Asian Journal of Psychiatry 15 (2015) 56–61
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Relationship of obsessive compulsive symptoms/disorder with clozapine: A retrospective study from a multispeciality tertiary care centre Sandeep Grover *, Nandita Hazari, Subho Chakrabarti, Ajit Avasthi Department of Psychiatry, Post-Graduate Institute of Medical Education and Research, Chandigarh 160012, India
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 November 2014 Received in revised form 26 April 2015 Accepted 3 May 2015
Objective: To study the prevalence, phenomenology and course of OCS/OCD in patients receiving clozapine. Methodology: Case records of 220 patients who received clozapine for at least 3 months were reviewed. Results: One fifth (N = 42; 19.1%) of patients had OCS/OCD, of which majority (13.2%) had onset of OCS/ OCD prior to starting of clozapine and remaining 5.9% developed OCS/OCD after starting of clozapine. About one fourth of the patients with pre-existing OCS/OCD had worsening with clozapine while the remaining maintained at the same level (55.17%) or improved (20.7%). Majority of the patients who developed de novo OCS/OCD on clozapine were females and OCS/OCD emerged within 12 months (69.2%) of starting of clozapine. In those who developed OCS/OCD with clozapine, among obsessions, pathological doubts were most common, followed by obsessions with sexual content; among compulsions repetitive checking was the most common. SSRIs were required for management in half the patients, while the remaining improved spontaneously or with reduction in clozapine dose. Conclusion: Clozapine can lead to aggravation or de novo presentation of OCS/OCD but these can be managed with reduction in dose or addition of SSRIs. ß 2015 Elsevier B.V. All rights reserved.
Keywords: Clozapine Obsessions Compulsions Obsessive compulsive disorder
1. Introduction Schizophrenia is known to be associated with obsessive compulsive symptoms (OCS) and obsessive compulsive disorder (OCD) with prevalence ranging from 10% to 64% for OCS (Bottas et al., 2005; Nolfe et al., 2010) and 7.8% to 29.8% for OCD (Bottas et al., 2005; Nolfe et al., 2010). However there are also reports of OCS/OCD starting de novo with use of second generation antipsychotics (SGAs) (Lykouras et al., 2003; Scheltema-Beduin et al., 2012). Due to this some authors suggest that high prevalence of OCS/OCD in patients of schizophrenia could also be due to use of SGAs (Bottas et al., 2005; Nolfe al., 2010; Schirmbeck and Zink, 2012). Among the various SGAs, OCS/OCD has been reported to be linked mostly to clozapine. Studies which have compared the prevalence of OCS in patients receiving various SGAs have also reported significantly higher prevalence of OCS with clozapine compared to those receiving olanzapine, risperidone and no antipsychotic (Scheltema-Beduin et al., 2012).
* Corresponding author. Tel.: +91 172 2756807; fax: +91 172 2744401/2745078. E-mail address: [email protected] (S. Grover). http://dx.doi.org/10.1016/j.ajp.2015.05.002 1876-2018/ß 2015 Elsevier B.V. All rights reserved.
A review of the topic suggested existence of 30 case reports linking this association (Lykouras et al., 2003). However, many retrospective and prospective studies have also evaluated this association. The sample sizes of these studies have varied from 41 to 200 and these studies suggest that 0–28.4% of patients have new symptoms of OCS/OCD while receiving clozapine (Ertugrul et al., 2005; de Haan et al., 1999, 2004; Ghaemi et al., 1995; Baker et al., 1992; Mahendran et al., 2007; Lin et al., 2006; Mukhopadhaya et al., 2009; Sa et al., 2009; Bleakley et al., 2011; Doyle et al., 2014). Some studies suggest that presence of OCS/OCD may be related to the severity of primary illness, higher doses of clozapine administered and the longer duration of clozapine use (Lin et al., 2006; Schirmbeck et al., 2011; Schirmbeck and Zink, 2013); however, others have reported no such association (Ertugrul et al., 2005; Kim et al., 2012). Some studies suggest that development of OCS/OCD may be related to plasma concentration of clozapine (Lin et al., 2006) and motoric impairment (Mukhopadhaya et al., 2009). The time to development of OCS/OCD in these studies also vary considerably with some studies reporting onset of symptoms as early as 1 month and as late as 5 years (Lykouras et al., 2003; Lin et al., 2006). With regards to the course of OCS/OCD some evidence suggest spontaneous resolution of OCS
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(Lykouras et al., 2003), while others suggest reduction in symptoms with reduction in doses of clozapine (Rocha and Hara, 2006; Zink et al., 2006; Englisch et al., 2009). Studies have also reported beneficial effect of aripiprazole (Englisch et al., 2009) and selective serotonin reuptake inhibitors (SSRIs) (de Haan et al., 1999; Lykouras et al., 2003). Studies have also reported worsening of OCS/OCD in a small proportion (1.4–20.6%) of patients receiving clozapine (Ghaemi et al., 1995; de Haan et al., 1999; Baker et al., 1992; Lin et al., 2006). Some of the studies have not given breakup of de novo OCS/OCD with clozapine and preexisting OCS/OCD, but have reported these features in 76.9% of their sample (Schirmbeck et al., 2011). Occasional reports also suggest improvement in OCS with clozapine in a subgroup of patients (Reznik et al., 2004). Recently some of the studies have also focused on the phenomenology of OCS induced by antipsychotics. Many studies have evaluated phenomenology of OCS associated with clozapine and have tried to compare the same with patients with OCD. However there is no consensus as to whether the phenomenology OCS/OCD induced by clozapine differ from that seen in patients of schizophrenia or that of OCD (Doyle et al., 2014; Kim et al., 2012). The commonly reported de novo OCS include obsessive doubts (Doyle et al., 2014), forbidden thoughts of aggressive or sexual content, contamination and hoarding (Kim et al., 2012). Some of the studies have suggested that phenomenology of de novo OCS associated with clozapine is similar to that seen in patients with OCD alone (Kim et al., 2012). Other studies have shown that phenomenology of de novo OCS associated with clozapine differ from those with OCD, with obsessive doubts being more common in clozapine induced OCD (Doyle et al., 2014). The mechanism of clozapine induced and aggravation of OC is considered to be related to its anti serotonergic action and antagonism at 5-HT1C, 5-HT2A and 5HT2C receptors (Kang and Simpson, 2010; Meltzer and Huang, 2008). This theory is in line with the therapeutic effects of SSRI action as anti-obsessive medication. Additional mechanisms of action recently considered include reciprocal interactions of clozapine with serotonergic receptors leading to altered glutamatergic neurotransmission (Lopez-Gil et al., 2010). As the literature is limited to few studies, there is a need to study the relationship of OCS/OCD with clozapine further. Pharmacogenomic studies have reported that the pharmacokinetics and pharmacodynamics of various psychotropics vary across various ethnic groups (Silva, 2013) and as there is some evidence of OCS/OCD to be linked to the dose and duration of clozapine use, there is a need to evaluate this relationship in all the ethnicities. There is a limited data from Asian countries (Kim et al., 2012) and there is no study from India which has evaluated this relationship. Accordingly, the aim of this study was to (1) to study the prevalence of OCS/OCD in patients with schizophrenia/affective disorder receiving clozapine; (2) to study the course of OCS and treatment used for management of OCS/OCD in patients; (3) to study the emergence of OCS/OCD associated with clozapine; (4) to study the phenomenology of OCS/OCD associated with clozapine. 2. Methodology This study was done in a multispeciality tertiary care hospital in North India. The study was approved by the Institute Ethics Committee. This study followed a retrospective study design. In our setting clozapine is usually considered for patients who have treatment resistant schizophrenia or are not able to tolerate other antipsychotics. In most cases clozapine is started in the inpatient setting after detailed evaluation. The detailed evaluation involves taking a detailed history with regards to the type of symptoms and
