Progress in Neuro-Psychopharmacology & Biological Psychiatry

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1 Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: Obsessive compulsive disorder with poor insight: A three-year prospective study Francesco Catapano, Francesco Perris, Michele Fabrazzo, Valeria Cioffi, Domenico Giacco, Valeria De Santis, Mario Maj Department of Psychiatry, University of Naples SUN, Largo Madonna delle Grazie, I Naples, Italy article info abstract Article history: Received 14 September 2009 Received in revised form 27 November 2009 Accepted 9 December 2009 Available online 16 December 2009 Keywords: Insight Long-term outcome Obsessive compulsive disorder Serotonin reuptake inhibitors Available evidence about the relationship between poor insight and other clinical characteristics in patients with obsessive compulsive disorder (OCD) is inconclusive and conflicting. There is also a paucity of data on the long-term course and treatment outcome of OCD patients with poor insight. The present study reports the findings of a relatively large sample (n=106) of outpatients fulfilling DSM-IV criteria for OCD, treated with serotonin reuptake inhibitors (SRIs) and prospectively followed up for 3 years. Baseline information was collected on demographic and clinical characteristics, using standardized instruments. Insight was assessed by means of the Brown Assessment of Beliefs Scale (BABS). Eighty-three patients were followed prospectively and evaluated systematically by validated measures of psychopathology. Compared to their good insight counterparts, the OCD patients with poor insight (22%) showed a greater severity of obsessive compulsive and depressive symptomatology; an earlier age at onset; a higher rate of schizophrenia spectrum disorder in their first-degree relatives; a higher comorbidity with schizotypal personality disorder. During the follow-up period, poor insight OCD patients were less likely to achieve at least a partial remission of obsessive compulsive symptoms; required a significantly greater number of therapeutic trials; received more frequently augmentation with antipsychotics. The results suggest that the specifier poor insight helps to identify a subgroup of patients at the more severe end of OCD spectrum, characterized by a more complex clinical presentation, a diminished response to standard pharmacological interventions, and a poorer prognosis. Further research is needed to identify alternative strategies for the management of these patients Elsevier Inc. All rights reserved. 1. Introduction Although standard classification systems such as DSM-IV and ICD-10 regard obsessive compulsive disorder (OCD) as a unitary nosological entity, there is an increasing evidence that this severe and potentially disabling condition is phenotypically heterogeneous (Lochner and Stein, 2003; Mathis et al., 2006). Delineation of homogeneous subgroups of OCD patients is a crucial step in the quest for identifying common pathophysiological mechanisms and developing specialized treatment approaches. Many different strategies have been used to define clinically meaningful subtypes of OCD, such as age at onset of obsessive compulsive symptoms (OC) (Rosario-Campos et al., 2001; Fontenelle et al., 2003; Maina et al., 2008), specific symptom profiles or dimensions (Mataix-Cols et al., 2004; Fontenelle et al., 2004; Leckman et al., 2007), comorbidity patterns (Nestadt et al., 2003; Poyurovsky and Koran, 2005; Abbreviations: BABS, Brown Assessment of Beliefs Scale; HDRS, Hamilton Rating Scale for Depression; OCD, obsessive compulsive disorder; SCID-I, Structured Clinical Interview for DSM-IV; SCID-II, Structured Clinical Interview for DSM-IV Axis II Personality Disorders; SRIs, serotonin reuptake inhibitors; Y-BOCS, Yale Brown Obsessive Compulsive Scale. Corresponding author. Tel.: ; fax: address: [email protected] (F. Catapano). Coles et al., 2007), and clinical course (Ravizza et al., 1997; Perugi et al., 1998). The DSM-IV includes a subtype of OCD called with poor insight for individuals who, for most of the time during the current episode, do not recognize that their symptoms are excessive or unreasonable. Several studies have reported that the rate of OCD patients with poor insight varies from 15 to 36% (Catapano et al., 2001; Matsunaga et al., 2002; Türksoy et al., 2002; Ravi Kishore et al., 2004; De Berardis et al., 2005; Alonso et al., 2007). Unfortunately, little systematic research has been conducted so far to evaluate the relationship between poor insight and other clinical characteristics in OCD patients. Poor insight has been associated with a greater severity of OC symptoms (Catapano et al., 2001; Matsunaga et al., 2002; Türksoy et al., 2002; Ravi Kishore et al., 2004; Bellino et al., 2005), a higher frequency of hoarding obsessions and compulsions (Matsunaga et al., 2002; Türksoy et al., 2002; De Berardis et al., 2005), an earlier age at onset (Matsunaga et al., 2002; Ravi Kishore et al., 2004), a longer duration of illness (Matsunaga et al., 2002; Ravi Kishore et al., 2004), a higher frequency of schizophrenia spectrum disorders in first-degree relatives (Catapano et al., 2001), a higher comorbidity rate, particularly major depression (Türksoy et al., 2002; Ravi Kishore et al., 2004) and schizotypal personality disorder (Matsunaga et al., 2002; Bellino et al., 2005; Alonso et al., 2007) /$ see front matter 2009 Elsevier Inc. All rights reserved. doi: /j.pnpbp

