Clozapine-induced obsessive-compulsive symptoms in schizophrenia: Clinical and cognitive determinants of dysfunctional checking

Abstract

Background: Obsessive-compulsive symptoms (OCS) emerge in a significant proportion of clozapine-treated schizophrenia patients, affecting social functioning and increasing depressive symptoms. This study investigates the underexplored cognitive mechanisms of clozapine-induced OCS, particularly focusing on dysfunctional checking behavior.

Methods: Clinical and cognitive profiles of OCS and their relationship to dysfunctional checking were investigated using a novel checking paradigm (image verification task or IVT) in four groups: clozapine-treated schizophrenia patients with clozapine-induced OCS (SCZ-OCS, n = 21) and without (SCZ-only, n = 15), patients with obsessive-compulsive disorder (OCD, n = 32) and IQ-matched healthy volunteers (HV, n = 30).

Results: Only SCZ-OCS patients showed a distinctive pattern of dysfunctional checking on the IVT. Compared with SCZ-OCS, SCZ-only patients exhibited functional checking while having equivalent deficits in executive cognition, clozapine dose, and treatment duration, though with less severe positive and depressive symptoms. In SCZ-OCS, dysfunctional checking was positively correlated with clozapine dose and working memory performance. By contrast, OCD patients' checking was positively related to intolerance of uncertainty. Checking in the OCD and SCZ-OCS groups was positively correlated with YBOCS-compulsion.

Conclusion: This study is the first to compare the distinct cognitive and clinical profiles of SCZ-OCS, SCZ-only, and OCD, with a focus on checking behavior, a major symptom in clozapine-treated patients. We introduced a novel and sensitive measure for checking, which showed dysfunctional checking only in SCZ-OCS patients treated with clozapine. These findings indicate that a subset of patients with schizophrenia with more severe positive symptoms and cognitive deficits are especially susceptible to OCD symptoms when treated with clozapine.

Keywords: OCD; checking; cognitive flexibility; schizophrenia; spatial working memory.

Figure 1.

A schematic representation of the Image verification task reproduced from Biria et al., . Participants observed two black and white drawings sequentially. The task was to compare them and decide if they are the same or different. There was an opportunity to check the images, before giving a response, by pressing on the red << sign. After each answer, there was a 4-choice confidence rating scale: ‘not confident at all’, ‘not very confident’, ‘fairly confident’, and ‘very confident’. Each stimulus presentation lasted 1 second with an 800 ms interstimulus interval. The remaining frames remained on the screen until an answer was given. (A) Block 1 is the high uncertainty block, which provided no feedback. In this example, the stimuli differ in angle. (B) Block 2 punished checking by adding one trial for each check (that is every time the participant pressed the checking sign on the screen) and feedback was provided for all trials to reduce uncertainty. Wrong and correct answers were followed by both visual (red and green, respectively) and auditory feedback (aversive and uplifting sound, respectively). Here, two different objects are depicted. (C) Three examples of stimuli used in this task. From left to right: 2 bears (the right bear is bigger), 2 ducks (the right duck is more crooked), and 2 umbrellas (the umbrellas are exactly the same).

Figure 2.

IVT performance under high uncertainty (A) showing the checking rate, and (B) the accuracy of answers. (C) depicts the relationship between checking and percentage accuracy under high uncertainty (block 1) as a measure of functionality of checking in healthy volunteers (HV; black), OCD (purple), SCZ-OCS (green), and SCZ-only (blue) patients. The line of best fit is shown with the 95% confidence intervals for the regression estimate in translucent bands around the regression lines. The r indicates Pearson correlation coefficient for which two-tailed tests were used. Acronyms: HV = healthy volunteers, OCD = obsessive compulsive disorder, SCZ-OCS = schizophrenia with OCS, SCZ-only = schizophrenia without OCS. *** p < 0.001.

Figure 3.

Relationship between checking and clinical measures. The upper panel shows the comparison between OCD and SCZ-OCS groups, whereas the lower panel compares the two schizophrenia groups. The following relationships are depicted: 1) between OCD (purple) and SCZ-OCS (green) patients: (A) checking under uncertainty and intolerance of uncertainty scores (IOU), (B) checking under punishment and anxiety state (STAI-S), (C) checking under punishment and YBOCS compulsion; 2) between the SCZ-OCS (green) and SCZ-only (blue) patients: (D) checking under uncertainty and clozapine dose, (E) checking under punishment and anxiety state (STAI-S), (F) checking under punishment and CANTAB SWMBE. The line of best fit is shown with the 95% confidence intervals for the regression estimate in translucent bands around the regression lines. The r_s indicates Spearman correlation coefficient for which two-tailed tests were used. The asterisks indicate significance and their color correspond to the group they are representing. Acronyms: HV = healthy volunteers, OCD = obsessive compulsive disorder, SCZ-OCS = schizophrenia with OCS, SCZ-only = schizophrenia without OCS, IOU Intolerance Of Uncertainty, STAI-S State Trait Anxiety Inventory-State, YBOCS Yale-Brown Obsessive Compulsive Scale, SWMBE Spatial Working Memory Between Errors (the number of times the subject incorrectly revisits a box in which a token has previously been found). * p < = 0.05, ** p < 0.01.