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Suicidality in clozapine-treated patients with schizophrenia: Role of obsessive-compulsive symptoms
Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Suicidality in clozapine-treated patients with schizophrenia: Role of obsessive-compulsive symptoms Alejandro G. Szmulewicz n, José M. Smith, Marina P. Valerio Hospital de Emergencias Psiquiátricas Torcuato de Alvear, Av Warnes 2630, Capital Federal, Argentina
art ic l e i nf o
a b s t r a c t
Article history: Received 17 March 2015 Received in revised form 9 June 2015 Accepted 30 July 2015
Patients with schizophrenia have an increased lifetime risk of comorbid obsessive-compulsive symptoms. Up to 30% of these patients experience such symptoms and 12% may be diagnosed with obsessivecompulsive disorder. The presence of these symptoms in schizophrenia seems to be associated with poor outcomes including a greater suicidal risk. A subgroup of patients develops this symptomatology after the initiation with Second Generation Antipsychotics (SGA). Also, there is evidence of a causal relationship for this association, particularly for clozapine. The primary aim of this study was to investigate the association of this comorbidity with suicidality in a population of clozapine-medicated schizophrenic and schizoaffective patients (N¼ 65). The prevalence of obsessive-compulsive symptoms in our sample was 29.2% (N ¼19) and the prevalence of obsessive-compulsive disorder was 13.8% (N¼ 9). Significant positive correlations between suicidality and total Y-BOCS score and between Y- BOCS score and depressive symptoms were found. Further analysis indicated that a Y-BOCS score greater or equal than 8 was an independent predictor of suicide attempt during clozapine treatment. Routine screening for this adverse event should be warranted for this population. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Obsessive-compulsive disorder Schizophrenia Clozapine Schizo-OCD-Suicide Suicide attempt
1. Introduction Patients with schizophrenia have an increased lifetime risk of comorbid obsessive-compulsive symptoms (OCS). These are characterized by obsessive, distressing, intrusive thoughts and related compulsions (Poyurovsky et al., 2004). Up to 30% of these patients experience OCS and up to 12% may be diagnosed with obsessivecompulsive disorder (OCD) (Swets et al., 2014). Since the prevalence of OCD in the general population has been reported to be 1.6% (Kessler et al., 2005) obsessive-compulsive symptomatology appears more often in schizophrenia than expected. Furthermore, recent large cohort studies reported that OCD patients carry an increased risk for schizophrenia spectrum disorders (Cederlöf et al., 2014; Meier et al., 2014). Whereas some patients experience OCS onset simultaneously with psychosis onset, others experience OCS onset after the initiation of Second Generation Antipsychotics (SGA) being prevalence rates in later disease stages significantly higher than in the early course of psychotic illness (De Haan, 2015). A recent study found that 13% of at-risk mental state patients reported OCS, while 5.4% fulfilled the criteria for OCD. Slightly higher averaged rates for OCS (17.1%) and OCD (7%) were found in first-episode patients n
Corresponding author. E-mail address: [email protected] (A.G. Szmulewicz).
(Zink et al., 2014). These rates are significantly lower than that descripted in cross sectional studies of chronic or late stage, as described above. Additionally, there has been an increase in the prevalence and in the study of this subject over the last 20 years that overlaps with the appearance of SGA in the market (Bleakley et al., 2011). A review of case reports (Lykouras et al., 2003) describes over 55 cases of de novo development or exacerbation of OCS during treatment with clozapine (30 cases), olanzapine (8 cases), risperidone (16 cases) and quetiapine (1 case). A comparison of schizophrenia patients under antipsychotic monotherapy with either mainly antiserotonergic SGAs (CLZ or OLZ; group I) or mainly dopaminergic SGAs (AMS or APZ; group II) revealed that more than 70% of group-I-patients suffered from OCS while less than 10% of patients in group-II reported OCS (Schirmbeck et al., 2011). Another study reported a prevalence of 28.4% of clozapine-induced OCS in a sample of one hundred and two patients with schizophrenia (Lin et al., 2006). Additionally, there is evidence of a causal relationship between OC symptomatology and treatment with SGA, particularly clozapine. This comes from retrospective cohort studies (Mahendran et al., 2007) and prospective ones (Schirmbeck et al., 2013a). Furthermore, a dose-response pattern (Lin et al., 2006; Schirmbeck et al., 2011) and an association between duration of clozapine treatment and OCS severity (Schirmbeck et al., 2011) have been described. This pharmacological argument based on correlations between OCS severity and
http://dx.doi.org/10.1016/j.psychres.2015.07.089 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Szmulewicz, A.G., et al., Suicidality in clozapine-treated patients with schizophrenia: Role of obsessivecompulsive symptoms. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.07.089i
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dosage as well as duration of clozapine application indicate a causal interaction and suggest OCS induction as a side effect of clozapine treatment (Scheltema Beduin et al., 2012). Atypical antipsychotics achieve their effects through preferential occupancy of 5HT2 receptors over D2 (Kapur et al., 1998;1999; 2006). This profile of antiserotoninergic properties is thought to be the cause of the OC symptomatology. Three lines of evidence supports this: first, SSRI drugs alleviate SGA induced OCS (Dodt et al., 1997; Rahman et al., 1998), second, first generation antipsychotics do not cause and even improve OCS (Keuneman et al., 2005) and finally, the disinhibition of the dopaminergic neurotransmission caused by the blockade of 5HT2a receptors is thought to activate the circuits involved in the OC symptomatology as explained by the antiobsessive effects of others SGA characterized by a more antidopaminergic effect (Schirmbeck et al., 2011; 2013a; Schirmbeck and Zink, 2012, 2013). The presence of OCS in schizophrenia seems to be associated with poor outcomes such as earlier age of onset (Faragian et al., 2012), poorer treatment response (Zink et al., 2014), more depressive (de Haan et al., 2013) and negative symptoms (Owashi et al., 2010) and greater cognitive deficits (Patel et al., 2010; Schirmbeck et al., 2013b). It remains unknown whether treatment for the OCS reverts these outcomes. Recent studies suggest that OCD and OCS are associated with a greater suicidal risk in patients with schizophrenia. OCD-schizophrenia comorbid patients are more likely to have a previous history of suicidal ideation and attempts. Also, OCS severity is associated with suicidality in adolescents at ultra-high risk for psychosis (Niendam et al., 2009; Sevincok et al., 2007). There are some controversies regarding the prevalence of this outcome in schizophrenia. While some authors estimated that 10% of persons with schizophrenia will die from suicide (Miles, 1977) other longer-term follow up studies found lower figures. For instance, Inskip et al. (1998) estimated lifetime risk to be 4% for schizophrenia and Palmer et al. (2005) 5.6%. Either way, deliberate self-harm or previous suicidal attempts increase the risk approximately two fold (Nordentoft et al., 2011). Therefore, suicide attempt should be considered a very important risk factor among patients with schizophrenia and other mental disorders, as underlined by the recent findings in a large Swedish cohort study (Runeson et al., 2010). Suicidality is a continuum phenomenon and the probability of making an attempt in a patient with suicidal plans is around 50% (Scocco et al., 2008) and with suicidal ideation 32.3% (Lee et al., 2012). This underlines the importance of the study of non-fatal aspects of suicidality in order to prevent death by suicide. There is some evidence suggesting that clozapine may have a beneficial effect on suicidality (Meltzer et al., 2003; Thomas et al., 2015; Ringbäck et al., 2014) and even treatment algorithms suggest its use in patients with schizophrenia with associated suicidality (Moore et al., 2007). In addition, this antipsychotic embarks important protective effects against suicidal behavior resulting in lower overall mortality of schizophrenics as documented in the large, naturalistic FIN11-study (Tiihonen et al., 2009). In general, OCS are neglected by clinicians when comorbid with an acute or chronic psychotic illness. The primary aim of this study was to investigate the association of this comorbidity with suicidality in a population of clozapine-medicated schizophrenic and schizoaffective patients.