2 324 F. Catapano et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) However, other studies failed to find any correlation between levels of insight and specific clinical features (Eisen and Rasmussen, 1993; Eisen et al., 2001; Marazziti et al., 2002). These inconsistent findings may be in part attributed to varying ways of expressing and measuring the concept of insight. Earlier studies have used either clinician based ratings of bizarreness and fixity that do not have reliability or validity data (Lelliott et al., 1988), clinician ratings on five items designed for the DSM-IV field trail (Foa et al., 1995), or the item 11 of Yale Brown Obsessive Compulsive Scale (Catapano et al., 2001; Marazziti et al., 2002; Matsunaga et al., 2002; De Berardis et al., 2005). Only a few recent studies have addressed this issue using standardized instruments developed specifically to assess insight, such as the Brown Assessment of Beliefs Scale (BABS) or the Overvalued Ideas Scale (Eisen et al., 2001; Ravi Kishore et al., 2004; Bellino et al., 2005; Alonso et al., 2007). The available evidence is also inconclusive about the relationship between insight and treatment outcome in OCD patients. Several clinical studies reported that overvalued or tightly held obsessional beliefs reduced the effectiveness of behaviour therapy, which could reflect a lack of cognitive change in patients with poorer insight (Foa, 1979; Solyom et al., 1985). More recent investigations also found poor insight to be a negative predictor of treatment response following individual or group behavioural therapy (Foa et al., 1999; Himle et al., 2006). In apparent contrast to these findings, other authors found that OCD patients with poor insight did well with exposure, either alone (Lelliott and Marks, 1987) or in addition to cognitive therapy (Salkovskis, 1985). Moreover, overvalued ideation before treatment was not predictive of post-treatment and 1-year outcome in several large group investigations (Basoglu et al., 1988; Lelliott et al., 1988; Ito et al., 1995). Similarly, conflicting results have been reported on the relationship between poor insight and response to serotonin reuptake inhibitors (SRIs). Three studies found unsatisfactory response in poor insight OCD patients at both 12 weeks and 6 months after SRI treatment (Catapano et al., 2001; Erzegovesi et al., 2001; Ravi Kishore et al., 2004), but other studies did not find any association between baseline insight and response to pharmacological treatment (Eisen et al., 2001; Matsunaga et al., 2002; Alonso et al., 2007). Nevertheless, the SRI treatment of OCD patients with poor insight may sometimes lead to a shift to good insight in parallel with the concomitant improvement of OC and depressive symptom severity (Eisen et al., 2001; Matsunaga et al., 2002; Alonso et al., 2007). To our knowledge, no study has been undertaken which prospectively evaluates the long-term (i.e., more than 1 year) course and outcome of OCD patients with poor insight treated with standard pharmacological interventions, using valid and reliable instruments to assess insight as well as specific operational criteria of response to treatment. In this paper, we report data on a relatively large sample of outpatients fulfilling DSM-IV criteria for OCD prospectively followed up for 3 years. The aims of the present study were to evaluate: 1) the clinical and demographic correlates of poor insight in OCD patients, using a well-validated instrument to assess insight, the BABS; 2) the response of poor insight patients to long-term naturalistic treatment with SRIs. 2. Materials and methods 2.1. Subjects This study was carried out in patients consecutively recruited at the Department of Psychiatry of the University of Naples SUN, between 2002 and The study was reviewed by an appropriate ethical committee at the University of Naples SUN and performed according to the latest version of the Declaration of Helsinki. Written informed consent has been obtained from each participant after the procedure had been fully explained. A patient was included in the study if he/she met the following criteria: 1) a principal diagnosis of OCD according to DSM-IV criteria, confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) (First et al., 1996); 2) age between 18 and 65 years; 3) a duration of illness of at least 1 year; 4) willingness to participate in the study. Exclusion criteria were: 1) the presence of a significant neurological illness, except tic disorder; 2) a history of past or current drug abuse or dependence; 3) a serious concomitant general medical condition which could contraindicate an antiobsessional drug treatment; 4) a current or previous diagnosis of schizophrenia or other psychotic disorders. Comorbidity with other DSM-IV Axis I disorders was not considered an exclusion criterion provided that OCD was the main diagnosis and the primary reason for seeking psychiatric treatment. The diagnosis of OCD was made by a senior psychiatrist (FC) who had received a formal training in the use of the assessment instruments and had an extensive clinical experience in OCD. During the selection period, 120 outpatients with OCD were initially assessed; 10 (8.3%) were ruled out in accordance with the exclusion criteria and 4 (3.3%) refused to participate Baseline assessment At baseline, each recruited patient was clinically assessed by the administration of the following instruments, in addition to the SCID-I: 1) the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) (First et al., 1997); 2) the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) (Goodman et al., 1989); 3) the 17-item Hamilton Rating Scale for Depression (HDRS) (Hamilton, 1960). OCD symptoms were recorded according to the clinician rated Y-BOCS Symptom Checklist (Y-BOCS-SC) (Goodman et al., 1989), which includes 13 major categories (excluding miscellaneous items) of obsessions and compulsions. Furthermore, patients' sociodemographic characteristics (age, sex, marital status, years of schooling, and employment) and clinical variables (age at onset of OCD, duration of illness, type of onset, previous treatments for OCD, and number of previous hospitalizations) were recorded by an ad-hoc schedule. The presence of psychiatric disorders in first-degree relatives was explored by the Family History Research