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course of illness, both from the patient and reliable informants, response to various medications, medical history and physical examination. Whenever the patients are found to have OCS/OCD, these are documented in detail in terms of the phenomenology. Diagnosis of OCD is based on ICD-10 criteria. Patients who are started on clozapine usually remain in the inpatient setting for a duration of 1–3 months. Once a patient is discharged, she/he is followed up regularly in the outpatient setting and her/his progress is regularly documented in the same treatment file, which is used during the inpatient setting. For this study, inpatient register was reviewed and all the patients who were on clozapine at the time of admission or were started on clozapine during the period of Jan 2007–April 2014 were identified. Data was also obtained from the consultants about the patients who were started on clozapine after detailed evaluation from the outpatient services. Treatment records of these patients were reviewed. To be included in the study, follow-up data of at least 3 months was required. Patients who were receiving clozapine prior to the specified admission period, but were admitted again during the evaluation period were also included. 3. Results Treatment records of 220 patients who were prescribed clozapine were reviewed. Follow-up data for at least 3 months after starting clozapine was available for all the patients, with longest follow-up data available for 18 years. Most of the patients (N = 165; 75%) were still on active follow-up and maximum followup duration of 18 years. For 87.7% (N = 193) of cases follow-up information for more than 1 year was available, for 5.5% (N = 12) follow-up information was available for a duration of more than 6 months but less than 1 year and for 6.8% (N = 15) follow-up information was for less than 6 months period. Majority of the patients were males (65%) and the mean age of the study sample was 33.5 (SD 11.2) with age range of 15–67 years. About two-third of them were single (65%) and more than half were unemployed (56.4%). About three-fourth of them were from nuclear families, from urban background and had income more than 6000 rupees per month. The mean age of onset of psychiatric illness was 23.0 (SD 9.5) years and the mean duration of illness was 110.4 (SD 93.9) months. Most of the patients were suffering from schizophrenia with paranoid schizophrenia (N = 107; 48.6%) and undifferentiated schizophrenia (N = 78; 35.5%) contributing to more than 80% of the study population. Other less common diagnosis included schizoaffective disorder (N = 10; 4.54%), psychosis NOS (N = 7; 3.18%), catatonic schizophrenia (N = 3; 1.36%), hebephrenic schizophrenia (N = 1; 0.45%), residual schizophrenia (N = 1; 0.45%), post-schizophrenic depression (N = 2; 0.91%), persistent delusional disorder (N = 3; 1.36%), bipolar disorder (N = 5; 2.27%) and recurrent depressive disorder with tardive dyskinesias (N = 3; 1.36%). The mean dose of clozapine used in the patients was 276.8 (SD 102.7; median 250) mg/day with a range of 75–700 mg, with majority (N = 152; 69.1%) of the patients receiving a dose between 200 and 350 mg/day. When started on clozapine, only other change in treatment which was done was stoppage of unnecessary psychotropics (which involved stoppage of medications like trihexiphenidyl and mood stabilizers in few cases) or continuing antipsychotic to which patient had not responded. Out of the 220 patients, review of treatment records revealed that 42 (19.1%) patients had OCS/OCD, of whom 29 (13.2%) had OCS/OCD prior to starting of clozapine. Of the 29 patients, with OCS/OCD prior to starting of clozapine, 16 (7.28%) had OCD and 13 (5.9%) had OCS. When the relationship of OCS/OCD with clozapine was evaluated in patients having OCS/OCD prior to starting of
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clozapine it was seen that in more than half [16 (55.17%) out of 29] of the cases, OCS/OCD remained at the same level of severity with continuation of clozapine, with (N = 10) or without (N = 6) antiobsessional medications. In about one fourth [7 (24.1%) out of 29] of the cases, the OCS/OCD worsened with starting of clozapine and in rest of the cases (N = 6; 20.7%) OCS/OCD improved with clozapine and these patients did not require any other treatment for the OCS/OCD. In over half of the cases [17 (58.6%)] management of OCS/OCD involved use of a SSRIs, with sertraline being used in seven patients. Other SSRIs which were used included fluoxetine (N-5), escitalopram (N-4), and paroxetine (N-1). As shown in Table 1, most common obsessions seen were sexual in nature, followed by obsessions of dirt and contamination. The most common compulsions were in the form of cleaning rituals following checking and repetitive acts. Other details are shown in Table 1. In terms of de novo emergence of OCS/OCD, 13 (6.8%) out of the remaining 191 patients developed OCS/OCD after starting of clozapine. OCS developed in eight (4.2%) patients, whereas OCD developed in five (2.6%) patients (details of these patients are shown in Table 2). Majority of the patients who developed OCS/ OCD were females and had psychotic illness for 2–18 years. OCS/ OCD emerged with clozapine at varying period with a range of 2 weeks–8 years. The dose at which OCS/OCD emerged varied from 100 to 450 mg/day. A common feature in all the cases was emergence of OCS/OCD while the psychosis was resolving or had resolved with clozapine. In eight out of the 13 cases, the obsessions involved development of obsessive doubts and in four patients had obsessions with sexual content. Presence of obsessive doubts was usually associated with yielding compulsions. Almost all cases had insight into their OCS/OCD symptoms, with one patient having partial insight. In terms of course of OCS/OCD, in three patients these symptoms were short lasting and resolved on their own without any intervention and in fact in one case clozapine could be increased further. Dose reduction was attempted in two cases, however it was useful in only one case and in the second case, this was partially useful. SSRIs were used in seven cases and addition of SSRIs led to improvement in OCS/OCD with no further recurrence.
