Management of Clozapine-Induced Obsessive–Compulsive Symptoms in a Man with Schizophrenia

The co-morbidity of psychosis and obsessive–compulsive symptoms (OCS) has been described in several epidemiological investigations [1, 2]. However, the neurobiological background and guidelines for psychopharmacological treatment are matters of current clinical research [3]. Several antipsychotic substances have been found to be effective in cases with treatment-resistant disorder (OCD) [4]. In contrast, other atypical antipsychotic substances, such as clozapine, might have elicited the onset of OCS in a subgroup of schizophrenic patients [5], most likely in a dose-dependent manner [6]. Here, we report the long-term improvement of clozapine-induced OCS after dose reduction in combination with aripiprazole.

A 30-year-old male patient first developed symptoms of a paranoid schizophrenia according to ICD-10 at the age of 22 years. He presented formal thought disturbances and persecutory delusions with the consequence of bizarre alterations in his behaviour, further parathymia and psychomotor withdrawal. In consequence, he was treated with bromperidol, sulpiride and risperidone. Due to extrapyramidal side effects and treatment-resistance, he was switched to clozapine (350 mg day⁻¹), and a sufficient response in the psychotic positive syndrome was achieved. Persisting negative symptoms prevented reintegration into his former profession as an unskilled motorcar mechanic. Therefore, rehabilitation in a sheltered workshop was initiated.

According to to the medical history, obtained from the patient and his parents he had never presented any OCS earlier in his life. With a delay of 3 years, and under continuous treatment with clozapine, he progressively developed OCS, such as asking stereotypical questions, repeatedly lifting his shirt, and controlling his clothing and his body. He experienced distress and had the insight to perceive that these symptoms were of his own thinking and were senseless. During these months, his work speed and accuracy deteriorated, and he was finally unable to continue his vocational rehabilitation. During outpatient treatment, the mentioned symptoms were diagnosed as obsessive–compulsive behaviours and clomipramine (150 mg day⁻¹) was added to clozapine (500 mg day⁻¹) over a period of 4 months without any beneficial effects. On admission to our psychiatric day clinic, the patient showed high negative and global psychopathological scores on the Positive and Negative Syndrome Scale (PANSS: +16, −35, global psychopathology (GP) 54) in parallel to severe OCS (Yale-Brown Obsessive Compulsive Scale [Y-BOCS]: 24). The clozapine serum level (500 mg day⁻¹) was 0.26 mg L⁻¹ (0.21 mg L⁻¹ desmethyl clozapine) at a body weight of 112°kg (body mass index: 36.6). We assumed clozapine-induced OCS, considering it as a dose-dependent side effect [6] and planned a dose reduction of clozapine. As an additional antipsychotic protection, we first implemented aripiprazole (30 mg day⁻¹) and reduced clozapine to 250 mg day⁻¹ (serum level 0.14 mg L⁻¹, desmethyl clozapine: 0.12 mg L⁻¹) in steps of 50 mg week⁻¹. We maintained the serotonin re-uptake inhibition (SRI), assuming a basal anti-obsessive effect. We switched from clomipramine to paroxetine, achieving both a significantly improved profile of side effects and comparable anti-obsessive potency [7]. Under treatment with clozapine (250 mg day⁻¹), aripiprazole (30 mg day⁻¹) and paroxetine (60 mg day⁻¹), we observed significantly improved psychotic negative symptoms and global psychopathology (PANSS: +9, −23, GP 35) and slightly improved OCS (Y-BOCS: 19). We dismissed the patient into outpatient treatment and were satisfied to observe a continuous decrease in OCS over the following 6 months. The patient was able to restart his work in the sheltered workshop, maintaining his improved state in psychotic symptoms (PANSS: +11, −22, GP 31). The response of his OCS to treatment was validated by the patient's mother and his psychiatrist, and in parallel evaluated with a reduction in the Y-BOCS to 16 points.

The reported patient developed OCS several years after the first manifestation of psychosis as an unfavourable pharmacological side effect of clozapine [5]. We therefore planned to reduce the clozapine dose as a causative treatment. Since tapering down clozapine can elicit psychotic exacerbations, we accompanied the dose reduction in our case by a supportive antipsychotic protection with aripiprazole. In line with a body of combination strategies with clozapine [8], several investigations recently reported successful clozapine-augmentations with aripiprazole [9]. After a reduction in the daily dose and serum levels by about 50%, and during additional antipsychotic treatment with aripiprazole, the OCS significantly improved and a vocational rehabilitation became feasible.

Several pharmacological mechanisms related to the dopamine–serotonin balance ought to be discussed. We assume that the reduced dose of clozapine allowed the reported partial recovery of the OCS. In addition, it might be argued that aripiprazole may have contributed to the treatment response. This atypical antipsychotic substance has so far not been associated with the induction of OCS. In contrast, anti-obsessive potency has been suggested in a small group of OCD patients [10] and two patients with psychosis and OCS [9]. Furthermore, relief from side effects of clozapine and clomipramine and the natural course of the illness cannot be excluded as supporting factors. The addition of clomipramine to an unchanged clozapine-dose failed in this case of clozapine-induced OCS. We nevertheless continued the treatment with a serotonergic antidepressant in order to maintain an assumed basal anti-obsessive effect. Since clomipramine might elicit significant side effects, we switched to paroxetine, a more compatible substance [7]. On an individual basis, patients might respond differently to specific SRIs or selective serotonin re-uptake inhibitors. However, it has not been established by clinical studies that paroxetine surpasses the anti-obsessive potency of clomipramine.

In conclusion, patients suffering from clozapine-induced OCS deserve closer attention and might benefit from pharmacological interventions in the dopaminergic and serotonergic systems. It might be helpful to reduce the dose of this ‘pro-obsessive’ substance using combinations with mainly dopaminergic antipsychotics. Prospective trials might discriminate the impact of different pharmacological mechanisms and establish whether this strategy might alleviate the highly disabling effects of OCS during the course of psychotic disorders.