Diagnostic Criteria (Andreasen et al., 1977), adapted to obtain DSM-IV diagnoses. Whenever possible, at least two family informants were interviewed to maximize the accuracy of family history information. Insight was assessed using the BABS (Eisen et al., 1998). The BABS is a semistructured, clinician-administered, seven-item scale with specific probes and anchors designed to assess degree of insight in a variety of psychiatric disorders. The psychometric properties of this scale have been formally assessed (Eisen et al., 1998). To administer the scale, the rater determines and rates the principal beliefs and associated consequences underlying the obsessions during the past week. To determine the dominant belief, all the OC symptoms were initially listed by administering the Y-BOCS checklist and subsequently inquiring about the severity of distress and interference associated with each symptom. The BABS individual items assess the following dimension: conviction; perception of other's views of beliefs; explanation of differing views; fixity of ideas; attempt to disprove beliefs; insight; and ideas of reference. Each item is rated from 0 (nondelusional or least pathological) to 4 (delusional or most pathological). The first six items are summed to create a total score (range, 0 to 24). The seventh item is not included in the total score. Poor insight is indicated by a total BABS score of 12 (mean score of 2 for each BABS item) and 3 for the conviction item (fairly or completely convinced that belief/worry is true). The clinician ratings were completed by research psychiatrists with at least 5 years' experience in the diagnosis and treatment of

3 F. Catapano et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) OCD patients. Each interviewer underwent a training program in the use of the assessment instruments, which included direct observation of experienced interviewers, direct supervision of interviews, and inter-rater reliability. Inter-rater reliability among the interviewers was high for Y-BOCS, HDRS, BABS, and SCID diagnoses (kappa= ). All the psychopathological evaluations were performed by researchers not involved in the patient's treatment. The raters were unaware of the specific aims and final hypotheses of the study at the time the data were being collected. Insight was assessed by raters blind to the SCID-I and SCID-II evaluation, to the pharmacological therapy received, and to pre- and post-treatment Y-BOCS and HDRS scores Treatment and follow-up After the initial assessment, 83 patients (67 with good insight and 16 with poor insight) were openly treated with an SRI. We did not find any significant difference in demographic and clinical parameters between patients who withdrew consent and those who accepted the treatment program. The SRI and its dose were decided by the psychiatrist in charge of each patient, on the basis of his/her clinical judgement. Since available evidence suggests that SRIs have similar efficacy in the treatment of OCD, but different tolerance and sideeffect profiles, drug selection took into account the patient current clinical characteristics, his/her response to previous therapies (if there was any), and the experience of psychiatrist with the usage. Although the choice of the drug was not controlled, medications were administered within a recommended range of dose known to be effective for the treatment of OCD (clomipramine: mg/day; fluoxetine: mg/day; fluvoxamine: mg/day; citalopram: mg/day; paroxetine: mg/day; and sertraline: mg/day). Full tolerated doses were maintained for at least 12 weeks. Response to treatment was defined as a decrease of at least 35% of the Y-BOCS total score from the baseline score. Patients who did not meet response criteria during the first drug trial underwent a flexible treatment pathway that involved sequential administration of different SRIs employed in maximum tolerated doses. During the follow-up, medications other than SRIs were employed as therapeutic alternatives in patients with treatment resistance to conventional antiobsessional drugs (venlafaxine: mg/day; mirtazapine: 30 mg/day; and imipramine: mg/day). Treatment was also enhanced with low doses of antipsychotics (pimozide: 2 4 mg/day; risperidone: 2 4 mg/day; and haloperidol: 2 4 mg/day) in patients with poor response to at least three adequate trials with SRIs. During the follow-up period (3 years), patients were seen with variable frequency, depending on clinical need, but were evaluated systematically, monthly during the first year and bimonthly thereafter, by means of the Y-BOCS, the HDRS, and the BABS. Information on ongoing drug treatment (including dosage, side effects and compliance), as well as on hospital admissions, was regularly recorded. On the occasion of each visit, patients had the opportunity to discuss with their reference psychiatrist all problems concerning treatment, its efficacy, and its side effects Data analysis Descriptive statistics and percentage were calculated for demographic and psychometric variables. Distributions were reviewed to evaluate underlying statistical assumptions of the data. Insight was examined as both a categorical and a continuous variable. Categorically, cut-offs previously employed in OCD literature were utilized. Comparisons between patients with good and poor insight were performed by the chi-square test or one-way analysis of variance (ANOVA), as appropriate. Afterward, Spearman's correlation analysis was used to examine the relationship between the baseline BABS total scores and other selected variables. Changes in Y-BOCS total and subtotal scores, HDRS total scores, and BABS total scores during the follow-up period were evaluated in the two groups by ANOVA with repeated measures. During the follow-up, the course of OCD was evaluated in terms of partial remission or full remission of symptoms. Full remission was defined as a Y-BOCS