4. Discussion To the best of our knowledge this is the first study from India which evaluated the prevalence of OCS/OCD in patients receiving clozapine. Although retrospective in nature, study included a Table 1 Phenomenology of OC symptoms in patients having OCS/OCD prior to starting of clozapine [N = 29]. Type of OC
N (%)
Obsession Sexual Obsessive doubts (dirt and contamination) Aggression Obsessive fear Religious/blasphemy Concern regarding appearance Hoarding Obsessive slowness Others
9 8 5 4 2 1 1 1 2
(31.0) (27.6) (17.2) (13.8) (6.9) (3.4) (3.4) (3.4) (6.9)
Compulsions Cleaning Checking Repetitive acts Ordering Mental rituals Intrusive sounds Lucky number
9 5 3 3 2 1 1
(31.0) (17.2) (10.3) (10.3) (6.9) (3.4) (3.4)
relatively large sample size compared to most of the previous studies (Ghaemi et al., 1995; Ertugrul et al., 2005; Lin et al., 2006; Mukhopadhaya et al., 2009; Schirmbeck et al., 2011) and data for most of the patients was available for the period of more than 1 year after starting of clozapine. Findings of this study suggests that about one-fifth (19.1%) of patients who are receiving clozapine have OCS/OCD, of whom 29 (13.18%) patients had OCS/OCD prior to starting of clozapine, 7.28% having OCS and 5.9% having OCD. In 6.8% cases OCS/OCD develop de novo with clozapine, with 4.2% developing OCS and 2.4% developing OCD. These prevalence figures are in the reported range of 10–64% for OCS and 7.8–29.8% for OCD for prevalence of OCS/OCD in patients with schizophrenia (Bottas et al., 2005; Nolfe al., 2010). However the prevalence findings of the present study can be considered to be lower than that reported in some of the western studies (Schirmbeck et al., 2011), which have reported OCS/OCD in about three-fourth of patients receiving clozapine. The most likely reason could be use of relatively lower doses in our study sample. There is some evidence to suggest the association of OCS/OCD with clozapine dose in the literature (Schirmbeck et al., 2011; Schirmbeck and Zink, 2012; Lin et al., 2006) and present study possibly provides indirect evidence for the same. The prevalence of de novo OCS/OCD with clozapine is also with the reported range of 0–28.4% (Ertugrul et al., 2005; de Haan et al., 1999, 2004; Ghaemi et al., 1995; Baker et al., 1992; Bleakley et al., 2011; Mahendran et al., 2007; Lin et al., 2006; Mukhopadhaya et al., 2009; Sa et al., 2009; Doyle et al., 2014). These findings suggest that clozapine is associated with development of OCS/OCD across various ethnic groups, including in those from Indian subcontinent. In the present study, the most common types of obsessions noted in patients who had OCS/OCD prior to starting of clozapine were in the form of sexual obsessions and obsessive doubts. The most common compulsions included that of cleaning and checking rituals. This profile is similar to OCS/OCD reported in patients with schizophrenia except for higher prevalence of sexual obsessions in our patients (Tibbo et al., 2000). In the present study patients who developed OCS/OCD after starting of clozapine were more likely to be females. Over half (53.8%) of the de novo cases of OCS/OCD were seen in females, who actually formed only one-third of the study population. None of the previous studies have reported such association, however, although preliminary this finding may be worthwhile evaluation in future studies. In the present study all the patients who developed OCS/OCD developed the same when their psychotic symptoms were resolving or had resolved. This finding suggest that severity of primary illness may not be a predictor of OCS/OCD associated with clozapine, as reported in some of the studies (Ertugrul et al., 2005; Kim et al., 2012). In the present study the time to development of OCS/OCD with clozapine varied between 3 weeks and 8 years, with nine out of the 13 cases developing OCS/OCD by 12 months of time. This finding is also akin to the reported literature (Lykouras et al., 2003; Lin et al., 2006) and suggests that 12 months may be a reasonable to time frame to monitor the patients for emergence of OCS/OCD. In terms of course of OCS/OCD in patients who develop OCS/ OCD with clozapine, in three out of the 13 cases these symptoms resolved on its own. Reduction in clozapine dose was useful in one case but not in other. However, whenever used, SSRIs were found to be useful in management of de novo OCS/OCD. There are reports of spontaneous resolution (Lykouras et al., 2003) and beneficial effect of dose reduction (Rocha and Hara, 2006; Zink et al., 2006; Englisch et al., 2009) and selective serotonin reuptake inhibitors (SSRIs) (de Haan et al., 1999; Lykouras et al., 2003). These findings suggest that whenever a patient develops de novo OCS/OCD with clozapine, the first strategy could be a wait and watch policy or
Table 2 Details of patients who developed OCS/OCD with clozapine.
Gender Age at the time of starting clozapine Diagnosis
Case-2
Case-3
Case-4
Case-5
Case-6
Male 21
Female 20
Female 30
Female 47
Female 30
Paranoid schizophrenia
Undifferentiated schizophrenia
Paranoid schizophrenia
Schizoaffective disorder
Undifferentiated schizophrenia
10 Treatment resistance
6 Treatment resistance
5 Treatment resistance
OCS 2.5 years 225 mg/day
OCS 6 months 450 mg/day
OCS 2 years 300 mg/day Psychotic symptoms resolved by 60% Obsessive doubt
Duration of illness in years Reason for starting clozapine
8 Treatment resistance
Undifferentiated schizophrenia Nicotine dependence Cannabis dependence Mild Mental Retardation 5 Treatment resistance
OCS/OCD Time to develop OCS/OCD Dose of clozapine in mg/day at which patient developed OCS/OCD Status of psychosis at the time of emergence of OCS/OCD Types of obsessions
OCS 6 months 300 mg/day
OCS 3 weeks 100 mg/day
2 Extrapyramidal symptoms with other atypical antipsychotics OCD 1 month 100 mg/day
Resolving
Resolving
Resolving
Resolved
Resolved
Fear of blurting out obscenities (sexual theme), obsessive doubts
Obsessive doubts
Obsessive thoughts of sexual content and blasphemous thoughts while praying
Obsessive doubts
Obsessive thoughts of sexual content with fear of blurting out obscenities and acting in indecent way
Compulsions
Compulsive checking
Compulsive checking
Insight into OCS/OCD Management of OCS/OCD
Present Escitalopram 15 mg/day
Present No active intervention
Outcome of OCS/OCD with management
>50% improvement in OCS/OCD which was sustained over 2.5 years follow up
Symptoms resolved on its own after 2 weeks and later clozapine could be increased upto 225 mg/day with no reemergence of symptoms over the next 11 months
Social Phobia
Compulsive checking Present Clozapine reduced to 87.5 mg/day, later added fluoxetine 40 mg/day OCS improved by 30% with reduction in clozapine to 87.5 mg/day; addition of Fluoxetine 40 mg/day led to improvement in OCS to 80%, maintained at the same level over the next 1 year
