Development of Obsessive-Compulsive Symptoms during Clozapine Treatment in Schizophrenia and Its Positive Response to Clomipramine
Authors: M. Biondi, L. Fedele, T. Arcangeli, P. Pancheri
Journal: Psychotherapy and Psychosomatics (1999)

The arising of obsessive-compulsive (OC) symptoms during clozapine treatment of schizophrenia has been described by several clinicians although recently criticised [1, 2, 3, 4, 5, 6, 7, 8, 9]. Checking rituals and contamination obsessions with clozapine treatment were reported by Patil [10]in 1992, while Baker et al. [1]reported cleaning, washing, sexual and, again, contamination obsessions; Cassady and Thaker [2]added religious obsessions to the list. None of the patients had any prior history of OC symptoms. Cases have also been described where clozapine seems to have acted upon a pre-existing OC symptomatology [5]. Only in a few cases symptoms were also assessed by means of rating scales [5, 11]. The dosage of the drug at which the first symptoms would arise ranges from 125 to 800 mg/day [2, 11]. The latency of appearance of OC symptoms as related to the beginning of clozapine treatment ranges from 2 months to 1 year of treatment [1, 2, 3, 4, 5, 6]. Patients who favourably respond to clozapine develop obsessive thoughts and compulsions at the same time. These symptoms disappear after clozapine suspension and reappear with its reintroduction. Since clozapine withdrawal is usually followed by psychotic relapse, anti-obsessive drug trials were made as add-on. A marked reduction of compulsive rituals has been reported with a daily fluoxetine dosage of 20, 40, 60 mg [2, 5, 10]and 50 and 75 mg of sertraline [3, 6]. Fluvoxamine, added to clozapine, yielded also fair results [11]. To our knowledge clomipramine treatment of clozapine-induced OC symptoms has been reported in only 1 case at the dosage of 100 mg with improvement of symptomatology [3].Mr. X, aged 27, a male who met the DSM-IV (Diagnostic and Statistical Manual of Mental Disorder) criteria for schizophrenia, chronic undifferentiated type [12], is the sibling of another schizophrenic patient. He presented at the age of 18 with progressive social withdrawal, difficulty to concentrate, apathy, affective flattening, anhedonia. The patient, in addition, showed hostile and aggressive attitude towards his relatives. His positive psychotic symptoms included auditory hallucinations and persecution delusions. He had received multiple trials of conventional neuroleptics in depot and oral form with only partial improvement in his psychotic symptoms. He had no prior history of obsessive-compulsive disorder (OCD) or personality disorder. He was hospitalised in October 1995 to be treated with clozapine. A regimen of clozapine was started and titrated up to 150 mg/day with significant improvement of his psychotic symptoms. After about 5 weeks of treatment OC symptoms emerged. The patient performed repetitive movements during his walk, repeated checking doors and locks to make sure they were shut, washing rituals with repeated cleaning of his hands, avoidance of the joints between tiles, he manifested aggressive obsessions like fear that he might harm himself and others and also fear that he could be responsible for something terrible happening and contamination obsessions as concerns dirt and germs. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score was 30 (fig. 1). Our patient's symptomatology belongs to the obsessive spectrum according to the DSM-IV criteria for OCD. His thoughts, indeed, showed the features of iteration, of strangeness and intrusion. The patient was critical towards his own obsessive experience and tried to resist anxiety, although with poor results. Oral clomipramine 110 mg/day was progressively introduced while keeping the clozapine dosage unchanged. In 5 weeks a remarkable improvement of symptomatology was reached. After clomipramine the Y-BOCS score [13, 14]decreased from 30 to 10. The improvement persisted at 9 months of follow-up.Our case suggests that clozapine, although rarely, can induce the appearance of full-blown OC symptomatology resembling that of OCD. The mechanism is unknown. CMI treatment induced a full improvement. The arising of OC symptoms may be mediated by the block of the 5-HT2 receptors induced by clozapine. 5-HT2 antagonists lead to a functional disinhibition of the dopamine system [15]. The serotonergic system is tightly connected with the dopaminergic one. The dorsal raphe nucleus projects to the cortex and the striatal regions, and the median raphe nucleus to the limbic regions. The 5-HT2 receptors located on the somatodendritic surface of the dopamine neurones seem to mediate the transmission from dorsal raphe nucleus to the substantia nigra and inhibit the firing of the dopaminergic neurones. The hyperactivity of the dopaminergic system in the striatum might cause the arising of OC symptoms. The favourable response to SSRIs and TCAs, independently from the presence of psychotic symptoms, seems to confirm the involvement of the serotonergic system in the development of the clozapine-induced obsessive symptomatology [16]. The anti-obsessional effect of clomipramine seems to be mediated by its serotonin transporter [17, 18]. Further studies, however, are needed to a better understanding of the pathophysiology and psychopathology of OC symptoms under clozapine.