total score below 8 for at least 8 consecutive weeks. Partial remission was defined as a Y-BOCS total score below 15 for at least 8 weeks. At the end of the study, patients were divided in two categories: 1) good outcome (those who met criteria for at least a partial remission for more than 40% of the follow-up period); 2) poor outcome (those who met criteria for at least a partial remission for less than 40% of the follow-up period). A stepwise linear regression analyses was performed in order to find which variables were associated with insight. The baseline score on the BABS was considered the dependent variable. Independent variables were: age at onset of the disorder; employment; Y-BOCS total score and subtotal scores for obsessions and compulsions at baseline; HDRS total score at baseline; presence of obsessive compulsive or schizotypal personality disorder; and family history of schizophrenia spectrum disorders. 3. Results 3.1. Descriptive data and group differences The study sample included 106 patients (56 males and 50 females), with a mean age at intake of 30.9 (SD=9.8) and an educational level ranging from 3 to 19 years (mean 11.05, SD=3.9). Fifty-three patients (50%) were married, and 53 (50%) were employed. The mean age at onset of OCD was 21.6 years (SD=8.6; range 6 54) and the mean duration of illness prior to study entry was 9.2 years (SD=6.7). Seventy-eight (73.6%) patients had received previous treatments, but only 28 subjects had received at least one adequate SRI trial and only 15 had received behavioural treatment. Thirty-five patients (33%) had a history of previous hospitalizations. Eighty-six patients (81.1%) met DSM-IV criteria for at least one personality disorder. Fourteen patients (13.2%) had a family history of affective disorder, 14 (13.2%) had a family history of OCD, and 7 (6.6%) had a family history of schizophrenia spectrum disorders (4=chronic schizophrenia; 2= schizoaffective disorder; and 1=unspecified functional psychosis). The mean Y-BOCS scores at intake were as follows: total 26.5 (SD=6.7); subtotal score for obsessions 13.9 (SD=2.9); subtotal score for compulsions 12.6 (SD=5.1). The mean HDRS total score was 14 (SD=5.6). The mean baseline BABS total score was 8.2 (SD=4.8; range 1 21). Considering insight as a dimension, we detected a significant positive correlation between BABS total scores and the Y-BOCS obsessive, compulsive, and total scores (r =0.377, P b.0001; r=0.396, Pb.0001; r=0.310, and Pb.001, respectively). The BABS scores were positively correlated with control over obsessions and compulsions (r=0.257, Pb.008; r=0.267, and Pb.006, respectively), and resistance to obsessions and compulsions (r=0.326, Pb.001; r=0.291, and Pb.002, respectively). A positive significant correlation was also found between insight assessed by the BABS and HDRS total scores (r=0.365, Pb.0001). Age, age at onset, and duration of illness, showed no relationship with level of insight. Based on the BABS score, the sample had 23 subjects (21.7%) with poor insight, whereas the remaining 83 (78.3%) had good insight. Demographic and clinical characteristics as a function of insight level are reported in Table 1. The two groups did not differ significantly by gender, age, marital status, years of education, illness duration, and current Axis I comorbid conditions. Compared to the patients with good insight, those with poor insight showed an earlier age at onset, a higher rate of schizophrenia spectrum disorders in their first-degree relatives, a greater severity of the OC and depressive symptoms at baseline, as measured by Y-BOCS total score, subtotal scores for

4 326 F. Catapano et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) Table 1 Clinical and sociodemographic characteristics of OCD patients with good and poor insight. Variable Good insight (n=83) Poor insight (n=23) F value/ df P χ 2 Sex, male, n (%) 43 (51.8) 13 (56.5) Age, years, mean ±SD 31.49± ± , Marital status, married, n (%) 40 (48.2) 13 (56.5) Years of education, mean±sd 11.74± ± , Work status, employed, n (%) 46 (55.4) 7 (30.4) Age at onset, years, mean±sd 22.65± ± , Length of illness, years, 8.83± ± , mean ±SD Obsessive compulsive 37 (44.5) 5 (21.7) personality disorder, yes, n (%) Schizotypal personality 5 (6) 11 (47.8) disorder, yes, n (%) Family history of affective 10 (12) 4 (17.4) disorders, yes, n (%) Family history of OCD, yes, n (%) 13 (15.7) 1 (4.3) Family history of schizophrenia 1 (1.2) 6 (26) spectrum disorders, yes, n (%) Y-BOCS total score, mean±sd 25.43± ± , Y-BOCS obsessions, mean±sd 13.49± ± , Y-BOCS compulsions, 11.96± ± , mean ±SD HDRS total score, mean±sd 13.45± ± , Current comorbid Axis I disorders, n (%) Any comorbid diagnosis 44 (53) 13 (56.5) Mood disorders 18 (21.7) 6 (26.1) Anxiety disorders 25 (30.1) 7 (30.4) Tic disorders 4 (4.8) 3 (13) Eating disorders 7 (8.4) 1 (4.3) Impulse-control disorders 6 (7.2) 2 (8.7) OCD = obsessive compulsive disorder; Y-BOCS = Yale Brown Obsessive Compulsive Scale; HDRS = Hamilton Depression Rating Scale. obsessions and compulsions, and HDRS total score. They also were more frequently unemployed than their good insight counterparts. No significant difference was detected between the two groups with respect to the frequency of OC symptom subtypes, as assessed by the Y-BOCS-SC (Table 2). In terms of Axis II comorbidity, 20 patients with poor insight (87%) and 62 patients with good insight (72.1%) had at least one personality disorder. When specific personality disorders were examined, two significant differences emerged from the comparison: schizotypal personality disorder was more frequent in the poor insight group Table 2 Current obsessive compulsive phenomenology according to the Y-BOCS-SC in OCD patients with good and poor insight. Variable Good insight (n=83) Poor insight (n=23) χ 2 df P Obsessions, n (%) Aggressive 26 (31.3) 10 (43.5) Contamination 43 (51.8) 14 (60.9) Sexual 12 (14.4) 5 (21.7) Hoarding/saving 6 (7.2) 2 (8.7) Religious 13 (15.7) 3 (13) Symmetry/order 42 (50.6) 11 (47.8) Somatic 13 (15.7) 2 (8.7) Compulsions, n (%) Checking 46 (55.4) 16 (69.6) Cleaning 42 (50.6) 16 (69.6) Repeating 30 (36.1) 11 (47.8) Ordering 34 (41) 6 (26.1) Counting 13 (15.7) 5 (21.7) Hoarding/collecting 7 (8.4) 2 (8.7) OCD = obsessive compulsive disorder. Y-BOCS-SC = Yale Brown Obsessive Compulsive Scale Symptoms Check List. (47.8% vs 6%, χ 2 =24.555, df=1; and Pb.0001), while obsessive compulsive personality disorder was more frequent in the good insight group (44.5% vs 21.7%, χ 2 =3.927, df=1; and Pb.05). The two groups did not differ in the rates of any other comorbid Axis II disorder Follow-up data Nineteen out of 67 (28.3%) patients with good insight and 5 out of 16 (31.2%) were lost at various stages of follow-up evaluations: ten patients in the first 3 months; nine in the first year; five in the second year. The reasons for dropping out included intolerance to side effects (n=11), non compliance with medications (n=5), medical illness (n =2), other problems not related to treatment (n =4), and unknown reasons (n=2). Retrospective analyses of the pretreatment data revealed no significant difference between patients who dropped out and that of those who remained in the treatment program for the following variables: baseline BABS total scores, baseline Y-BOCS total, obsessions, and compulsions subscales and baseline HDRS total scores. Thirteen of the 59 completers (22%) received at least one SRI trial, 14 (23.7%) two SRI trials and 32 (54.2%) three or more SRI trials, always prescribed in a sequential fashion. During the follow-up period, 34 patients were treated with clomipramine (mean dose±sd=194.1± 28.2 mg/day); 30 with fluvoxamine (mean dose±sd=240±54.8 mg/ day); 35 with fluoxetine (mean dose±sd=57.1±12.1 mg/day); 26 with sertraline (mean dose±sd=178.8±34.4 mg/day); 27 with citalopram (mean dose±sd=55.5±10.1 mg/day); and 25 with paroxetine (mean dose±sd=51.2±10.1 mg/day). The occurrence of adverse effects was responsible for relatively reduced doses of clomipramine used during the follow-up period. Antidepressants other than SRIs were employed five times: three patients were treated with venlafaxine (mean dose±sd=208.3±28.9 mg/day), one patient received mirtazapine (30 mg/day), and one patient was treated with imipramine (225 mg/ day). Treatment was enhanced with low doses of antipsychotics in sixteen patients: eight were treated with pimozide (mean dose± SD=3.2 ±1.1 mg/day), five received risperidone (mean dose± SD = 3.3 ± 1.1 mg/day), and three haloperidol (mean dose ± SD = 2.6 ± 1.1 mg/day). Compared with the good insight group, patients with poor insight required a greater number of different drug trials (6.2±1.3 vs 2.6±1.5, F =54.813, df=1,57; and P b.0001) and were more likely to receive augmentation with antipsychotics (11/ 11, 100% vs 5/48, 10.4%, χ 2 =36.337, df =1; and P b.0001). No significant difference in response rate (a decrease of at least 35% of the Y-BOCS total score) to the addition of low doses of antipsychotic was observed between the two groups (5/11, 45.4% vs 3/5, 60%, χ 2 =.291, df=1; and P b.500). The mean scores on rating scales during the observation period showed a significant improvement in all areas investigated for both groups, as reported in Table 3. The percent decrease from baseline Y-BOCS total score was smaller in the group with poor insight compared to patients with good insight (20.8% vs 49.5%, F=32.926, df=1,57; and Pb.0001). The effect size was 0.98 for the poor insight group and 0.89 for the good insight group. A significant difference was found between baseline and final BABS scores (8.2±4.8 vs 5.7±3.8, F= , df=1,58; and Pb.0001). The correlation between the change in BABS total score and change in Y-BOCS total score was.52 (Pb.0001). The correlation between baseline total BABS score and change in Y-BOCS score from baseline to end point was.58 (Pb.0001). Five out of 11 (45.5%) subjects in the poor insight group were assessed to have good insight in the followup assessments. No significant difference in pretreatment data was detected between patients whose insight remained unchanged and those who demonstrated a change to good insight status. However, the former group was more likely to have a comorbid schizotypal

5 F. Catapano et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) Table 3 Changes in Y-BOCS, HDRS and BABS scores in OCD patients with good (n=48) and poor (n=11) insight during the 3-year follow-up period. Scale Months of follow-up ANOVA with repeated measures F value P Y-BOCS total score (mean±sd) OCD with GI 24.8± ± ± ± ± ± OCD with PI 31.8± ± ± ± ± ± Y-BOCS obsessions (mean±sd) OCD with GI 13.6± ± ± ± ± ± OCD with PI 15.7± ± ± ± ± ± Y-BOCS compulsions (mean±sd) OCD with GI 11.2± ± ± ± ± ± OCD with PI 16.1± ± ± ± ± ± HDRS total score (mean±sd) OCD with GI 13.1± ± ± ± ± ± OCD with PI 16.3± ± ± ± ± ± BABS total score (mean±sd) OCD with GI 6± ± ± ± ± ± OCD with PI 17± ± ± ± ± ± OCD = obsessive compulsive disorder; GI = good insight; PI = poor insight. Y-BOCS = Yale Brown Obsessive Compulsive Scale; HDRS = Hamilton Depression Rating Scale. BABS = Brown Assessment of Beliefs Scale. personality disorder (66.7% vs 20%), although this difference did not reach statistical significance. At the end of the follow-up, 10 (91%) patients with poor insight and 17 (35.4%) with good insight still met full criteria for OCD, while 31 (64.6%) patients with good insight and only one (9%) with poor insight were at least in partial remission. All patients (n=12) in full remission had a good insight (Table 4). Out of 59 completers, 20 (33.9%) satisfied criteria for at least partial remission for more than 75% of the time, 8 (13.6%) for less than 75% but more than 40% of the time, and 31 (52.5%) for less than 40% of the time. Based on the criteria reported