Present Reduction in dose of clozapine to 200 mg/day Symptoms resolved with no recurrence of symptoms for next 1.5 years of follow-up period
Present Sertraline 150 mg/day OCS improved by 90%, maintained at the same level over the next 17 year
Cleaning and washing rituals Present Resolved spontaneously after 4 months No recurrence of symptoms for next 1 year of follow-up period
Case-8
Case-9
Case-10
Case-11
Case-12
Case-13
Female 32
Male 32
Female 23
Male 33
Female 29
Male 45
Male 20
Paranoid schizophrenia
Undifferentiated schizophrenia
Undifferentiated schizophrenia
Undifferentiated schizophrenia
Paranoid schizophrenia
Paranoid schizophrenia Manic episode in past
Duration of illness in years Reason for starting clozapine
6 Treatment resistance OCD 8 months
7 Treatment resistance OCD 6 months
4 Treatment resistance OCD 15 month
18 Treatment resistance OCD 1 year
11 Treatment resistance OCS 3 months
Undifferentiated schizophrenia Moderate depressive episode Sedative hypnoticHarmful use 5 Treatment resistance OCS 8 years
OCS/OCD Time to develop OCS/OCD
2 Treatment resistance OCS 5 months
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Case-7 Gender Age at the time of starting clozapine Diagnosis
S. Grover et al. / Asian Journal of Psychiatry 15 (2015) 56–61
Case-1 Male 30
Present Under monitoring for symptoms
OC symptoms under observation, no medication given currently
Present Resolved spontaneously after 3 months
No recurrence of OCS for next 1 year of follow-up period OCS improved fully in 1 year, maintained well at 4 years follow up
Compulsive checking Compulsive checking
Compulsive movements in front of mirror Partial Fluvoxamine 150 mg followed by Sertraline 150 mg and distraction techniques OCD improved in 1 year, recurred after 12 years when clozapine dose was increased to 400 mg. After change of SSRI to Sertraline and distraction techniques, remained well at 4 years follow up Washing rituals
Present Fluoxetine 20 mg/day
Obsessive doubts Obsessive doubts Obsessive fear with aggressive content Obsessive thoughts of dirt and contamination Obsessive doubts
Obsessive images of sexual content
Resolving Resolved
Present Clomipramine 100 mg
OCD improved fully over 1 year, remained well at 4.5 years follow up
Present Sertraline 50 mg/day
>50% improvement in OCD, at 9 months follow up
Compulsive checking
Present Sertraline 150 mg/day
>70% improvement in OCD which was sustained over 1.5 years follow up
Compulsions
Insight into OCS/OCD Management of OCS/OCD
Outcome of OCS/OCD with management
Resolving
Obsessive doubts
Resolving Resolved Resolving
Resolving
325 mg/day
Case-12 Case-11 Case-10
350 mg/day
Case-9
325 mg/day
Case-8
350 mg/day 200 mg/day
Case-7
Dose of clozapine in mg/day at which patient developed OCS/OCD Status of psychosis at the time of emergence of OCS/OCD Types of obsessions
Table 2 (Continued )
400 mg/day
Case-13
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325 mg/day
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dose reduction, depending on the severity of primary psychotic illness. If the symptoms persist for a reasonable time frame than use of pharmacotherapy must be attempted to improve the overall outcome of patients. In terms of phenomenology of OCS/OCD in those who developed de novo OCS/OCD with clozapine, most common type of obsessions were in the form of obsessive doubts and obsessions with sexual content. This finding is very similar to that reported in earlier studies (Doyle et al., 2014; Kim et al., 2012). Accordingly it is important for the busy clinicians to at least ask about this subgroup of symptoms from patients receiving clozapine. To conclude findings of the present study suggest that approximately one-fifth of the patients receiving clozapine have OCS/OCD. Of these most of the patients have OCS/OCD prior to starting of clozapine and only 6.8% of patients develop OCS/OCD with clozapine. Most common types of obsessions noted in patients who had OCS/OCD prior to starting of clozapine were sexual obsessions and obsessive doubts. The most common compulsions included that of cleaning and checking rituals. De novo OCS/OCD is more commonly seen in females. Most of the patients (69.2%) who develop OCS/OCD develop so within 12 months of starting clozapine. The commonly reported de novo OCS symptoms include obsessive doubts and forbidden thoughts of sexual content (Kim et al., 2012). De novo OCS/OCD follow a variable course with spontaneous resolution in some of the cases whereas in other cases these symptoms require specific intervention. The findings of the present study must be interpreted in the light of its limitations. The study followed a retrospective study design and the information about OCS/OCD was obtained from the treatment record. It is quite possible that this could have led to some underestimation of de novo OCS/OCD associated with clozapine. We also did not rate the severity of OCS/OCD on a specific rating scale to assess the severity of the symptoms. We also did not evaluate the association of OCS/OCD with other symptoms of psychosis and with clozapine levels. The presence of OCD was ascertained on the basis of ICD-10 criteria and the presence of OCS/ OCD was not assessed by using any specific diagnostic instrument. It is known that OC symptoms can occur at various stages of schizophrenia during the naturalistic course of the illness and accordingly the causation/association with clozapine would need to be ascertained with a lot of caution. However, current study did not allow us to do so. Future studies should prospectively assess patients on appropriate OC checklist and rate the severity of OC symptoms along with rating of other symptoms. Source of funding None. References Baker, R.W., Chengappa, K.N., Baird, J.W., Steingard, S., Christ, M.A., Schooler, N.R., 1992. Emergence of obsessive compulsive symptoms during treatment with clozapine. J. Clin. Psychiatry 53 (12), 439–442. Bleakley, S., Brown, D., Taylor, D., 2011. Does clozapine cause or worsen obsessive compulsive symptoms? An analysis and literature review. Ther. Adv. Psychopharmacol. 1 (6), 181–188. Bottas, A., Cooke, R.G., Richter, M.A., 2005. Comorbidity and patho-physiology of obsessive–compulsive disorder in schizophrenia: is there evidence for a schizoobsessive subtype of schizophrenia? J. Psychiatry Neurosci. 30 (3), 187–193. deHaan, L., Linszen, D.H., Gorsira, R., 1999. Clozapine and obsessions in patients with recent-onset schizophrenia and other psychotic disorders. J. Clin. Psychiatry 60 (6), 364–365. deHaan, L., Oekeneva, A., van, A.T., Linszen, D., 2004. Obsessive–compulsive disorder and treatment with clozapine in 200 patients with recent–onset schizophrenia or related disorders. Eur. Psychiatry 19 (8), 524. Doyle, M., Chorcorain, A.N., Griffith, E., Trimble, T., O’Callaghan, E., 2014. Obsessive compulsive symptoms in patients with schizophrenia on clozapine and with obsessive compulsive disorder: a comparison study. Compr. Psychiatry 55 (1), 130–136.