2. Methods 2.1. Subjects The study sample was recruited from the totality of clozapine-
medicated patients in the Hospital de Emergencias Psiquiátricas Torcuato de Alvear by September 2014 (N ¼98). Data was obtained from pharmacy and pharmacovigilance program databases. Patients were screened for participation in the present study from September 2014 to January 2015. Inclusion criteria were: age 18 years or older; DSM-IV diagnosis of schizophrenia or schizoaffective disorder based on the Mini International Neuropsychiatric Interview (MINI); being on treatment with clozapine for 18 weeks or longer. The exclusion criteria were: OCS or OCD previous to clozapine treatment, history of mental retardation, neurological diseases and inability to participate due to severe psychotic symptoms or deafness. Of the initial 98 subjects, 65 were recruited for the study. The 33-nonincluded subjects either did not met inclusion criteria or met exclusion criteria or refused to participate. 8 patients refuse to provide written consent, 5 patients were under 18 years old, 8 patients presented previous history of OCS/OCD and 5 patients did not meet DSM-IV criteria for a diagnosis of schizophrenia or schizoaffective disorder, 2 patients were mentally retarded, 3 patients were unable to participate due to acute psychotic symptoms, 1 patient was excluded due to neurologic disease and 1 patient was deaf. The Ethics Committee of the Hospital de Emergencias Psiquiátricas Torcuato de Alvear approved recruitment and assessment procedures. All included subjects provided written informed consent after receiving a complete description of the study. 2.2. Assessment Interviews were conducted by physicians in a quiet testing room according to a standardized order. The total procedure was done in an interview of 1–2 h with one or two breaks to avoid fatigue. Interviewers were trained and unaware of patient's previous history. 2.2.1. Diagnosis Diagnoses were confirmed using the MINI-International Neuropsychiatric Interview (Sheehan et al., 1998). 2.2.2. Obsessive-compulsive symptomatology Subjects were evaluated with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in order to measure the severity of OCS. This scale is considered suitable for assessing OCS in schizophrenia (de Haan et al., 2006; Boyette et al., 2011). A cut-off score of 8 was established to determine the presence of OCS as previously used by Schirmbeck et al. (2011; 2013a). In addition, the corresponding section of the MINI was used to assess the presence of OCD. Subjects were asked to respond for symptoms that appeared after the initiation of clozapine treatment. Patients who reported symptoms onset prior to clozapine initiation were excluded from the analysis. 2.2.3. Depressive symptoms Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1994) was used to identify the presence of depressive symptoms. 2.2.4. Suicidality assessment Suicidality during clozapine treatment was assessed using the items 102–107 of the Mood Spectrum Self-Report (MOODS-SR) Spanish Version. This scale evaluates whether the subject has ever experienced a period of 3–5 days or more when he or she: (1) felt like life was not worth living; (2) hoped to die; (3) wanted to die; (4) made suicide plans, and two questions asking; (5) whether he/ she actually made a suicide attempt and (6) whether medical attention was required following the attempt.
Please cite this article as: Szmulewicz, A.G., et al., Suicidality in clozapine-treated patients with schizophrenia: Role of obsessivecompulsive symptoms. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.07.089i
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If more than one item was answered affirmatively, the most severe item was taken into account. The patient was asked to respond only for events occurred after clozapine initiation. Answers were checked with the patient charts. Patients who reported suicidality prior to clozapine initiation were excluded from the analysis.
ratios. The odds ratios and confidence intervals for the independent variables were derived. The level of statistical significance was defined as an alpha less than 0.05.
2.2.5. Severity Severity was assessed by the number of hospitalizations (as recorded in the patient medical records), the age of onset and the duration of illness. These parameters were chosen because they are stable, reliable and objective markers of illness severity. The age of onset was established as the age when the patient first met DSM-IV TR criteria for schizophrenia or schizoaffective disorder and the duration of illness was recorded as the difference between patient's age and the age of onset.
