A cross sectional study of impact and clinical risk factors of antipsychotic-induced OCD.

A large proportion of schizophrenia patients treated with second generation antipsychotics will develop Obsessive Compulsive Disorder (OCD). However, there are few studies about the impact of this comorbidity and who is at higher risk. In this study of clozapine-treated patients, we aimed to determine the impact on outcome of clozapine-induced OCD, as well as the clinical and sociodemographic risk factors related to OCD-onset in clozapine patients. We had strict and novel inclusion criteria to minimise mis-identification of cases. The Obsessive-Compulsive Inventory-Revised (OCI-R) was used to divide 231 clozapine-treated patients into extreme cases of OCD (OCI  ≥ 24 or checking subscale ≥6) versus non-OCD (OCI <15 and checking subscale <4). The Global Assessment of Functioning (GAF), short version of Warwick-Edinburgh Wellbeing scale and Clinical Global Impression for schizophrenia (CGI) scales were used to determine outcome. Socio-demographic information was used to identify the risk factors for OCD development. We found that schizophrenia patients with OCD symptoms had a significantly lower patient rated wellbeing scores (p < 0.001) only (no difference in clinician rated wellbeing scores), higher CGI positive (p < 0.01) and higher CGI depressive scores (p < 0.05). The only risk factors that reached significance level were higher treatment dose (p < 0.01) and younger paternal age at birth (p < 0.05). There is scope for future studies based on e.g. imaging and genetic studies to further investigate causality, and in improving clinician screening for OCD.MB was supported by her studentship from the Mental Health Research UK. YW is supported by the Association Française du syndrome de Gilles de la Tourette, Foundation de recherche Medicale and Dystonia Foundation for Medical Research (USA). NF has held research or networking grants from the ECNP, UK NIHR, EU H2020, has accepted paid speaking engagements including travel and hospitality in industry supported symposia for Abbott, SunPharma, has accepted travel and hospitality expenses from the BAP, ECNP, RCPsych, CINP, receives payment from Taylor and Francis for editorial duties. TWR was supported by Wellcome Trust Senior Investigator Award 104631/X/14/Z. EF received intramural funding from CPFT/NIHR-CRN supported setting the database

Action-sequence learning, habits and automaticity in obsessive-compulsive disorder

Enhanced habit formation, greater automaticity and impaired goal/habit arbitration in obsessive-compulsive disorder (OCD) are key hypotheses from the goal/habit imbalance theory of compulsion which have not been directly investigated. This article tests these hypotheses using a combination of newly developed behavioral tasks. First, we trained patients with OCD and healthy controls, using a novel smartphone app, to perform chunked action sequences, previously shown to engage habit brain circuitry. The motor training was daily over one month period. There was equivalent procedural learning and attainment of habitual performance (measured with an objective criteria of automaticity) in both groups, despite greater subjective habitual tendencies in patients with OCD, self-reported via a recently developed questionnaire. We then used a combination of follow-up behavioral tasks to further assess the arbitration between previous automatic and new goal-directed action sequences. We found no evidence for impairments of goal/habit arbitration in OCD following re-evaluation based on monetary feedback, although there was a greater preference for engaging in the trained habitual sequence under certain conditions which may have derived from its intrinsic value. These findings may lead to a reformulation of the goal/habit imbalance hypothesis in OCD. Finally, OCD patients with higher compulsivity scores and habitual tendencies showed more engagement with the motor habit-training app and reported symptom alleviation, with implications for its potential use as a form of habit reversal therapy

Neuropsychological and biological mechanisms of checking in OCD and clozapine induced Schizo-OCS