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schizophrenia and schizoaffective disorder: a cause for clinical concern. J. Psychopharmacol. 23 (1), 6–13. Nolfe, G., Milano, W., Zontini, G., Petrella, C., De, R.M., Rundle- Smith, S., Nolfe, G., 2010. Obsessive–compulsive symptoms in schizophrenia: their relationship with clinical features and pharmacological treatment. J. Psychiatr. Pract. 16 (4), 235–242. Reznik, I., Yavin, I., Stryjer, R., Spivak, B., Gonen, N., Strous, R., Mester, R., Weizman, A., Kotler, M., 2004. Clozapine in the treatment of obsessive–compulsive symptoms in schizophrenia patients: a case series study. Pharmacopsychiatry 37 (2), 52–56. Rocha, F.L., Hara, C., 2006. Benefits of combining aripiprazole to clozapine: three case reports. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 30 (6), 1167–1169. Sa, A.R., Hounie, A.G., Sampaio, A.S., Arrais, J., Miguel, E.C., Elkis, H., 2009. Obsessive– compulsive symptoms and disorder in patients with schizophrenia treated with clozapine or haloperidol. Compr. Psychiatry 50 (5), 437–442. Scheltema-Beduin, A.A., Swets, M., Machielsen, M., Korver, N., 2012. Genetic risk and outcome of psychosis investigators. obsessive-compulsive symptoms in patients with schizophrenia: a naturalistic cross-sectional study comparing treatment with clozapine, olanzapine, risperidone, and no antipsychotics in 543 patients. J. Clin. Psychiatry 73 (11), 1395–1402. Schirmbeck, F., Esslinger, C., Rausch, F., Englisch, S., Meyer- Lindenberg, A., Zink, M., 2011. Antiserotonergic antipsychotics are associated with obsessive–compulsive symptoms in schizophrenia. Psychol. Med. 41 (11), 2361–2373. Schirmbeck, F., Zink, M., 2012. Clozapine-induced obsessive–compulsive symptoms in schizophrenia: a critical review. Curr. Neuropharmacol. 10, 88–95. Schirmbeck, F., Zink, M., 2013. Comorbid obsessive–compulsive symptoms in schizophrenia: contributions of pharmacological and genetic factors. Front. Pharmacol. 27 (4), 349–357. Silva, H., 2013. Ethnopsychopharmacology and pharmacogenomics. Adv. Psychosom. Med. 33, 88–96. Tibbo, P., Kroetsch, M., Chue, P., Warnecke, L., 2000. Obsessive compulsive disorder in schizophrenia. J. Psychiatr. Res. 34 (2), 139–146. Zink, M., Knopf, U., Kuwilsky, A., 2006. Management of clozapine-induced obsessive compulsive symptoms in a man with schizophrenia. Austr. N. Z. J. Psychiatry 41 (3), 293–294.
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Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Relationship of obsessive compulsive symptoms/disorder with clozapine: A retrospective study from a multispeciality tertiary care centre Sandeep Grover *, Nandita Hazari, Subho Chakrabarti, Ajit Avasthi Department of Psychiatry, Post-Graduate Institute of Medical Education and Research, Chandigarh 160012, India
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 November 2014 Received in revised form 26 April 2015 Accepted 3 May 2015
Objective: To study the prevalence, phenomenology and course of OCS/OCD in patients receiving clozapine. Methodology: Case records of 220 patients who received clozapine for at least 3 months were reviewed. Results: One fifth (N = 42; 19.1%) of patients had OCS/OCD, of which majority (13.2%) had onset of OCS/ OCD prior to starting of clozapine and remaining 5.9% developed OCS/OCD after starting of clozapine. About one fourth of the patients with pre-existing OCS/OCD had worsening with clozapine while the remaining maintained at the same level (55.17%) or improved (20.7%). Majority of the patients who developed de novo OCS/OCD on clozapine were females and OCS/OCD emerged within 12 months (69.2%) of starting of clozapine. In those who developed OCS/OCD with clozapine, among obsessions, pathological doubts were most common, followed by obsessions with sexual content; among compulsions repetitive checking was the most common. SSRIs were required for management in half the patients, while the remaining improved spontaneously or with reduction in clozapine dose. Conclusion: Clozapine can lead to aggravation or de novo presentation of OCS/OCD but these can be managed with reduction in dose or addition of SSRIs. ß 2015 Elsevier B.V. All rights reserved.
Keywords: Clozapine Obsessions Compulsions Obsessive compulsive disorder
1. Introduction Schizophrenia is known to be associated with obsessive compulsive symptoms (OCS) and obsessive compulsive disorder (OCD) with prevalence ranging from 10% to 64% for OCS (Bottas et al., 2005; Nolfe et al., 2010) and 7.8% to 29.8% for OCD (Bottas et al., 2005; Nolfe et al., 2010). However there are also reports of OCS/OCD starting de novo with use of second generation antipsychotics (SGAs) (Lykouras et al., 2003; Scheltema-Beduin et al., 2012). Due to this some authors suggest that high prevalence of OCS/OCD in patients of schizophrenia could also be due to use of SGAs (Bottas et al., 2005; Nolfe al., 2010; Schirmbeck and Zink, 2012). Among the various SGAs, OCS/OCD has been reported to be linked mostly to clozapine. Studies which have compared the prevalence of OCS in patients receiving various SGAs have also reported significantly higher prevalence of OCS with clozapine compared to those receiving olanzapine, risperidone and no antipsychotic (Scheltema-Beduin et al., 2012).
* Corresponding author. Tel.: +91 172 2756807; fax: +91 172 2744401/2745078. E-mail address: [email protected] (S. Grover). http://dx.doi.org/10.1016/j.ajp.2015.05.002 1876-2018/ß 2015 Elsevier B.V. All rights reserved.
A review of the topic suggested existence of 30 case reports linking this association (Lykouras et al., 2003). However, many retrospective and prospective studies have also evaluated this association. The sample sizes of these studies have varied from 41 to 200 and these studies suggest that 0–28.4% of patients have new symptoms of OCS/OCD while receiving clozapine (Ertugrul et al., 2005; de Haan et al., 1999, 2004; Ghaemi et al., 1995; Baker et al., 1992; Mahendran et al., 2007; Lin et al., 2006; Mukhopadhaya et al., 2009; Sa et al., 2009; Bleakley et al., 2011; Doyle et al., 2014). Some studies suggest that presence of OCS/OCD may be related to the severity of primary illness, higher doses of clozapine administered and the longer duration of clozapine use (Lin et al., 2006; Schirmbeck et al., 2011; Schirmbeck and Zink, 2013); however, others have reported no such association (Ertugrul et al., 2005; Kim et al., 2012). Some studies suggest that development of OCS/OCD may be related to plasma concentration of clozapine (Lin et al., 2006) and motoric impairment (Mukhopadhaya et al., 2009). The time to development of OCS/OCD in these studies also vary considerably with some studies reporting onset of symptoms as early as 1 month and as late as 5 years (Lykouras et al., 2003; Lin et al., 2006). With regards to the course of OCS/OCD some evidence suggest spontaneous resolution of OCS
S. Grover et al. / Asian Journal of Psychiatry 15 (2015) 56–61
(Lykouras et al., 2003), while others suggest reduction in symptoms with reduction in doses of clozapine (Rocha and Hara, 2006; Zink et al., 2006; Englisch et al., 2009). Studies have also reported beneficial effect of aripiprazole (Englisch et al., 2009) and selective serotonin reuptake inhibitors (SSRIs) (de Haan et al., 1999; Lykouras et al., 2003). Studies have also reported worsening of OCS/OCD in a small proportion (1.4–20.6%) of patients receiving clozapine (Ghaemi et al., 1995; de Haan et al., 1999; Baker et al., 1992; Lin et al., 2006). Some of the studies have not given breakup of de novo OCS/OCD with clozapine and preexisting OCS/OCD, but have reported these features in 76.9% of their sample (Schirmbeck et al., 2011). Occasional reports also suggest improvement in OCS with clozapine in a subgroup of patients (Reznik et al., 2004). Recently some of the studies have also focused on the phenomenology of OCS induced by antipsychotics. Many studies have evaluated phenomenology of OCS associated with clozapine and have tried to compare the same with patients with OCD. However there is no consensus as to whether the phenomenology OCS/OCD induced by clozapine differ from that seen in patients of schizophrenia or that of OCD (Doyle et al., 2014; Kim et al., 2012). The commonly reported de novo OCS include obsessive doubts (Doyle et al., 2014), forbidden thoughts of aggressive or sexual content, contamination and hoarding (Kim et al., 2012). Some of the studies have suggested that phenomenology of de novo OCS associated with clozapine is similar to that seen in patients