The prevalence of OCS and OCD in our sample were 29.2% (N ¼19) and 13.8% (N ¼ 9), respectively. The subgroups of patients with schizophrenia and comorbid OCD, with schizophrenia and OCS and schizophrenia alone did not differ in baseline characteristics except for CDSS score (Table 1). Of the total sample, 9 (13.8%) had at least one suicide attempt while treated with clozapine. Suicidal attempters and non-attempters did not differ in gender, age, age of onset, clozapine dosage, duration of illness, CDSS score and SSRI use. The attempters were more likely to have more hospitalizations and a higher Y-BOCS total score (Table 2). The correlation analysis in the total sample showed that there were significant positive correlations between suicidality (MOODS-SR score) and total (r¼ 0.513, po 0.01), obsession (r ¼0.444, p o0.01) and compulsion subscale scores of Y-BOCS (r ¼0.433, p o0.01). Also, we found significant correlations between Y-BOCS score and depressive symptoms (r ¼0.389, po 0.01). Finally, we found a trend for higher Y-BOCS score in patients with higher clozapine dosage (r ¼0.192, p ¼0.08). After Bonferroni adjustement for multiple comparisons, all p remained significant. To determine which variables independently conferred a risk for suicide attempt, a forward logistic regression was conducted. Variables included in the regression analysis were selected since they proved to be significant in Table 2. Those variables were the number of hospitalizations and a Y-BOCS score greater or equal to 8, while the presence of absence of suicide attempt was used as the dependent variable. The analysis indicated that Y-BOCS 48 (B ¼2.24, S.E ¼1.14, Wald ¼3.87, df ¼1, OR¼ 9.38, p ¼0.04) was a significant independent predictor of suicide attempts (Table 3.)
2.2.6. Clozapine dosage and concomitant medications Clozapine dosage as well as medications other than clozapine was assessed through pharmacy data according to the last prescription received by the patient. 2.3. Data analysis Data were analyzed using the Statistical Package for Social Scientists, version 17.0 (SPSS, Chicago, IL). We performed chisquare test with Fisher's exact test when appropriate for categorical variables (gender, SSRI use, benzodiazepines use, OCD diagnosis and suicidal attempt during clozapine treatment) and Kruskal Wallis or Mann Whitney's U Test when appropriate for quantitative variables (age, duration of illness, number of hospitalizations, age of onset, clozapine dosage, Y-BOCS score, CDSS score and suicidality score) to compare individuals with OCSschizophrenia, with OCD- schizophrenia and non-OCS schizophrenia, and between the suicide attempters with non attempters. Spearman's correlation was used to assess the relationship between several clinical variables such as age, duration of illness, number of hospitalization, clozapine dosage, Y BOCS score, CDSS score, and the suicidality score. Multiple comparisons were corrected by Bonferroni adjustement. In order to exclude the effect of baseline severity on the obtained data, we performed a forward stepwise logistic regression analysis using as covariates, those variables found to be significantly different between suicide attempters and non-attempters. In this analysis, the presence or absence of suicide attempts since initiation of clozapine therapy was considered the dependent variable, while a Y-BOCS score greater than 8 and number of hospitalizations where the independent ones, in order to obtain a crude and adjusted odds
3. Results
4. Discussion In this study we examined the relationship between OC symptomatology and suicidality in clozapine-medicated patients with schizophrenia. To assess this matter we evaluated a sample of clozapine-medicated patients with schizophrenia using structured interviews, taking into account OC symptomatology and suicidality that emerged after clozapine initiation. If OCS were present before clozapine initiation, the patient was excluded from the analysis. Suicidal events that occurred prior to clozapine initiation
Table 1 Baseline characteristics of schizophrenic patients without OCS, with OCS and with OCD. Baseline Covariates
Without OCS (N ¼37)
OCS (N ¼19)
OCD (N ¼9)
X2; dF; p1
Age (years) (median, IQR) Male (%) Age of Onset (years) (median, IQR) Clozapine dosage (mg) (median, IQR) Duration of illness (years) (median, IQR) Calgary Score (median, IQR)
32 [22.5–39] 40.5 21 [17–25.5] 400 [300–500] 8 [4–15] 1 [0–4]
27 [24–37] 52.6 19 [16–24] 400 [300–500] 9 [5–12] 3 [1–5]
37 [32.5–41.5] 44.4 21[18–26] 575 [300–800] 18 [9.5–20] 6 [2–11]
Suicidality Score (median, IQR)
0 [0–0]
1 [0–4]
2 [1.5–3.5]
Number of hospitalizations (median, IQR) SSRI use (%) Suicidal attempt (%)
2 [1–3] 10.8 2.7
3 [1–7] 21.1 31.6
3 [3–5] 22.2 22.2
4.64; 2; 0.09 0.74; 2; 0.70 0.76; 2; 0.69 5.45; 2; 0.66 4.86; 2; 0.88 12.22; 2; o 0.01* 24.95; 2; o 0.01* 6.11; 2; 0.04 1.39; 2; 0.50 9.39; 2; o 0.01*
Abbreviations: SSRI (Selective Serotonin reuptake inhibitors). *
Significant after multiple comparison adjustment. Non-normal distributed variables are expressed in median and interquartile range (IQR, 25th–75th percentile). Medians are compared with Kruskal–Wallis test and dichotomous variables with the Pearson chi square test. 1
Please cite this article as: Szmulewicz, A.G., et al., Suicidality in clozapine-treated patients with schizophrenia: Role of obsessivecompulsive symptoms. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.07.089i
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Table 2 Baseline characteristics of schizophrenic patients without suicidal attempts and with suicidal attempts. Baseline covariates
Without suicidal attempt (N¼ 56)
With suicidal attempt (N¼ 9)
Z or X2; p1
Age (years) (median, IQR) Male (%) Age of Onset (years)(median, IQR) Clozapine dosage (mg) (median, IQR) Duration of illness (years) (median, IQR) Calgary Score (median, IQR) Y-BOCS Score (median, IQR) Number of hospitalizations (median, IQR) SSRI use (%)
31.5 [24–38.75] 44.6 20 [18–25]
34 [22.5–39.5] 44.4 19 [15–26]
0.05; 0.97 0.00; 1.00 0.67; 0.51
400 [300–500]
300 [250–425]
0.53; 0.61
9 [4–15]
9 [6.5–14.5]
0.48; 0.64
2 [0–4.75] 0 [0–10] 2 [1–3.75]
6 [1.5–8] 11 [8–14] 6 [3–8]
1.94; 0.05 2.04; 0.04* 2.87; o 0.01*
16.1
11.1
0.15; 0.70
Abbreviations: SSRI (Selective Serotonin Reuptake inhibitors) Non-normal distributed variables are expressed in median and interquartile range (IQR, 25th–75th percentile). *
Significant at p o 0,05. Medians are compared with Mann Whitney's U test and dichotomous variables with the Fisher exact test. 1
Table 3 Crude and adjusted hazard ratio (HR) for the occurrence of suicidal attempts. Candidate covariate Crude HR (95% CI) p1
Adjusted HR (95% CI)
p2
Number of hospitalizations
o 0.01*
1.51 (1.07– 2.14)
0.02* Y-BOCS4 8
1.64 (1.19–2.27)
14.4 (1.68–123.56)
0.01* 9.38 (1.01–87.26)
0.04*
*
