

A study conducted on the Moroccan population found that the obsessive and compulsive themes in schizophrenia patients with comorbid OCD were similar to those without OCD, with no significant differences in the severity of psychotic symptoms between the two groups [16]. Additionally, antipsychotic-induced OCS are frequently observed, particularly with antipsychotics that exhibit strong antiserotonergic activity [13]. Among atypical antipsychotics, clozapine, risperidone, olanzapine, and quetiapine have been associated with OCS, listed in descending order of incidence [12].

The prevalence of OCS among patients treated with these medications varies widely, with estimates ranging from 11 to 64% for OCS and from 0% to 37.5% for OCD [20], Seow et al., 2025). Some studies have also identified a positive correlation between OCS severity and the severity of depression, as well as with positive and negative symptoms of schizophrenia and general psychopathology [6, 20], (Seow et al. 2025).

A recent scoping review consolidated evidence on the prevalence of OCS in schizophrenia patients treated with clozapine. The review identified fourteen studies reporting OCS prevalence rates between 20 and 76%, with de novo OCS occurring in 4.8% to 46.4% of cases. Clozapine doses in these studies ranged from 196 to 525 mg/day, with treatment durations spanning 5 to 210 months. It is not uncommon to find obsessive–compulsive symptoms (OCS) in patients treated with clozapine. These symptoms are attributed to the anti-serotonergic effects of clozapine [12], [18]. The most frequently reported obsessions were related to aggression and checking, with symptom severity ranging from mild to moderate [16].

Therapeutic management becomes particularly challenging in cases of this comorbidity, as it often results in dual resistance to treatment for both psychotic and obsessive–compulsive symptoms [14, 15].

This report presents a case of a patient with treatment-resistant schizophrenia who developed obsessive–compulsive symptoms following clozapine administration and demonstrated unexpected improvement with a combination of cariprazine and sertraline. Our goal for this clinical case is to draw the attention of clinicians and researchers to the potential of D3 partial agonists such as cariprazine.

Patient information

Saad, a 25-year-old unemployed single male, discontinued his education after high school and lives with his parents. In early 2018, he was brought to a psychiatrist under parental coercion due to social withdrawal, unexplained cessation of studies, and noticeable behavioral changes. Saad had no family history of psychiatric illness and no personal history of substance use disorder, except for tobacco use, which he began a year prior. There was also no history of obsessive–compulsive disorder or obsessive personality. There was no evidence of neurodevelopmental disorders, intellectual disabilities, or significant cognitive impairments. Saad comes from a high socioeconomic background. His father is a construction entrepreneur, and his mother, who holds an engineering degree, chose to stay at home and occasionally help her husband with his work. Saad has a younger brother and a younger sister. Saad had a good childhood, both in terms of schooling and leisure activities. He had the opportunity to travel with his parents all over the world. There is no reported history of abuse at home or at school. Similarly, there were no marital conflicts between his parents, and the emotional atmosphere at home was positive.

None of his first-degree relatives have had known psychiatric disorders, except for a paternal cousin who is under psychiatric care—though no precise information is available about him.

Clinical findings

During the summer of 2017, after failing his high school examinations, Saad began isolating himself and rarely left the house. His interactions with his parents became infrequent and emotionally detached. He showed little interest in household activities, often locking himself in his room for up to three days at a time, surviving on only soda and biscuits. Following his academic failure, he was unable to pursue further studies, enroll in vocational training, or establish meaningful interpersonal relationships.

Timeline.

By early 2018, Saad began expressing persecutory delusions, particularly about his neighbors, passersby, and vehicles stopping near his home. Aside from these delusional thoughts, his interactions were strained and occasionally semi-mute, especially when his parents urged him to leave his room for basic tasks like cleaning.

During initial psychiatric consultations, Saad appeared suspicious and resistant to assistance, believing he would recover without intervention. His affect was markedly blunted, and he displayed indifference to his parents’ accounts of his behavior. He denied experiencing hallucinations and did not exhibit overt hallucinatory behavior.

The patient's physical examination, particularly the neurological exam, was completely normal. The MRI scan revealed no brain abnormalities, and no paroxysmal activity was recorded on the electroencephalogram. C-reactive protein, blood glucose, thyroid hormones, and vitamin B12 levels were normal. HIV serology, hepatitis B and C surface antigen tests were negative. Similarly, urine drug screening tests were negative.

Diagnostic assessment

Saad’s thought process was difficult to assess and often impenetrable. His reasoning was abstract, focusing on insignificant and trivial details. His personality was described as introverted, with no hobbies or social relationships except for a single childhood friend whom he still trusted.

He had no history of substance abuse other than smoking (one pack per day). There were no depressive, manic, or hypomanic episodes, ruling out affective disorders. However, he admitted to hearing internal voices once, warning him of an undefined but imminent threat.

Following multiple psychiatric evaluations, Saad met the DSM-5 criteria for schizophrenia; thus, following multiple psychiatric evaluations, Saad met the DSM-5 criteria for schizophrenia. (Persecutory Delusion, Negative symptoms eg: diminished emotional expression, familial and social isolation).