with OCD alone (Kim et al., 2012). Other studies have shown that phenomenology of de novo OCS associated with clozapine differ from those with OCD, with obsessive doubts being more common in clozapine induced OCD (Doyle et al., 2014). The mechanism of clozapine induced and aggravation of OC is considered to be related to its anti serotonergic action and antagonism at 5-HT1C, 5-HT2A and 5HT2C receptors (Kang and Simpson, 2010; Meltzer and Huang, 2008). This theory is in line with the therapeutic effects of SSRI action as anti-obsessive medication. Additional mechanisms of action recently considered include reciprocal interactions of clozapine with serotonergic receptors leading to altered glutamatergic neurotransmission (Lopez-Gil et al., 2010). As the literature is limited to few studies, there is a need to study the relationship of OCS/OCD with clozapine further. Pharmacogenomic studies have reported that the pharmacokinetics and pharmacodynamics of various psychotropics vary across various ethnic groups (Silva, 2013) and as there is some evidence of OCS/OCD to be linked to the dose and duration of clozapine use, there is a need to evaluate this relationship in all the ethnicities. There is a limited data from Asian countries (Kim et al., 2012) and there is no study from India which has evaluated this relationship. Accordingly, the aim of this study was to (1) to study the prevalence of OCS/OCD in patients with schizophrenia/affective disorder receiving clozapine; (2) to study the course of OCS and treatment used for management of OCS/OCD in patients; (3) to study the emergence of OCS/OCD associated with clozapine; (4) to study the phenomenology of OCS/OCD associated with clozapine. 2. Methodology This study was done in a multispeciality tertiary care hospital in North India. The study was approved by the Institute Ethics Committee. This study followed a retrospective study design. In our setting clozapine is usually considered for patients who have treatment resistant schizophrenia or are not able to tolerate other antipsychotics. In most cases clozapine is started in the inpatient setting after detailed evaluation. The detailed evaluation involves taking a detailed history with regards to the type of symptoms and
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course of illness, both from the patient and reliable informants, response to various medications, medical history and physical examination. Whenever the patients are found to have OCS/OCD, these are documented in detail in terms of the phenomenology. Diagnosis of OCD is based on ICD-10 criteria. Patients who are started on clozapine usually remain in the inpatient setting for a duration of 1–3 months. Once a patient is discharged, she/he is followed up regularly in the outpatient setting and her/his progress is regularly documented in the same treatment file, which is used during the inpatient setting. For this study, inpatient register was reviewed and all the patients who were on clozapine at the time of admission or were started on clozapine during the period of Jan 2007–April 2014 were identified. Data was also obtained from the consultants about the patients who were started on clozapine after detailed evaluation from the outpatient services. Treatment records of these patients were reviewed. To be included in the study, follow-up data of at least 3 months was required. Patients who were receiving clozapine prior to the specified admission period, but were admitted again during the evaluation period were also included. 3. Results Treatment records of 220 patients who were prescribed clozapine were reviewed. Follow-up data for at least 3 months after starting clozapine was available for all the patients, with longest follow-up data available for 18 years. Most of the patients (N = 165; 75%) were still on active follow-up and maximum followup duration of 18 years. For 87.7% (N = 193) of cases follow-up information for more than 1 year was available, for 5.5% (N = 12) follow-up information was available for a duration of more than 6 months but less than 1 year and for 6.8% (N = 15) follow-up information was for less than 6 months period. Majority of the patients were males (65%) and the mean age of the study sample was 33.5 (SD 11.2) with age range of 15–67 years. About two-third of them were single (65%) and more than half were unemployed (56.4%). About three-fourth of them were from nuclear families, from urban background and had income more than 6000 rupees per month. The mean age of onset of psychiatric illness was 23.0 (SD 9.5) years and the mean duration of illness was 110.4 (SD 93.9) months. Most of the patients were suffering from schizophrenia with paranoid schizophrenia (N = 107; 48.6%) and undifferentiated schizophrenia (N = 78; 35.5%) contributing to more than 80% of the study population. Other less common diagnosis included schizoaffective disorder (N = 10; 4.54%), psychosis NOS (N = 7; 3.18%), catatonic schizophrenia (N = 3; 1.36%), hebephrenic schizophrenia (N = 1; 0.45%), residual schizophrenia (N = 1; 0.45%), post-schizophrenic depression (N = 2; 0.91%), persistent delusional disorder (N = 3; 1.36%), bipolar disorder (N = 5; 2.27%) and recurrent depressive disorder with tardive dyskinesias (N = 3; 1.36%). The mean dose of clozapine used in the patients was 276.8 (SD 102.7; median 250) mg/day with a range of 75–700 mg, with majority (N = 152; 69.1%) of the patients receiving a dose between 200 and 350 mg/day. When started on clozapine, only other change in treatment which was done was stoppage of unnecessary psychotropics (which involved stoppage of medications like trihexiphenidyl and mood stabilizers in few cases) or continuing antipsychotic to which patient had not responded. Out of the 220 patients, review of treatment records revealed that 42 (19.1%) patients had OCS/OCD, of whom 29 (13.2%) had OCS/OCD prior to starting of clozapine. Of the 29 patients, with OCS/OCD prior to starting of clozapine, 16 (7.28%) had OCD and 13 (5.9%) had OCS. When the relationship of OCS/OCD with clozapine was evaluated in patients having OCS/OCD prior to starting of
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clozapine it was seen that in more than half [16 (55.17%) out of 29] of the cases, OCS/OCD remained at the same level of severity with continuation of clozapine, with (N = 10) or without (N = 6) antiobsessional medications. In about one fourth [7 (24.1%) out of 29] of the cases, the OCS/OCD worsened with starting of clozapine and in rest of the cases (N = 6; 20.7%) OCS/OCD improved with clozapine and these patients did not require any other treatment for the OCS/OCD. In over half of the cases [17 (58.6%)] management of OCS/OCD involved use of a SSRIs, with sertraline being used in seven patients. Other SSRIs which were used included fluoxetine (N-5), escitalopram (N-4), and paroxetine (N-1). As shown in Table 1, most common obsessions seen were sexual in nature, followed by obsessions of dirt and contamination. The most common compulsions were in the form of cleaning rituals following checking and repetitive acts. Other details are shown in Table 1. In terms of de novo emergence of OCS/OCD, 13 (6.8%) out of the remaining 191 patients developed OCS/OCD after starting of clozapine. OCS developed in eight (4.2%) patients, whereas OCD developed in five (2.6%) patients (details of these patients are shown in Table 2). Majority of the patients who developed OCS/ OCD were females and had psychotic illness for 2–18 years. OCS/ OCD emerged with clozapine at varying period with a range of 2 weeks–8 years. The dose at which OCS/OCD emerged varied from 100 to 450 mg/day. A common feature in all the cases was emergence of OCS/OCD while the psychosis was resolving or had resolved with clozapine. In eight out of the 13 cases, the obsessions involved development of obsessive doubts and in four patients had obsessions with sexual content. Presence of obsessive doubts was usually associated with yielding compulsions. Almost all cases had insight into their OCS/OCD symptoms, with one patient having partial insight. In terms of course of OCS/OCD, in three patients these symptoms were short lasting and resolved on their own without any intervention and in fact in one case clozapine could be increased further. Dose reduction was attempted in two cases, however it was useful in only one case and in the second case, this was partially useful. SSRIs were used in seven cases and addition of SSRIs led to improvement in OCS/OCD with no further recurrence.