Significant at p o 0,05. P value based on a univariate Cox regression model. P value based on a Cox regression model including number of hospitalizations and a Y-BOCS score greater or equal than 8. 1 2
were excluded as well. To be included in the study patients should be on treatment with clozapine for 18 weeks or longer. These criteria were applied to raise the likelihood that OC symptoms onset, suicidal events and clozapine initiation were associated events. As described by Schirmbeck and Zink (2013), the development of OCS after initiation of clozapine suggests that pharmacodynamic mechanisms might be involved, being OCS a pharmacological adverse event. Additionally, we used a validated scale for assessing the level of depression in schizophrenia to examine the relationship between OCS and depressive symptoms. We found that de-novo OC symptomatology is highly prevalent in clozapine-medicated patients with schizophrenia. The prevalence of de-novo OCS was 29.2% (N ¼ 19) and the prevalence of de-novo OCD was 13.8% (N ¼ 9). These results are in line with previous reports (Owashi et al., 2010; Achim et al., 2011; Swets et al., 2014). Most studies have broadly examined clozapine-induced OCS without distinguishing between rates of de-novo versus exacerbated OCS. This study provides a new insight in this area. Subtype analyses of previous studies suggested that clozapine treatment can induce de-novo onset of OCS at a rate of 20– 28% (Lin et al., 2006; Ertugrul et al., 2005; Lim et al., 2007). These findings also suggest that clozapine can induce full threshold OCD, although less frequently. De Haan et al. (2004) reported that 9.8% of clozapine-treated patients developed de-novo OCD. Overall, the comparable de-novo OCS/OCD rates across studies indicate that this outcome is relatively stable across samples. This is in contrast
to variable rates of OCS exacerbation, which may indicate that this outcome is a consequence of other treatment parameters, such as duration or dose (Fonseka et al., 2014). Regarding the recognition and treatment of OCS/OCD, only about 20% of our patients identified by means of Y-BOCS interview as having OCS/OCD were receiving SSRI treatment by their clinicians. This observation suggests that clinicians usually neglect this condition. Regarding this issue, heterogeneous findings are reported. Cosoff and Haffner (1998) stated that “almost none of those with anxiety disorders were [recognized or] being treated for them” in a sample of patients with schizophrenia/schizoaffective disorder or bipolar disorder with psychotic features. Owashi et al. (2010) in a sample of 92 inpatients with chronic reported that only 25% of OCD comorbid patients received treatment with anxiolytic drugs while only 14.7% of schizophrenic patients with OCS received treatment. Mukhopadhaya et al. (2009) reported that, in sample of 59 clozapine-treated patients with schizophrenia and schizoaffective disorder, 24% had a concomitant OCD diagnosis. Of those, only 50% were recognized and treated for this condition. On the other hand, Braga et al. (2005) reported that 72.3% of their patient’s sample with schizophrenia and comorbid anxiety disorders was receiving treatment with anxiolytic drugs. This figure is higher than those reported above, probably because it included benzodiazepines as an anti-anxiety drugs in patients with any comorbid anxiety disorder and benzodiazepines prescription is rather frequent in patients with schizophrenia. Although treatment with SSRI is not the only therapeutic approach for this condition, it leads us to conclude that these symptoms were not as detected as they should. In our study, clozapine-medicated patients with schizophrenia and OC symptomatology differed from those without OC symptomatology in terms of suicidality and number of hospitalizations. In the correlation analysis, there were significant associations between the total, compulsion and obsession subscale scores of Y-BOCS and the suicidality score. These subgroups of patients also differed in terms of depressive symptomatology. Significant association between the Y-BOCS total score and the CDSS score was found as well. This finding has been consistently reported in literature (de Haan et al., 2005, 2013; Hagen et al., 2013). Also, we found a trend towards higher Y-BOCS score in patients with higher clozapine dosage. A key finding in our sample was that OC symptomatology was an independent predictor of suicidal attempts. Some studies have found a reduction in suicidality in patients with schizophrenia taking clozapine (Meltzer et al., 2003; Tiihonen et al., 2009). Despite some limitations, the results of the present study suggest that this beneficial effect may be less clinically relevant in the subgroup of patients that experience OCS as an adverse event. Moreover, the fact that almost all patients with suicidal attempts experienced clinically significant OCS (8 out of 9) reflects the severity of this adverse event given the relationship between attempts and completed suicides. These results lead us to conclude that patients with clozapine should be routinely screened for this adverse event. There are some limitations of the study design. First, the study sample is relatively small. Although we have screened the totality of clozapine-medicated patients with schizophrenia in a major neuropsychiatric hospital, this could have reduced the power of the analysis performed. Second, given that the study was not design in a prospective method, we are not able to confirm the causality of the results presented. We addressed this issue by asking the patient to respond on suicidality and OCS after the initiation of clozapine treatment but this may be affected by a recall bias. Our reliance on patient interview to assess initiation of OCS is a limitation. We reduced this bias by checking suicidal behavior and onset of OCS with the patient chart but this was not always
Please cite this article as: Szmulewicz, A.G., et al., Suicidality in clozapine-treated patients with schizophrenia: Role of obsessivecompulsive symptoms. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.07.089i
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available. Also, suicide attempts were assessed retrospectively while OCS and OCD were evaluated in a cross-sectional manner. Finally, we must note that the fact that informed consent was obtained may have inadvertently introduced a selection bias against anxious respondents, although this limitation would have been common to all such studies. Additional research, including replication of the current results and a prospective study in a larger study group, is required to provide a definitive answer to the question of whether OCS in schizophrenia are associated with suicidal behavior.
Funding body agreements and policies None
Author's contributions AGS, MPV and JMS contributed to and approved the submitted draft of the paper. All authors read and approved the final manuscript.