above, twenty-eight out of 48 (58.3%) patients with good insight and none (0/11) of the patients with poor insight had a good outcome ; but eleven (100%) patients with poor insight and twenty (41.7%) with good insight had a poor outcome (χ 2 =12.212, df=1; and P=.0001). The results of stepwise linear regression showed that three variables were significantly and independently related to the BABS score in our sample: presence of schizotypal personality disorder (R 2 =0.224, B=0.417, β=0.362, t=4.065; and P=.0001), severity of obsessive symptoms as measured by Y-BOCS subtotal scores for obsessions (R 2 =0.277, B =0.032, β =0.223, t =2.725; and Table 4 Treatment response variables in OCD patients with good and poor insight. Variable Good insight (n=48) Poor insight (n=11) F value/ df P χ 2 Number of different 2.6± ± , drug trials, mean±sd Augmentation with 5 (10.4) 11 (100) antipsychotics, n (%) Reduction in Y-BOCS total , score after treatment, (%) Status at last assessment Full OCD, n (%) 17 (35.4) 10 (91) Partial remission, n (%) 19 (39.6) 1 (9) Full remission, n (%) 12 (25) 0 (0) Patients with a poor outcome, n (%) 20 (41.7) 11 (100) OCD = obsessive compulsive disorder. Y-BOCS=Yale Brown Obsessive Compulsive Scale. Poor outcome = patients who met criteria for at least a partial remission for less than 40% of the follow-up period. P=.008), and occurrence of schizophrenia spectrum disorders in first-degree relatives (R 2 =0.315, B=0.383, β=0.231, t=2.578; and P=.01). 4. Discussion The present study evaluated a large clinical sample of OCD patients using a well-validated and reliable instrument to assess insight, the BABS, applied by experienced and carefully trained clinicians, and considering simultaneously a whole set of clinical issues comprising personality comorbidity, OCD severity, and treatment response. To our knowledge, this is the longest prospective, naturalistic follow-up study evaluating the long-term outcome (3 years) of OCD patients with poor insight treated with SRIs. Additional strengths of current report include: monthly or bimonthly assessment during the whole observation period, which allowed to verify directly the patients' clinical conditions, rather than relying on their retrospective evaluations; pharmacological treatment in keeping with internationally accepted guidelines (March et al., 1997); use of specific operational criteria to define full remission and partial remission, corresponding to those recently proposed in the literature (Eisen et al., 1999; Steketee et al., 1999; Pallanti and Quercioli, 2006); and efforts to optimise compliance by seeing patients and their relatives frequently and giving them the opportunity to discuss regularly all treatment-related problems. The results of the present study are in line with previous research showing that insight in OCD patients varies widely. Based on the BABS score, 21.7% of our OCD patients showed an important and stable impairment of the critical capacity and a strong belief in the rightness of obsessive ideas and compulsive behaviors. This finding is within the range of previously reported rates of poor insight in patients with OCD (Insel and Akiskal, 1986; Foa et al., 1995; Catapano et al., 2001; Marazziti et al., 2002; Matsunaga et al., 2002; Türksoy et al., 2002; Ravi Kishore et al., 2004; Bellino et al., 2005; De Berardis et al., 2005; Alonso et al., 2007). Compared to their good insight counterparts, the OCD patients with poor insight were characterized by a greater severity of obsessive and depressive symptomatology; an earlier age at onset; a higher rate of schizophrenia spectrum disorders in their first-degree relatives; a higher comorbidity with schizotypal personality disorder. We did not

6 328 F. Catapano et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) detect any significant difference between the two groups with respect to the gender ratio, the length of illness, the frequency of OC symptom subtypes, and current comorbid Axis I disorders. The relationship between insight and severity of OCD remains a controversial issue. On the basis of our data, it is impossible to exclude that the impairment of insight is an epiphenomenon of a greater severity of OC symptomatology. In the literature, both no correlation with OC symptoms severity (Marazziti et al., 2002), or significant relationships with Y-BOCS scores have been reported (Catapano et al., 2001; Matsunaga et al., 2002; De Berardis et al., 2005; Alonso et al., 2007). Our findings are consistent with the latter, as we found a significant correlation between BABS scores and Y-BOCS obsessive, compulsive and total scores. Recently, Alonso et al. (2007) have stressed that relationship between insight and OCD severity, when assessed by means of the Y-BOCS, may be at least partially tautological, because the definition of poor insight includes the lack of resistance against obsessions and compulsions that are not considered senseless. Our findings are in accordance with this hypothesis, as we found that the degree of insight was significantly correlated with resistance to and control over obsessions and compulsions. However, poor insight has been found to be highly linked to other indicators of severity of illness in clinically diagnosed OCD, including greater number of OC symptoms, severity of compulsive symptoms, increased rates of comorbid diagnoses, longer duration and chronic course (Catapano et al., 2001; Matsunaga et al., 2002; Türksoy et al., 2002; Ravi Kishore et al., 2004; Bellino et al., 2005; Alonso et al., 2007). We also found that poor insight in OCD patients is associated with more severe depressive symptomatology, as assessed by HDRS. Although other groups have been unable to support this relationship (Marazziti et al., 2002; Bellino et al., 2005), several authors have reported that poor insight OCD patients exhibited more severe depressive symptoms (Catapano