4. Discussion To the best of our knowledge this is the first study from India which evaluated the prevalence of OCS/OCD in patients receiving clozapine. Although retrospective in nature, study included a Table 1 Phenomenology of OC symptoms in patients having OCS/OCD prior to starting of clozapine [N = 29]. Type of OC
N (%)
Obsession Sexual Obsessive doubts (dirt and contamination) Aggression Obsessive fear Religious/blasphemy Concern regarding appearance Hoarding Obsessive slowness Others
9 8 5 4 2 1 1 1 2
(31.0) (27.6) (17.2) (13.8) (6.9) (3.4) (3.4) (3.4) (6.9)
Compulsions Cleaning Checking Repetitive acts Ordering Mental rituals Intrusive sounds Lucky number
9 5 3 3 2 1 1
(31.0) (17.2) (10.3) (10.3) (6.9) (3.4) (3.4)
relatively large sample size compared to most of the previous studies (Ghaemi et al., 1995; Ertugrul et al., 2005; Lin et al., 2006; Mukhopadhaya et al., 2009; Schirmbeck et al., 2011) and data for most of the patients was available for the period of more than 1 year after starting of clozapine. Findings of this study suggests that about one-fifth (19.1%) of patients who are receiving clozapine have OCS/OCD, of whom 29 (13.18%) patients had OCS/OCD prior to starting of clozapine, 7.28% having OCS and 5.9% having OCD. In 6.8% cases OCS/OCD develop de novo with clozapine, with 4.2% developing OCS and 2.4% developing OCD. These prevalence figures are in the reported range of 10–64% for OCS and 7.8–29.8% for OCD for prevalence of OCS/OCD in patients with schizophrenia (Bottas et al., 2005; Nolfe al., 2010). However the prevalence findings of the present study can be considered to be lower than that reported in some of the western studies (Schirmbeck et al., 2011), which have reported OCS/OCD in about three-fourth of patients receiving clozapine. The most likely reason could be use of relatively lower doses in our study sample. There is some evidence to suggest the association of OCS/OCD with clozapine dose in the literature (Schirmbeck et al., 2011; Schirmbeck and Zink, 2012; Lin et al., 2006) and present study possibly provides indirect evidence for the same. The prevalence of de novo OCS/OCD with clozapine is also with the reported range of 0–28.4% (Ertugrul et al., 2005; de Haan et al., 1999, 2004; Ghaemi et al., 1995; Baker et al., 1992; Bleakley et al., 2011; Mahendran et al., 2007; Lin et al., 2006; Mukhopadhaya et al., 2009; Sa et al., 2009; Doyle et al., 2014). These findings suggest that clozapine is associated with development of OCS/OCD across various ethnic groups, including in those from Indian subcontinent. In the present study, the most common types of obsessions noted in patients who had OCS/OCD prior to starting of clozapine were in the form of sexual obsessions and obsessive doubts. The most common compulsions included that of cleaning and checking rituals. This profile is similar to OCS/OCD reported in patients with schizophrenia except for higher prevalence of sexual obsessions in our patients (Tibbo et al., 2000). In the present study patients who developed OCS/OCD after starting of clozapine were more likely to be females. Over half (53.8%) of the de novo cases of OCS/OCD were seen in females, who actually formed only one-third of the study population. None of the previous studies have reported such association, however, although preliminary this finding may be worthwhile evaluation in future studies. In the present study all the patients who developed OCS/OCD developed the same when their psychotic symptoms were resolving or had resolved. This finding suggest that severity of primary illness may not be a predictor of OCS/OCD associated with clozapine, as reported in some of the studies (Ertugrul et al., 2005; Kim et al., 2012). In the present study the time to development of OCS/OCD with clozapine varied between 3 weeks and 8 years, with nine out of the 13 cases developing OCS/OCD by 12 months of time. This finding is also akin to the reported literature (Lykouras et al., 2003; Lin et al., 2006) and suggests that 12 months may be a reasonable to time frame to monitor the patients for emergence of OCS/OCD. In terms of course of OCS/OCD in patients who develop OCS/ OCD with clozapine, in three out of the 13 cases these symptoms resolved on its own. Reduction in clozapine dose was useful in one case but not in other. However, whenever used, SSRIs were found to be useful in management of de novo OCS/OCD. There are reports of spontaneous resolution (Lykouras et al., 2003) and beneficial effect of dose reduction (Rocha and Hara, 2006; Zink et al., 2006; Englisch et al., 2009) and selective serotonin reuptake inhibitors (SSRIs) (de Haan et al., 1999; Lykouras et al., 2003). These findings suggest that whenever a patient develops de novo OCS/OCD with clozapine, the first strategy could be a wait and watch policy or
Table 2 Details of patients who developed OCS/OCD with clozapine.
