The antipsychotic medication clozapine can trigger severe obsessive-compulsive symptoms (OCS) in patients


A review published in the current issue of Psychotherapy and Psychosomatics analyzes the obsessions and compulsions associated with the use of clozapine, an antipsychotic drug.

It is not uncommon to find obsessive-compulsive symptoms (OCS) in patients treated with clozapine. These symptoms are attributed to anti-serotonergic effects of clozapine.

The objective of this study was to conduct a systematic review of reported cases of clozapine-associated OCS to better understand the nature and management of these symptoms.

MEDLINE, Embase, and PsycINFO databases were searched with no publication year or language restrictions. Fifty-seven studiesreporting cases of clozapine-associated OCS, either de novo or exacerbation of preexisting OCS (107 cases total; 75 de novo, 32 exacerbated OCS) were included.

Results showed that clozapine triggered moderate-severe OCS at varying doses (100–900 mg/day) and treatment durations (median six months, interquartile range two to 24 months).

Higher severity was significantly associated with preexisting OCS, poorer insight into OCS, and active psychosis at the time of OCS. Common strategies to treat clozapine-associated OCS included adding selective serotonin reuptake inhibitors, clomipramine, or aripiprazole, often accompanied by clozapine dose reduction.

The rate of response to antidepressants was 49% (29/59), where younger age, shorter duration of underlying illness, shorter clozapine treatment duration, better insight into OCS, and presence of taboo thoughts were significantly associated with antidepressant response.

Subsequent clozapine dose reduction was effective in many non-responders, where aripiprazole was simultaneously added in 50% (8/16).

These findings suggest that clozapine can trigger severe OCS. Adding aripiprazole with/without clozapine dose reduction may be a good alternative to antidepressants for managing clozapine-associated OCS. Clinicians should be more vigilant about these adverse effects and administer appropriate treatments.

Clozapine is more effective than other drugs in treatment-resistant schizophrenia [Kane et al. 1988]. Clozapine, however, is arguably the most toxic of all antipsychotics and requires particular precautions and monitoring. Why clozapine is more effective in refractory schizophrenia is unclear, however it has a diverse and unique pharmacology affecting multiple receptors which may in part explain its wide range of adverse effects.

These include agranulocytosis, constipation, tachycardia, hypersalivation and metabolic changes such as weight gain, diabetes and hyperlipidaemia. Even with this considerable burden of adverse events clozapine remains an essential treatment choice in schizophrenia and in those with an enduring, recurrent illness clozapine probably represents their best hope for recovery. One adverse event occasionally reported in the clinical literature with clozapine is the emergence or unmasking of obsessive compulsive disorder (OCD) or related symptoms.

The formal diagnosis of OCD is characterized by the presence of either obsessions, compulsions or both. An obsession is an unwanted thought, image or urge which repeatedly enters the mind and are usually unpleasant.

A compulsion is a repetitive behaviour or mental act the person is driven to perform. To meet the diagnosis of OCD these obsessive compulsive symptoms (OCS) must cause significant distress or interfere with daily functioning and not be better explained by another mental illness [National Institute for Health and Clinical Excellence, 2006].

The relationship between clozapine and worsening or developing OCS is complex. Both OCS and OCD are common in schizophrenia even in the absence of the use of antipsychotics. Between 10% and 64% of those with schizophrenia are reported to have OCS while 7.8% and 29.8% have comorbid OCD [Bottas et al. 2005; Nolfe et al. 2010].

In comparison the individual lifetime prevalence rate for OCD in the general population lies between 2% and 3% [National Institute for Health and Clinical Excellence, 2006]. Those with OCS and schizophrenia have more pronounced symptoms [Cunil et al. 2009], poorer social functioning, more motor symptoms [Nolfe et al. 2010] and a higher incidence of depression than seen in the individual illnesses [Cunil et al. 2009].

Some authors have suggested there may be enough evidence for a special category of schizophrenia coined as schizo-obsessive and that the two disorders are merely different expressions of the same disease [Bottas et al. 2005]. However, reports from the last three decades have revealed higher comorbidity rates of schizophrenia and OCD than recognized previously [Bottas et al. 2005; Nolfe et al. 2010] and this coincides with the increasing use of the second-generation antipsychotics which may be a contributing factor.

Many second-generation antipsychotics (olanzapine, risperidone and quetiapine) have rare reports of worsening or developing OCS [Lykouras et al. 2003]. Clozapine has the most reports with over 30 individual cases published. The first two cases appeared in 1992 a year after clozapine received a UK licence [Patil, 1992] and since then there has been a number of more extensive studies.

There have been five previous retrospective chart reviews published which investigated the relationship between clozapine and OCD. Ertugrul and colleagues from Hacettepe University in Turkey presented their investigation as a short communication in 2005. They reviewed 50 patients receiving clozapine for emerging OCS and found 10 (20%) had new onset OCS which was not related to severity of illness, dose or duration of clozapine [Ertugrul et al. 2005]. In a letter by De Hann and colleagues, of 41 patients, 4 (9.1%) developed de novo OCD while on clozapine [De Haan et al. 2004].

In a further report by De Haan and colleagues, 7 (20.6%) of 32 patients receiving clozapine reported an increase in obsessions after clozapine was started [De Haan et al. 1999]. Both studies by De Hann and colleagues included patients receiving other antipsychotics besides clozapine. Ghaemia and colleagues randomly selected 142 clozapine patients and reviewed medical records before and after clozapine treatment.

They searched for symptoms of OCS and a diagnosis of OCD. Of 142 patients, 41 had schizophrenia and 52 had schizoaffective disorder, the remainder had a wide variety of disorders. No one in the study developed de novo OCD after starting clozapine, but two (1.4%) experienced a moderate worsening of OCS symptoms [Ghaemia et al. 1995].

Baker and colleagues in 1992 investigated 49 chronic patients with schizophrenia and noted that 5 (10.2%) had developed either de novo or exacerbation of pre-existing OCS [Baker et al. 1992].

From the current limited literature it is not possible to infer the exact relationship between clozapine and OCS. The incidence of de novo OCS while on clozapine is reported to be between 3.5% and 28.4% [Mahendran et al. 2007; Lin et al. 2006] a range which includes in it the naturally occurring incidence of comorbid schizophrenia and OCS described above.

Some have been unable to establish any relationship [Mukhopadhaya et al. 2009; Ghaemia et al. 1995] and a small case series suggested clozapine may be beneficial in specific subgroups of patients with OCS and schizophrenia [Reznik et al. 2004] although this is disputed by others [McDougle et al. 1995].

The majority of the literature suggests a tentative increased risk of OCS associated with clozapine, which is possibly more likely at higher doses. Reasons for a possible link between clozapine and OCS include a dopaminergic / serotoninergic imbalance, supersensitivity at 5-HT2C receptors, specific neuromorphological abnormalities [Nolfe et al. 2010] or alterations in serotonin metabolism [Ma et al. 2007].

Journal of Psychotherapy and Psychosomatics


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