A retrospective PANSS assessment revealed high scores in negative symptoms and general psychopathology. MRI findings were unremarkable, EEG did not show any paroxysmal activity, and laboratory investigations did not rule out organic or neurological etiologies, the investigations included routine biological tests (blood glucose, urea, creatinine, transaminases) including thyroid hormones and vitamin B12, as well as HIV and hepatitis B and C serology.

Therapeutic intervention

Initially, he was prescribed risperidone (4 mg/day) for five months, with no notable improvement. Subsequently, he was switched to haloperidol (10 mg/day), trihexyphenidyl (5 mg/day), and chlorpromazine (up to 300 mg/day), which led to partial symptom improvement over six months. His pharmacological regimen was adjusted three more times—first to olanzapine (20 mg/day) and haloperidol for six months, then to aripiprazole (20 mg/day) for three months, Clozapine was introduced in the psychiatric unit and gradually titrated to 350 mg/day. Saad adhered well to these treatment regimens. Saad was never hospitalized, except once during the introduction of clozapine, and psychiatric follow-up was entirely done on outpatient mode.

Table 1 summarizes the evolution of the administered treatment and included the obtained results.

Table 1.

History of pharmacological treatments attempt with duration of treatment and summary of symptoms and treatment response

Treatment duration	Pharmacological treatment	Symptoms and treatment response
January 2018 5 months	Risperidone 4 mg/day	Social withdrawal, self-neglect, elaborate paranoid delusions, predominantly persecutory ideation. Anxiety. Suspiciousness Insufficient treatment response
July 2018 6 months	Risperidone 6 mg Haloperidol 10 mg/day Chlorpromazine 300 mg/day Trihexyphénidyle 5 mg/day	Less intense persecutory delusions, few hallucinations. Anxiety. Agitation Insufficient treatment response
January 2019 6 months	Olanzapine 20 mg/day Haloperidol 10 mg/day Trihexyphénidyle 5 mg/day	Less intense persecutory delusions, few hallucinations. Anxiety Insufficient treatment response
December 2020 3 months	Aripiprazole 20 mg/day Haloperidol 10 mg/day Trihexyphénidyle 5 mg/day	Persistent persecutory delusions, does not leave the house. Anxiety Insufficient treatment response
April 2021 6 months	Clozapine 25 mg to 350 mg/day Haloperidol 10 mg/day	Notable improvement after one month. Parents are satisfied with the treatment Sufficient treatment response After six months of clozapine treatment, the emergence of washing and checking rituals

Treatment modifications were necessitated by recurrent psychotic exacerbations. Even during periods of partial remission, he remained socially withdrawn, reluctant to leave home, and fearful of social interactions.

By late 2022, clozapine was introduced and gradually titrated to 350 mg/day, resulting in a significant reduction in psychotic symptoms, as evidenced by improved PANSS scores and parental reports. Within one month, the PANSS total score improved from 70 (mild illness) to 44 (normal range). However, six to seven months after initiating clozapine, severe obsessive–compulsive symptoms (OCS) emerged, characterized by excessive washing rituals that consumed significant amounts of time.

Follow-up and outcomes

Due to the disabling nature of these OCS, Saad was switched to cariprazine (6 mg/day) in combination with clozapine (300 mg/day) and sertraline (100 mg/day). After three weeks, he exhibited significant clinical improvement for the first time since the onset of his illness, with marked amelioration in both obsessive–compulsive and psychotic symptoms. Table 2. summarizes the evolution of the second round of the administered treatment and included the obtained results. Over the following year, he remained stable on this regimen, with continued improvements in CGI-I and PANSS scores. We stopped the prescribed treatments, then moved on to the second sequence. After that, we discontinued the medications from the second sequence and switched to the third sequence's medication. Finally, we stopped those as well to initiate clozapine in a hospital setting.

Table 2.

Pharmacological treatment timeline with summary of clinical state and psychometric scales results. (With PANSS: Positive and Negative Symptoms Scale [10],CGI: Clinical Global Impression [9],YBOCCS: Yale Brown Obsessive Compulsive Symptoms (Y-BOCS; [7]),and OCS: Obsessive Compulsive Symptoms (American Psychiatric Association [APA], 2013))

Date. Duration	Pharmacological treatments	Clinical State	Psychometric scales
December, 2022 6 months	Clozapine 350 mg/Day; Chlorpromazine	Mild delusion, very subtly expressed, it is beginning to emerge, and the patient does not report any persecutory thoughts. The onset of washing and checking rituals was observed in April 2023	PANSS: 70 to 44 CGI: highly improved 6 months later, induced OCS YBOCCS: 18
May, 2023	Clozapine 300 mg/day; Cariprazine 6 mg/Day; Sertraline 100 mg/Day	Improvement of OCS Remission of psychotic symptoms until July 2024	PANSS: 40 YBOCCS: 10

Discussion

Although clozapine effectively alleviated the patient's psychotic symptoms, the emergence of obsessive–compulsive symptoms (OCS) proved to be a highly debilitating side effect. De novo OCS has been well-documented in the literature and is associated with clozapine as well as other atypical antipsychotics, including risperidone, olanzapine, and quetiapine [13].