Competing interests The authors declare that they have no competing interests.
Acknowledgments None
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Suicidality in clozapine-treated patients with schizophrenia: Role of obsessive-compulsive symptoms Alejandro G. Szmulewicz n, José M. Smith, Marina P. Valerio Hospital de Emergencias Psiquiátricas Torcuato de Alvear, Av Warnes 2630, Capital Federal, Argentina
art ic l e i nf o
a b s t r a c t
Article history: Received 17 March 2015 Received in revised form 9 June 2015 Accepted 30 July 2015
Patients with schizophrenia have an increased lifetime risk of comorbid obsessive-compulsive symptoms. Up to 30% of these patients experience such symptoms and 12% may be diagnosed with obsessivecompulsive disorder. The presence of these symptoms in schizophrenia seems to be associated with poor outcomes including a greater suicidal risk. A subgroup of patients develops this symptomatology after the initiation with Second Generation Antipsychotics (SGA). Also, there is evidence of a causal relationship for this association, particularly for clozapine. The primary aim of this study was to investigate the association of this comorbidity with suicidality in a population of clozapine-medicated schizophrenic and schizoaffective patients (N¼ 65). The prevalence of obsessive-compulsive symptoms in our sample was 29.2% (N ¼19) and the prevalence of obsessive-compulsive disorder was 13.8% (N¼ 9). Significant positive correlations between suicidality and total Y-BOCS score and between Y- BOCS score and depressive symptoms were found. Further analysis indicated that a Y-BOCS score greater or equal than 8 was an independent predictor of suicide attempt during clozapine treatment. Routine screening for this adverse event should be warranted for this population. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Obsessive-compulsive disorder Schizophrenia Clozapine Schizo-OCD-Suicide Suicide attempt
1. Introduction Patients with schizophrenia have an increased lifetime risk of comorbid obsessive-compulsive symptoms (OCS). These are characterized by obsessive, distressing, intrusive thoughts and related compulsions (Poyurovsky et al., 2004). Up to 30% of these patients experience OCS and up to 12% may be diagnosed with obsessivecompulsive disorder (OCD) (Swets et al., 2014). Since the prevalence of OCD in the general population has been reported to be 1.6% (Kessler et al., 2005) obsessive-compulsive symptomatology appears more often in schizophrenia than expected. Furthermore, recent large cohort studies reported that OCD patients carry an increased risk for schizophrenia spectrum disorders (Cederlöf et al., 2014; Meier et al., 2014). Whereas some patients experience OCS onset simultaneously with psychosis onset, others experience OCS onset after the initiation of Second Generation Antipsychotics (SGA) being prevalence rates in later disease stages significantly higher than in the early course of psychotic illness (De Haan, 2015). A recent study found that 13% of at-risk mental state patients reported OCS, while 5.4% fulfilled the criteria for OCD. Slightly higher averaged rates for OCS (17.1%) and OCD (7%) were found in first-episode patients n
Corresponding author. E-mail address: [email protected] (A.G. Szmulewicz).
(Zink et al., 2014). These rates are significantly lower than that descripted in cross sectional studies of chronic or late stage, as described above. Additionally, there has been an increase in the prevalence and in the study of this subject over the last 20 years that overlaps with the appearance of SGA in the market (Bleakley et al., 2011). A review of case reports (Lykouras et al., 2003) describes over 55 cases of de novo development or exacerbation of OCS during treatment with clozapine (30 cases), olanzapine (8 cases), risperidone (16 cases) and quetiapine (1 case). A comparison of schizophrenia patients under antipsychotic monotherapy with either mainly antiserotonergic SGAs (CLZ or OLZ; group I) or mainly dopaminergic SGAs (AMS or APZ; group II) revealed that more than 70% of group-I-patients suffered from OCS while less than 10% of patients in group-II reported OCS (Schirmbeck et al., 2011). Another study reported a prevalence of 28.4% of clozapine-induced OCS in a sample of one hundred and two patients with schizophrenia (Lin et al., 2006). Additionally, there is evidence of a causal relationship between OC symptomatology and treatment with SGA, particularly clozapine. This comes from retrospective cohort studies (Mahendran et al., 2007) and prospective ones (Schirmbeck et al., 2013a). Furthermore, a dose-response pattern (Lin et al., 2006; Schirmbeck et al., 2011) and an association between duration of clozapine treatment and OCS severity (Schirmbeck et al., 2011) have been described. This pharmacological argument based on correlations between OCS severity and
http://dx.doi.org/10.1016/j.psychres.2015.07.089 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Szmulewicz, A.G., et al., Suicidality in clozapine-treated patients with schizophrenia: Role of obsessivecompulsive symptoms. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.07.089i
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dosage as well as duration of clozapine application indicate a causal interaction and suggest OCS induction as a side effect of clozapine treatment (Scheltema Beduin et al., 2012). Atypical antipsychotics achieve their effects through preferential occupancy of 5HT2 receptors over D2 (Kapur et al., 1998;1999; 2006). This profile of antiserotoninergic properties is thought to be the cause of the OC symptomatology. Three lines of evidence supports this: first, SSRI drugs alleviate SGA induced OCS (Dodt et al., 1997; Rahman et al., 1998), second, first generation antipsychotics do not cause and even improve OCS (Keuneman et al., 2005) and finally, the disinhibition of the dopaminergic neurotransmission caused by the blockade of 5HT2a receptors is thought to activate the circuits involved in the OC symptomatology as explained by the antiobsessive effects of others SGA characterized by a more antidopaminergic effect (Schirmbeck et al., 2011; 2013a; Schirmbeck and Zink, 2012, 2013). The presence of OCS in schizophrenia seems to be associated with poor outcomes such as earlier age of onset (Faragian et al., 2012), poorer treatment response (Zink et al., 2014), more depressive (de Haan et al., 2013) and negative symptoms (Owashi et al., 2010) and greater cognitive deficits (Patel et al., 2010; Schirmbeck et al., 2013b). It remains unknown whether treatment for the OCS reverts these outcomes. Recent studies suggest that OCD and OCS are associated with a greater suicidal risk in patients with schizophrenia. OCD-schizophrenia comorbid patients are more likely to have a previous history of suicidal ideation and attempts. Also, OCS severity is associated with suicidality in adolescents at ultra-high risk for psychosis (Niendam et al., 2009; Sevincok et al., 2007). There are some controversies regarding the prevalence of this outcome in schizophrenia. While some authors estimated that 10% of persons with schizophrenia will die from suicide (Miles, 1977) other longer-term follow up studies found lower figures. For instance, Inskip et al. (1998) estimated lifetime risk to be 4% for schizophrenia and Palmer et al. (2005) 5.6%. Either way, deliberate self-harm or previous suicidal attempts increase the risk approximately two fold (Nordentoft et al., 2011). Therefore, suicide attempt should be considered a very important risk factor among patients with schizophrenia and other mental disorders, as underlined by the recent findings in a large Swedish cohort study (Runeson et al., 2010). Suicidality is a continuum phenomenon and the probability of making an attempt in a patient with suicidal plans is around 50% (Scocco et al., 2008) and with suicidal ideation 32.3% (Lee et al., 2012). This underlines the importance of the study of non-fatal aspects of suicidality in order to prevent death by suicide. There is some evidence suggesting that clozapine may have a beneficial effect on suicidality (Meltzer et al., 2003; Thomas et al., 2015; Ringbäck et al., 2014) and even treatment algorithms suggest its use in patients with schizophrenia with associated suicidality (Moore et al., 2007). In addition, this antipsychotic embarks important protective effects against suicidal behavior resulting in lower overall mortality of schizophrenics as documented in the large, naturalistic FIN11-study (Tiihonen et al., 2009). In general, OCS are neglected by clinicians when comorbid with an acute or chronic psychotic illness. The primary aim of this study was to investigate the association of this comorbidity with suicidality in a population of clozapine-medicated schizophrenic and schizoaffective patients.