Gender Age at the time of starting clozapine Diagnosis
Case-2
Case-3
Case-4
Case-5
Case-6
Male 21
Female 20
Female 30
Female 47
Female 30
Paranoid schizophrenia
Undifferentiated schizophrenia
Paranoid schizophrenia
Schizoaffective disorder
Undifferentiated schizophrenia
10 Treatment resistance
6 Treatment resistance
5 Treatment resistance
OCS 2.5 years 225 mg/day
OCS 6 months 450 mg/day
OCS 2 years 300 mg/day Psychotic symptoms resolved by 60% Obsessive doubt
Duration of illness in years Reason for starting clozapine
8 Treatment resistance
Undifferentiated schizophrenia Nicotine dependence Cannabis dependence Mild Mental Retardation 5 Treatment resistance
OCS/OCD Time to develop OCS/OCD Dose of clozapine in mg/day at which patient developed OCS/OCD Status of psychosis at the time of emergence of OCS/OCD Types of obsessions
OCS 6 months 300 mg/day
OCS 3 weeks 100 mg/day
2 Extrapyramidal symptoms with other atypical antipsychotics OCD 1 month 100 mg/day
Resolving
Resolving
Resolving
Resolved
Resolved
Fear of blurting out obscenities (sexual theme), obsessive doubts
Obsessive doubts
Obsessive thoughts of sexual content and blasphemous thoughts while praying
Obsessive doubts
Obsessive thoughts of sexual content with fear of blurting out obscenities and acting in indecent way
Compulsions
Compulsive checking
Compulsive checking
Insight into OCS/OCD Management of OCS/OCD
Present Escitalopram 15 mg/day
Present No active intervention
Outcome of OCS/OCD with management
>50% improvement in OCS/OCD which was sustained over 2.5 years follow up
Symptoms resolved on its own after 2 weeks and later clozapine could be increased upto 225 mg/day with no reemergence of symptoms over the next 11 months
Social Phobia
Compulsive checking Present Clozapine reduced to 87.5 mg/day, later added fluoxetine 40 mg/day OCS improved by 30% with reduction in clozapine to 87.5 mg/day; addition of Fluoxetine 40 mg/day led to improvement in OCS to 80%, maintained at the same level over the next 1 year
Present Reduction in dose of clozapine to 200 mg/day Symptoms resolved with no recurrence of symptoms for next 1.5 years of follow-up period
Present Sertraline 150 mg/day OCS improved by 90%, maintained at the same level over the next 17 year
Cleaning and washing rituals Present Resolved spontaneously after 4 months No recurrence of symptoms for next 1 year of follow-up period
Case-8
Case-9
Case-10
Case-11
Case-12
Case-13
Female 32
Male 32
Female 23
Male 33
Female 29
Male 45
Male 20
Paranoid schizophrenia
Undifferentiated schizophrenia
Undifferentiated schizophrenia
Undifferentiated schizophrenia
Paranoid schizophrenia
Paranoid schizophrenia Manic episode in past
Duration of illness in years Reason for starting clozapine
6 Treatment resistance OCD 8 months
7 Treatment resistance OCD 6 months
4 Treatment resistance OCD 15 month
18 Treatment resistance OCD 1 year
11 Treatment resistance OCS 3 months
Undifferentiated schizophrenia Moderate depressive episode Sedative hypnoticHarmful use 5 Treatment resistance OCS 8 years
OCS/OCD Time to develop OCS/OCD
2 Treatment resistance OCS 5 months
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Case-7 Gender Age at the time of starting clozapine Diagnosis
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Case-1 Male 30
Present Under monitoring for symptoms
OC symptoms under observation, no medication given currently
Present Resolved spontaneously after 3 months
No recurrence of OCS for next 1 year of follow-up period OCS improved fully in 1 year, maintained well at 4 years follow up
Compulsive checking Compulsive checking
Compulsive movements in front of mirror Partial Fluvoxamine 150 mg followed by Sertraline 150 mg and distraction techniques OCD improved in 1 year, recurred after 12 years when clozapine dose was increased to 400 mg. After change of SSRI to Sertraline and distraction techniques, remained well at 4 years follow up Washing rituals
Present Fluoxetine 20 mg/day
Obsessive doubts Obsessive doubts Obsessive fear with aggressive content Obsessive thoughts of dirt and contamination Obsessive doubts
Obsessive images of sexual content
Resolving Resolved
Present Clomipramine 100 mg
OCD improved fully over 1 year, remained well at 4.5 years follow up
Present Sertraline 50 mg/day
>50% improvement in OCD, at 9 months follow up
Compulsive checking
Present Sertraline 150 mg/day
>70% improvement in OCD which was sustained over 1.5 years follow up
Compulsions
Insight into OCS/OCD Management of OCS/OCD
Outcome of OCS/OCD with management
Resolving
Obsessive doubts
Resolving Resolved Resolving
Resolving
325 mg/day
Case-12 Case-11 Case-10
350 mg/day
Case-9
325 mg/day
Case-8
350 mg/day 200 mg/day
Case-7
Dose of clozapine in mg/day at which patient developed OCS/OCD Status of psychosis at the time of emergence of OCS/OCD Types of obsessions
Table 2 (Continued )
400 mg/day
Case-13
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325 mg/day
60
dose reduction, depending on the severity of primary psychotic illness. If the symptoms persist for a reasonable time frame than use of pharmacotherapy must be attempted to improve the overall outcome of patients. In terms of phenomenology of OCS/OCD in those who developed de novo OCS/OCD with clozapine, most common type of obsessions were in the form of obsessive doubts and obsessions with sexual content. This finding is very similar to that reported in earlier studies (Doyle et al., 2014; Kim et al., 2012). Accordingly it is important for the busy clinicians to at least ask about this subgroup of symptoms from patients receiving clozapine. To conclude findings of the present study suggest that approximately one-fifth of the patients receiving clozapine have OCS/OCD. Of these most of the patients have OCS/OCD prior to starting of clozapine and only 6.8% of patients develop OCS/OCD with clozapine. Most common types of obsessions noted in patients who had OCS/OCD prior to starting of clozapine were sexual obsessions and obsessive doubts. The most common compulsions included that of cleaning and checking rituals. De novo OCS/OCD is more commonly seen in females. Most of the patients (69.2%) who develop OCS/OCD develop so within 12 months of starting clozapine. The commonly reported de novo OCS symptoms include obsessive doubts and forbidden thoughts of sexual content (Kim et al., 2012). De novo OCS/OCD follow a variable course with spontaneous resolution in some of the cases whereas in other cases these symptoms require specific intervention. The findings of the present study must be interpreted in the light of its limitations. The study followed a retrospective study design and the information about OCS/OCD was obtained from the treatment record. It is quite possible that this could have led to some underestimation of de novo OCS/OCD associated with clozapine. We also did not rate the severity of OCS/OCD on a specific rating scale to assess the severity of the symptoms. We also did not evaluate the association of OCS/OCD with other symptoms of psychosis and with clozapine levels. The presence of OCD was ascertained on the basis of ICD-10 criteria and the presence of OCS/ OCD was not assessed by using any specific diagnostic instrument. It is known that OC symptoms can occur at various stages of schizophrenia during the naturalistic course of the illness and accordingly the causation/association with clozapine would need to be ascertained with a lot of caution. However, current study did not allow us to do so. Future studies should prospectively assess patients on appropriate OC checklist and rate the severity of OC symptoms along with rating of other symptoms. Source of funding None. References Baker, R.W., Chengappa, K.N., Baird, J.W., Steingard, S., Christ, M.A., Schooler, N.R., 1992. Emergence of obsessive compulsive symptoms during treatment with clozapine. J. Clin. Psychiatry 53 (12), 439–442. Bleakley, S., Brown, D., Taylor, D., 2011. Does clozapine cause or worsen obsessive compulsive symptoms? An analysis and literature review. Ther. Adv. Psychopharmacol. 1 (6), 181–188. Bottas, A., Cooke, R.G., Richter, M.A., 2005. Comorbidity and patho-physiology of obsessive–compulsive disorder in schizophrenia: is there evidence for a schizoobsessive subtype of schizophrenia? J. Psychiatry Neurosci. 30 (3), 187–193. deHaan, L., Linszen, D.H., Gorsira, R., 1999. Clozapine and obsessions in patients with recent-onset schizophrenia and other psychotic disorders. J. Clin. Psychiatry 60 (6), 364–365. deHaan, L., Oekeneva, A., van, A.T., Linszen, D., 2004. Obsessive–compulsive disorder and treatment with clozapine in 200 patients with recent–onset schizophrenia or related disorders. Eur. Psychiatry 19 (8), 524. Doyle, M., Chorcorain, A.N., Griffith, E., Trimble, T., O’Callaghan, E., 2014. Obsessive compulsive symptoms in patients with schizophrenia on clozapine and with obsessive compulsive disorder: a comparison study. Compr. Psychiatry 55 (1), 130–136.
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