Some studies have identified a correlation between plasma levels of clozapine and its metabolite, norclozapine, and the severity of OCS. Obsessions tend to be less frequent, while compulsions—particularly those related to control—are more predominant [8]. Younger age and earlier onset of psychosis have been identified as risk factors for this comorbidity. However, neither the severity of the psychotic illness nor the dose of clozapine was found to be associated with the development of OCS or obsessive–compulsive disorder (OCD) in patients treated with clozapine [23].

A systematic review of clozapine-associated OCS, encompassing 57 studies and 107 cases (75 de novo and 32 exacerbated OCS), found that clozapine induced moderate to severe OCS across a wide range of doses (100–900 mg/day) and treatment durations (median 6 months, interquartile range 2–24 months). Higher OCS severity was significantly associated with preexisting OCS, poorer insight into OCS, and active psychosis at the time of OCS onset [12].

In a cohort study of 196 clozapine-treated patients with longitudinal assessments of OCS and psychosis, the prevalence of OCS was 37.9%, with checking compulsions being the most common. These checking compulsions were correlated with plasma clozapine levels. Notably, the study did not identify any glutamatergic or serotonergic genetic variants that moderated the relationship between psychosis and OCS [6].

Currently, there is no consensus on the management of OCS in patients with treatment-resistant schizophrenia (TRS) [12]. Common strategies include the addition of selective serotonin reuptake inhibitors (SSRIs), clomipramine, or aripiprazole, often combined with a reduction in the clozapine dose. Further dose reduction of clozapine has been effective in many non-responders, particularly when aripiprazole is added [12].

In this clinical case, the addition of an SSRI, specifically sertraline, was necessary. The choice of antidepressant should be guided by its safety profile, particularly regarding potential drug interactions with clozapine. Antidepressants that inhibit clozapine metabolism or increase the anticholinergic burden by inhibiting CYP enzymes (e.g., fluvoxamine, fluoxetine, paroxetine) should be avoided [26].

To our knowledge, only two similar cases have been reported in the literature. Renemane et al. described a patient with treatment-resistant schizophrenia and self-aggressive compulsive behavior who showed significant improvement in both positive and negative symptoms, as well as a substantial reduction in self-aggressive behavior, after treatment with cariprazine [21]. Another case, reported by De Berardis et al., involved a young patient who developed OCD after one year of complete remission from schizophrenia symptoms while on long-acting paliperidone injection. The OCD symptoms resolved rapidly after the addition of a low dose of cariprazine, with no adverse effects reported from the combination of cariprazine and long-acting paliperidone [2, 4].

The introduction of cariprazine, a third-generation antipsychotic, combined with sertraline, could lead to significant clinical improvement in both psychotic and obsessive–compulsive symptoms. This combination therapy might represent a promising approach (or a possible alternative) for patients with similar complications, particularly when traditional treatments fail. An integrative view from Vellucci et al. showed the pharmacological modulation of dopaminergic, serotonergic, and glutamatergic systems as current therapeutic strategies in schizophrenia with obsessive–compulsive symptoms (OCS). The recent discovery of midbrain dopamine neurons and dopamine D1- and D2-like receptors as orchestrating hubs in repetitive and psychotic behaviors was also highlighted [25].

Cariprazine, a third-generation antipsychotic, acts as a partial agonist at dopamine D2 and D3 receptors, with a preferential affinity for D3 receptors. In contrast, clozapine exerts broader antagonistic effects on serotonin receptors. Both medications share 5-HT2A receptor antagonism, which may contribute to their therapeutic effects. Similarly, there is interest in the combination of long-acting injectable antipsychotics and cariprazine [4].

Strengths and limitations

To our knowledge, this is only the second reported case of its kind, following the one by Renemane & Rancans in 2023. A limitation of this case is the lack of baseline PANSS and Y-BOCS scores prior to clozapine treatment, which restricts the ability to assess symptom progression before and after clozapine administration. Additionally, there remains the issue of attributing the improvement in OCD symptoms to cariprazine rather than to sertraline. Two strategies to better demonstrate the efficiency of cariprazine in de novo OCD which are: 1) discontinuing sertraline, and 2) gradually reducing clozapine doses.

Patient perspective

This case highlights the challenges of managing treatment-resistant schizophrenia complicated by clozapine-induced obsessive–compulsive symptoms (OCS). The introduction of cariprazine, a third-generation antipsychotic, combined with sertraline, led to significant clinical improvement in both psychotic and obsessive–compulsive symptoms. This combination therapy offers a promising approach for patients experiencing similar complications, particularly when traditional treatments fail. Further clinical research is needed to establish standardized guidelines for managing clozapine-induced OCS and to explore the efficacy of cariprazine in such cases.

Authors’ contributions

IR, SH, KA, OE, and JD contributed to the manuscript writing, data analysis, and subsequent revisions. IR wrote the first draft of the manuscript. SB contributed to the edition of the text. SB and IR contributed to the article and approved the submitted version.

Funding

Not applicable.

Data availability

The raw data for this article will be made available by the authors upon request, without any restrictions.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for the publication of this case.

Competing interests

Not applicable.