2. Methods 2.1. Subjects The study sample was recruited from the totality of clozapine-
medicated patients in the Hospital de Emergencias Psiquiátricas Torcuato de Alvear by September 2014 (N ¼98). Data was obtained from pharmacy and pharmacovigilance program databases. Patients were screened for participation in the present study from September 2014 to January 2015. Inclusion criteria were: age 18 years or older; DSM-IV diagnosis of schizophrenia or schizoaffective disorder based on the Mini International Neuropsychiatric Interview (MINI); being on treatment with clozapine for 18 weeks or longer. The exclusion criteria were: OCS or OCD previous to clozapine treatment, history of mental retardation, neurological diseases and inability to participate due to severe psychotic symptoms or deafness. Of the initial 98 subjects, 65 were recruited for the study. The 33-nonincluded subjects either did not met inclusion criteria or met exclusion criteria or refused to participate. 8 patients refuse to provide written consent, 5 patients were under 18 years old, 8 patients presented previous history of OCS/OCD and 5 patients did not meet DSM-IV criteria for a diagnosis of schizophrenia or schizoaffective disorder, 2 patients were mentally retarded, 3 patients were unable to participate due to acute psychotic symptoms, 1 patient was excluded due to neurologic disease and 1 patient was deaf. The Ethics Committee of the Hospital de Emergencias Psiquiátricas Torcuato de Alvear approved recruitment and assessment procedures. All included subjects provided written informed consent after receiving a complete description of the study. 2.2. Assessment Interviews were conducted by physicians in a quiet testing room according to a standardized order. The total procedure was done in an interview of 1–2 h with one or two breaks to avoid fatigue. Interviewers were trained and unaware of patient's previous history. 2.2.1. Diagnosis Diagnoses were confirmed using the MINI-International Neuropsychiatric Interview (Sheehan et al., 1998). 2.2.2. Obsessive-compulsive symptomatology Subjects were evaluated with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in order to measure the severity of OCS. This scale is considered suitable for assessing OCS in schizophrenia (de Haan et al., 2006; Boyette et al., 2011). A cut-off score of 8 was established to determine the presence of OCS as previously used by Schirmbeck et al. (2011; 2013a). In addition, the corresponding section of the MINI was used to assess the presence of OCD. Subjects were asked to respond for symptoms that appeared after the initiation of clozapine treatment. Patients who reported symptoms onset prior to clozapine initiation were excluded from the analysis. 2.2.3. Depressive symptoms Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1994) was used to identify the presence of depressive symptoms. 2.2.4. Suicidality assessment Suicidality during clozapine treatment was assessed using the items 102–107 of the Mood Spectrum Self-Report (MOODS-SR) Spanish Version. This scale evaluates whether the subject has ever experienced a period of 3–5 days or more when he or she: (1) felt like life was not worth living; (2) hoped to die; (3) wanted to die; (4) made suicide plans, and two questions asking; (5) whether he/ she actually made a suicide attempt and (6) whether medical attention was required following the attempt.
Please cite this article as: Szmulewicz, A.G., et al., Suicidality in clozapine-treated patients with schizophrenia: Role of obsessivecompulsive symptoms. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.07.089i
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If more than one item was answered affirmatively, the most severe item was taken into account. The patient was asked to respond only for events occurred after clozapine initiation. Answers were checked with the patient charts. Patients who reported suicidality prior to clozapine initiation were excluded from the analysis.
ratios. The odds ratios and confidence intervals for the independent variables were derived. The level of statistical significance was defined as an alpha less than 0.05.
2.2.5. Severity Severity was assessed by the number of hospitalizations (as recorded in the patient medical records), the age of onset and the duration of illness. These parameters were chosen because they are stable, reliable and objective markers of illness severity. The age of onset was established as the age when the patient first met DSM-IV TR criteria for schizophrenia or schizoaffective disorder and the duration of illness was recorded as the difference between patient's age and the age of onset.