et al., 2001; Matsunaga et al., 2002; De Berardis et al., 2005; Alonso et al., 2007), and a greater frequency of comorbid major depressive disorder (Türksoy et al., 2002; Ravi Kishore et al., 2004). It has been argued that severe depression may play an important role in lack of insight, contributing to the transformation of obsessions into overvalued ideas or delusional beliefs (Lelliott et al., 1988; Kozak and Foa, 1994). Alternatively, it is possible that depression is the consequence of more severe OC symptoms associated with poor insight. The finding of an earlier age at onset of OC symptoms in patients with poor insight is consistent with previous reports (Solyom et al., 1985; Matsunaga et al., 2002; Ravi Kishore et al., 2004). However, several groups have not supported this relationship (Eisen et al., 2001; Marazziti et al., 2002; Bellino et al., 2005; De Berardis et al., 2005; Alonso et al., 2007). It is important to mention that children with OCD routinely exhibit poor insight into the nature of their obsessions and compulsions, and that there is a close relation between level of insight, symptom severity, and functioning among pediatric OCD patients (Storch et al., 2008). Results of regression analysis showed that the presence of schizotypal personality disorder and schizophrenia spectrum disorders in first-degree relatives are the two principal variables significantly associated with poor insight. These findings confirm previous studies demonstrating that OCD patients with poor insight (Matsunaga et al., 2002; Alonso et al., 2007) or those with psychotic or delusional OC symptoms (Stanley et al., 1990; Pigott et al., 1994) have a relatively increased rate of cluster A personality disorder, particularly a schizotypal one. A recently completed study have found that OCD patients with schizotypal personality disorder, compared to those who have OCD alone, showed poorer insight, more negative symptoms, lower functioning and, similarly to our data, more firstdegree relatives with schizophrenia spectrum disorders (Poyurovsky et al., 2008). Several lines of evidence suggest a complex interaction between OCD and schizophrenia spectrum disorders (Poyurovsky and Koran, 2005). An increased rate of OCD has consistently been found in schizophrenia patients (Poyurovsky and Koran, 2005). Both retrospective (Jenike et al., 1986) and, more recently, prospective studies (Joffe et al., 1988; Baer et al., 1990; Stanley et al., 1990; Sobin et al., 2000) have shown that a significant percentage of OCD patients have comorbid schizotypal personality disorders. Positive symptoms of schizotypy have been found to be highly linked to severity indicators in OCD patients, including earlier age of onset, greater number of comorbid diagnoses, increased rates of OC symptoms, and treatment failure (Sobin et al., 2000; Moritz et al., 2004). Compelling evidence indicates that when symptoms of both obsessive compulsive and schizotypal personality disorder are present, the prognosis is worse and neuropsychological impairment is more severe (Harris and Dinn, 2003; Poyurovsky and Koran, 2005; Shin et al., 2008). Recently, it has been hypothesized that OCD with poor insight and schizotypal personality disorder may represent a separate subgroup characterized by distinct clinical features, poor treatment response and prognosis, and by a relationship to the schizophrenia spectrum (Poyurovsky and Koran, 2005; Poyurovsky et al., 2008). The results of the present study lead further support to the claim that OCD patients with poor insight exhibit a worse treatment outcome than those with good insight (Foa et al., 1999; Catapano et al., 2001; Erzegovesi et al., 2001; Ravi Kishore et al., 2004; Himle et al., 2006). Although both groups exhibited a significant improvement of OC and depressive symptomatology over the course of a 3-year follow-up, we found that poor insight OCD patients: were less likely to achieve at least a partial remission throughout the study duration; showed a smaller decrease in Y-BOCS total scores at the end of the study; required a significantly greater number of therapeutic trials with different medications during the observational period; were more likely to receive augmentation with antipsychotics. In contrast to our findings, some previous studies have found that poor insight OCD patients were as likely to respond to pharmacological treatment as those with better insight (Eisen et al., 2001; Alonso et al., 2007). A possible explanation for this discrepancy is the use in the current study of stricter criteria to define treatment outcome than those previously adopted by other authors. One can only speculate about the causes of the apparent treatment resistance to standard pharmacological interventions among poor insight OCD patients. Our poor insight group tended to have a greater severity of symptoms at intake, a finding already reported in previous studies (Catapano et al., 2001; Matsunaga et al., 2002; De Berardis et al., 2005; Alonso et al., 2007). However, severity of symptoms was not predictive of long-term outcome in most behavioural and drug studies (Eisen and Steketee, 1997; Foa and Franklin, 2002), indicating that severity alone does not necessarily indicate a poor prognosis. Although poor insight has been generally associated with treatment noncompliance, we did not find a correlation between these variables. The impact of the above-mentioned personality characteristics should be also taken into account. Schizotypal personality disorder has been associated with a less favourable course of OCD and with an enhanced risk for treatment failure in both drug and behavioural studies (Jenike et al., 1986; Minichiello et al., 1987; Ravizza et al., 1995; Moritz et al., 2004). Several reports suggest that the presence of this Axis II disorder in OCD patients is a good predictor of response to low doses of antipsychotic added to ongoing SRI therapy (McDougle et al., 1994; Bogetto et al., 2000). However, no study assessed whether insight predicts response to antipsychotic augmentation in OCD. We found that only 45% of OCD patients with poor insight responded to the addition of low doses of antipsychotic to the ongoing SRI therapy. It has been hypothesized that the specifier poor insight helps to identify a subgroup of OCD at the more organic end of the spectrum (Aigner et al., 2005). Neuroimaging findings have found that poor insight OCD patients show more MRI abnormalities of the brain than subjects with good insight (Aigner et al., 2005). Neuropsychological studies have also reported that OCD patients with poor insight or overvalued ideas were more likely to share cognitive deficits with