The prevalence of OCS and OCD in our sample were 29.2% (N ¼19) and 13.8% (N ¼ 9), respectively. The subgroups of patients with schizophrenia and comorbid OCD, with schizophrenia and OCS and schizophrenia alone did not differ in baseline characteristics except for CDSS score (Table 1). Of the total sample, 9 (13.8%) had at least one suicide attempt while treated with clozapine. Suicidal attempters and non-attempters did not differ in gender, age, age of onset, clozapine dosage, duration of illness, CDSS score and SSRI use. The attempters were more likely to have more hospitalizations and a higher Y-BOCS total score (Table 2). The correlation analysis in the total sample showed that there were significant positive correlations between suicidality (MOODS-SR score) and total (r¼ 0.513, po 0.01), obsession (r ¼0.444, p o0.01) and compulsion subscale scores of Y-BOCS (r ¼0.433, p o0.01). Also, we found significant correlations between Y-BOCS score and depressive symptoms (r ¼0.389, po 0.01). Finally, we found a trend for higher Y-BOCS score in patients with higher clozapine dosage (r ¼0.192, p ¼0.08). After Bonferroni adjustement for multiple comparisons, all p remained significant. To determine which variables independently conferred a risk for suicide attempt, a forward logistic regression was conducted. Variables included in the regression analysis were selected since they proved to be significant in Table 2. Those variables were the number of hospitalizations and a Y-BOCS score greater or equal to 8, while the presence of absence of suicide attempt was used as the dependent variable. The analysis indicated that Y-BOCS 48 (B ¼2.24, S.E ¼1.14, Wald ¼3.87, df ¼1, OR¼ 9.38, p ¼0.04) was a significant independent predictor of suicide attempts (Table 3.)
2.2.6. Clozapine dosage and concomitant medications Clozapine dosage as well as medications other than clozapine was assessed through pharmacy data according to the last prescription received by the patient. 2.3. Data analysis Data were analyzed using the Statistical Package for Social Scientists, version 17.0 (SPSS, Chicago, IL). We performed chisquare test with Fisher's exact test when appropriate for categorical variables (gender, SSRI use, benzodiazepines use, OCD diagnosis and suicidal attempt during clozapine treatment) and Kruskal Wallis or Mann Whitney's U Test when appropriate for quantitative variables (age, duration of illness, number of hospitalizations, age of onset, clozapine dosage, Y-BOCS score, CDSS score and suicidality score) to compare individuals with OCSschizophrenia, with OCD- schizophrenia and non-OCS schizophrenia, and between the suicide attempters with non attempters. Spearman's correlation was used to assess the relationship between several clinical variables such as age, duration of illness, number of hospitalization, clozapine dosage, Y BOCS score, CDSS score, and the suicidality score. Multiple comparisons were corrected by Bonferroni adjustement. In order to exclude the effect of baseline severity on the obtained data, we performed a forward stepwise logistic regression analysis using as covariates, those variables found to be significantly different between suicide attempters and non-attempters. In this analysis, the presence or absence of suicide attempts since initiation of clozapine therapy was considered the dependent variable, while a Y-BOCS score greater than 8 and number of hospitalizations where the independent ones, in order to obtain a crude and adjusted odds
3. Results
4. Discussion In this study we examined the relationship between OC symptomatology and suicidality in clozapine-medicated patients with schizophrenia. To assess this matter we evaluated a sample of clozapine-medicated patients with schizophrenia using structured interviews, taking into account OC symptomatology and suicidality that emerged after clozapine initiation. If OCS were present before clozapine initiation, the patient was excluded from the analysis. Suicidal events that occurred prior to clozapine initiation
Table 1 Baseline characteristics of schizophrenic patients without OCS, with OCS and with OCD. Baseline Covariates
Without OCS (N ¼37)
OCS (N ¼19)
OCD (N ¼9)
X2; dF; p1
Age (years) (median, IQR) Male (%) Age of Onset (years) (median, IQR) Clozapine dosage (mg) (median, IQR) Duration of illness (years) (median, IQR) Calgary Score (median, IQR)
32 [22.5–39] 40.5 21 [17–25.5] 400 [300–500] 8 [4–15] 1 [0–4]
27 [24–37] 52.6 19 [16–24] 400 [300–500] 9 [5–12] 3 [1–5]
37 [32.5–41.5] 44.4 21[18–26] 575 [300–800] 18 [9.5–20] 6 [2–11]
Suicidality Score (median, IQR)
0 [0–0]
1 [0–4]
2 [1.5–3.5]
Number of hospitalizations (median, IQR) SSRI use (%) Suicidal attempt (%)
2 [1–3] 10.8 2.7
3 [1–7] 21.1 31.6
3 [3–5] 22.2 22.2
4.64; 2; 0.09 0.74; 2; 0.70 0.76; 2; 0.69 5.45; 2; 0.66 4.86; 2; 0.88 12.22; 2; o 0.01* 24.95; 2; o 0.01* 6.11; 2; 0.04 1.39; 2; 0.50 9.39; 2; o 0.01*
Abbreviations: SSRI (Selective Serotonin reuptake inhibitors). *
Significant after multiple comparison adjustment. Non-normal distributed variables are expressed in median and interquartile range (IQR, 25th–75th percentile). Medians are compared with Kruskal–Wallis test and dichotomous variables with the Pearson chi square test. 1
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Table 2 Baseline characteristics of schizophrenic patients without suicidal attempts and with suicidal attempts. Baseline covariates
Without suicidal attempt (N¼ 56)
With suicidal attempt (N¼ 9)
Z or X2; p1
Age (years) (median, IQR) Male (%) Age of Onset (years)(median, IQR) Clozapine dosage (mg) (median, IQR) Duration of illness (years) (median, IQR) Calgary Score (median, IQR) Y-BOCS Score (median, IQR) Number of hospitalizations (median, IQR) SSRI use (%)
31.5 [24–38.75] 44.6 20 [18–25]
34 [22.5–39.5] 44.4 19 [15–26]
0.05; 0.97 0.00; 1.00 0.67; 0.51
400 [300–500]
300 [250–425]
0.53; 0.61
9 [4–15]
9 [6.5–14.5]
0.48; 0.64
2 [0–4.75] 0 [0–10] 2 [1–3.75]
6 [1.5–8] 11 [8–14] 6 [3–8]
1.94; 0.05 2.04; 0.04* 2.87; o 0.01*
16.1
11.1
0.15; 0.70
Abbreviations: SSRI (Selective Serotonin Reuptake inhibitors) Non-normal distributed variables are expressed in median and interquartile range (IQR, 25th–75th percentile). *
Significant at p o 0,05. Medians are compared with Mann Whitney's U test and dichotomous variables with the Fisher exact test. 1
Table 3 Crude and adjusted hazard ratio (HR) for the occurrence of suicidal attempts. Candidate covariate Crude HR (95% CI) p1
Adjusted HR (95% CI)
p2
Number of hospitalizations
o 0.01*
1.51 (1.07– 2.14)
0.02* Y-BOCS4 8
1.64 (1.19–2.27)
14.4 (1.68–123.56)
0.01* 9.38 (1.01–87.26)
0.04*
*
Significant at p o 0,05. P value based on a univariate Cox regression model. P value based on a Cox regression model including number of hospitalizations and a Y-BOCS score greater or equal than 8. 1 2
were excluded as well. To be included in the study patients should be on treatment with clozapine for 18 weeks or longer. These criteria were applied to raise the likelihood that OC symptoms onset, suicidal events and clozapine initiation were associated events. As described by Schirmbeck and Zink (2013), the development of OCS after initiation of clozapine suggests that pharmacodynamic mechanisms might be involved, being OCS a pharmacological adverse event. Additionally, we used a validated scale for assessing the level of depression in schizophrenia to examine the relationship between OCS and depressive symptoms. We found that de-novo OC symptomatology is highly prevalent in clozapine-medicated patients with schizophrenia. The prevalence of de-novo OCS was 29.2% (N ¼ 19) and the prevalence of de-novo OCD was 13.8% (N ¼ 9). These results are in line with previous reports (Owashi et al., 2010; Achim et al., 2011; Swets et al., 2014). Most studies have broadly examined clozapine-induced OCS without distinguishing between rates of de-novo versus exacerbated OCS. This study provides a new insight in this area. Subtype analyses of previous studies suggested that clozapine treatment can induce de-novo onset of OCS at a rate of 20– 28% (Lin et al., 2006; Ertugrul et al., 2005; Lim et al., 2007). These findings also suggest that clozapine can induce full threshold OCD, although less frequently. De Haan et al. (2004) reported that 9.8% of clozapine-treated patients developed de-novo OCD. Overall, the comparable de-novo OCS/OCD rates across studies indicate that this outcome is relatively stable across samples. This is in contrast
to variable rates of OCS exacerbation, which may indicate that this outcome is a consequence of other treatment parameters, such as duration or dose (Fonseka et al., 2014). Regarding the recognition and treatment of OCS/OCD, only about 20% of our patients identified by means of Y-BOCS interview as having OCS/OCD were receiving SSRI treatment by their clinicians. This observation suggests that clinicians usually neglect this condition. Regarding this issue, heterogeneous findings are reported. Cosoff and Haffner (1998) stated that “almost none of those with anxiety disorders were [recognized or] being treated for them” in a sample of patients with schizophrenia/schizoaffective disorder or bipolar disorder with psychotic features. Owashi et al. (2010) in a sample of 92 inpatients with chronic reported that only 25% of OCD comorbid patients received treatment with anxiolytic drugs while only 14.7% of schizophrenic patients with OCS received treatment. Mukhopadhaya et al. (2009) reported that, in sample of 59 clozapine-treated patients with schizophrenia and schizoaffective disorder, 24% had a concomitant OCD diagnosis. Of those, only 50% were recognized and treated for this condition. On the other hand, Braga et al. (2005) reported that 72.3% of their patient’s sample with schizophrenia and comorbid anxiety disorders was receiving treatment with anxiolytic drugs. This figure is higher than those reported above, probably because it included benzodiazepines as an anti-anxiety drugs in patients with any comorbid anxiety disorder and benzodiazepines prescription is rather frequent in patients with schizophrenia. Although treatment with SSRI is not the only therapeutic approach for this condition, it leads us to conclude that these symptoms were not as detected as they should. In our study, clozapine-medicated patients with schizophrenia and OC symptomatology differed from those without OC symptomatology in terms of suicidality and number of hospitalizations. In the correlation analysis, there were significant associations between the total, compulsion and obsession subscale scores of Y-BOCS and the suicidality score. These subgroups of patients also differed in terms of depressive symptomatology. Significant association between the Y-BOCS total score and the CDSS score was found as well. This finding has been consistently reported in literature (de Haan et al., 2005, 2013; Hagen et al., 2013). Also, we found a trend towards higher Y-BOCS score in patients with higher clozapine dosage. A key finding in our sample was that OC symptomatology was an independent predictor of suicidal attempts. Some studies have found a reduction in suicidality in patients with schizophrenia taking clozapine (Meltzer et al., 2003; Tiihonen et al., 2009). Despite some limitations, the results of the present study suggest that this beneficial effect may be less clinically relevant in the subgroup of patients that experience OCS as an adverse event. Moreover, the fact that almost all patients with suicidal attempts experienced clinically significant OCS (8 out of 9) reflects the severity of this adverse event given the relationship between attempts and completed suicides. These results lead us to conclude that patients with clozapine should be routinely screened for this adverse event. There are some limitations of the study design. First, the study sample is relatively small. Although we have screened the totality of clozapine-medicated patients with schizophrenia in a major neuropsychiatric hospital, this could have reduced the power of the analysis performed. Second, given that the study was not design in a prospective method, we are not able to confirm the causality of the results presented. We addressed this issue by asking the patient to respond on suicidality and OCS after the initiation of clozapine treatment but this may be affected by a recall bias. Our reliance on patient interview to assess initiation of OCS is a limitation. We reduced this bias by checking suicidal behavior and onset of OCS with the patient chart but this was not always
Please cite this article as: Szmulewicz, A.G., et al., Suicidality in clozapine-treated patients with schizophrenia: Role of obsessivecompulsive symptoms. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.07.089i
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available. Also, suicide attempts were assessed retrospectively while OCS and OCD were evaluated in a cross-sectional manner. Finally, we must note that the fact that informed consent was obtained may have inadvertently introduced a selection bias against anxious respondents, although this limitation would have been common to all such studies. Additional research, including replication of the current results and a prospective study in a larger study group, is required to provide a definitive answer to the question of whether OCS in schizophrenia are associated with suicidal behavior.
Funding body agreements and policies None
Author's contributions AGS, MPV and JMS contributed to and approved the submitted draft of the paper. All authors read and approved the final manuscript.
Competing interests The authors declare that they have no competing interests.
Acknowledgments None
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Please cite this article as: Szmulewicz, A.G., et al., Suicidality in clozapine-treated patients with schizophrenia: Role of obsessivecompulsive symptoms. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.07.089i