7 F. Catapano et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) schizophrenia patients, especially in terms of frontal lobe dysfunction (Kitis et al., 2007; Tumkaya et al., 2009). It is possible that the worse treatment outcome of OCD patients with poor insight is related to specific neurobiological mechanisms involving neurotransmitter pathways other than the serotoninergic ones, most probably a dopaminergic dysfunction (Ravi Kishore et al., 2004; Alonso et al., 2007). Prospective and experimental studies should be undertaken to further elucidate these important issues. Finally, we found that insight in OCD improves over the course of follow-up in parallel with the improvement of OC symptoms. This finding is consistent with a number of previous studies (Eisen et al., 2001; Matsunaga et al., 2002; Alonso et al., 2007). In addition, a significant percentage (46%) of patients with poor insight showed a shift to good insight at the end of the observational period. Similarly to us, Matsunaga et al. (2002) reported that 56% of their patients no longer exhibited poor insight 6 months after combined pharmacological and behavioural treatment; OCD patients with poor insight and comorbid schizotypal personality disorder were more likely not to gain better insight during treatment. Although no statistical significance was reached, in the current study we observed a trend towards a similar correlation. Some limitations of the present study should be considered. First, the study was carried out at a specialized university centre, to which the most severe cases are especially likely to be referred. Because of this, the results of the study may be not generalized to the entire population of patients with OCD. Second, since the study had a naturalistic design, no attempt was made to control the assignment of treatments. Although patients had the best chance to receive the appropriate treatment, as is usual in general practice, we cannot rule out the possibility that different kinds of outcomes could be attributed to different prescription patterns. Third, the number of patients lost to follow-up evaluation is considerable, a problem common to many long-term studies on OCD (Fontenelle et al., 2003; Reddy et al., 2005; van Oppen et al., 2005). This high drop-out rate may have introduced a degree of bias into our analysis of the relationship between insight and response and course of OCD. Further controlled studies using larger samples are needed to confirm our findings. A relevant limitation of our study is the underutilization of cognitive behavioural therapy. This finding is consistent with the results of previous studies conducted in specialized settings (Orloff et al., 1994; Eisen et al., 1999; Reddy et al., 2005). We are unable to determine whether the limited use of this treatment approach was caused by patient, clinician, or system factors: the primary focus of our study on pharmacological treatment of OCD, the limited availability of trained behavioural therapists, the preference of the psychiatrist in charge of each patient, the concerns about reimbursement for psychotherapy, the refusal of the patient to engage in more active and directive treatment after multiple failed medications trials. Further work needs to be done to investigate the reasons that lead to the underutilization of cognitive behavioural therapy and to increase the use of this treatment on a large scale. However, although experts in OCD generally agree that cognitive behavioural therapy should be considered when resistance to SRIs appears, few data are available regarding the impact of providing this approach to partial or nonresponders to medications (Huppert and Franklin, 2005; Pallanti and Quercioli, 2006). A further methodological limitation of the current study concerns the rationale for setting the BABS cutoff for poor insight. Although this cutoff is the one usually employed in the adult OCD literature, its validity still remains to be definitively established. In addition, we used the family history method to assess psychiatric morbidity in first-degree relatives. This approach entails the risk of biased rates of affected family members. In order to overcome this problem, in this study indirect family history information was obtained with the help of at least two family members, primarily first-degree relatives, whenever possible. Finally, a dimensional assessment of schizotypy, using valid and reliable instruments, is warranted to further characterize the interrelationship between insight, specific schizotypal traits or dimensions, and treatment outcome in OCD patients. 5. Conclusions In conclusion, our findings converge with the results of previous studies suggesting that the systematic assessment of insight in OCD is a potentially fruitful enterprise. Taken together, these results confirm that the specifier poor insight helps to identify a subgroup of patients at the more severe end of OCD spectrum, characterized by a more complex clinical presentation, a worse response to standard pharmacological interventions, and a poorer prognosis. 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