The introductory Chapter 1 reviewed several possible explanations of compulsive behaviour as manifested especially in Obsessive Compulsive Disorder (OCD), and schizophrenia, following treatment with the second generation antipsychotic medication clozapine. Particular focus is placed on compulsive checking behaviours and their relationship to current theories of compulsivity based on the hypothesis of imbalance between the goal-directed and habit systems and aberrant prediction-error learning. Chapter 2 describes experimental attempts in this thesis to measure human checking behaviour in the laboratory. Initially, a previously published test of checking was employed which however failed to show significant increases in OCD. I then designed a new testing procedure to measure checking, based on perceptual decision-making under a time constraint. This was administered together with other cognitive tests to patients with OCD, clozapine treated schizophrenia patients without and with obsessive compulsive symptoms, and a healthy volunteer group. In general, there were no major differences compared to controls, although patients with schizophrenia performed worse. In a second study, contingency degradation learning and checking were measured using a second variant of the task in which there was no time constraint. However, significant increases in checking behaviour were shown in another group of OCD patients compared with healthy volunteers. In Chapter 3, after a review of previous findings in OCD using the Magnetic Resonance Spectroscopy (MRS) technique at 7T, the same participants employed in the last checking study, were subjected to MRS scans to measure GABA, Glutamate (Glu), Glutamine (Gln), and NAA in three areas of brain including the Anterior Cingulate Cortex (ACC), Supplementary Motor Area (SMA) and the Visual Cortex. The most important findings were in the ACC, where significantly higher levels of Glu and Gln and lower levels of GABA and GABA:Glu ratio were found in OCD patients compared to the healthy group. In Chapter 4, the relationship between the behavioural results from chapter 2 and the neurometabolites measured with MRS in our OCD and healthy participants in chapter 3 was examined. The major findings were: 1) Higher ACC GABA/Glu ratio was related to superior accuracy of decision-making as well as increased checking on the checking task in OCD patients. 2) Checking was negatively correlated with SMA Glu in the healthy group but not in OCD. Moreover, in a test of goal directed behaviour and habit learning based on contingency degradation, a positive relationship was evident between performance and the ACC GABA/Glu ratios in patients for full degradation of the task contingencies. A similar positive relationship was observed for healthy volunteers for GABA/Glu ratios in SMA for partial degradation of the contingencies. Chapter 5 discusses neuropsychological interpretations of our findings in relation to the symptomatology of OCD and schizophrenia, together with their implications for understanding the role of the anterior cingulate cortex in decision-making and compulsive behaviour

Exploring visual processing of illusory contours in 22q11.2 deletion syndrome using high density EEG

In order to investigate the electroencephalographic (EEG) biomarkers of visual processing of illusory contours in schizophrenia, we studied patients with 22q11.2DS who are known to have 30% risk for developing schizophrenia in adulthood. This is much higher than the 1% risk in the general population and makes them a group with a high risk profile for schizophrenia. We performed high-density EEG source imaging to study the visual processing in response to illusory contours in 14 participants with 22q11.2DS and 15 age-matched healthy controls in the age range of 14 to 28 years. Two circle and square shapes were used that would form or not form an illusory contour. We found impairments at all the latencies for the 22q11.2DS, such as the P1, N1, Ncl and the visual P3. However, compared with controls, the patient group showed a good performance and significantly faster RT, that could be explained by overactivity of the DLPFC and the ACC, which may play a compensatory role. Moreover, there were also faster RTs and overactivity in the ACC in response to the illusory contours in both groups that could show the role of the ACC in attentional guiding towards relevance detection..

Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) Imaging in Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is characterised by structural and functional deficits in the cortico-striato-thalamic-cortical (CSTC) circuitry and abnormal neurochemical changes are thought to modulate these deficits. The hypoth- esis that an imbalanced concentration of the brain neurotransmitters, in particular glutamate (Glu) and gamma-amino-butyric acid (GABA), could impair the normal functioning of the CSTC, thus leading to OCD symptoms, has been tested in humans using magnetic resonance spectroscopy (MRS) and positron emission tomography (PET). This chapter summarises these neurochemical findings and represents an attempt to condense such scattered literature. We also discuss potential challenges in the field that may explain the inconsistent findings and suggest ways to overcome them. There is some convergent research from MRS pointing towards abnormalities in the brain concentration of neurometabolite markers of neuronal integrity, such as N-acetylaspartate (NAA) and choline (Cho). Lower NAA levels have been found in dorsal and rostral ACC of OCD patients (as compared to healthy volunteers), which increase after CBT and SSRI treatment, and higher Cho concentration has been reported in the thalamus of the OCD brain. However, findings for other neurometabolites are very inconsistent. Studies have reported abnormalities in the concentrations of creatine (Cr), GABA, glutamate (Glu), glutamine (Gln), Ins (myo-inositol), and serotonin (5-HT), but most of the results were not replicated. The question remains whether the NAA and Cho findings are genuinely the only neurochemical abnormalities in OCD or whether the lack of consistent findings for the other neurometabolites is caused by the lower magnetic field (1–3 Tesla (T)) used by the studies conducted so far, their small sample sizes or a lack of proper control for medication effects. To answer these questions and to further inform the biolog- ical underpinning of the symptoms and the cognitive problems at the basis of OCD we need better controlled studies using clear medicated vs unmedicated groups, larger sample sizes, stronger magnetic fields (e.g. at 7 T), and more consistency in the definition of the regions of interest

Abnormal development of early auditory processing in 22q11.2 Deletion Syndrome

Abstract The 22q11.2 Deletion Syndrome (22q11.2 DS) is one of the highest genetic risk factors for the development of schizophrenia spectrum disorders. In schizophrenia, reduced amplitude of the frequency mismatch negativity (fMMN) has been proposed as a promising neurophysiological marker for progressive brain pathology. In this longitudinal study in 22q11.2 DS, we investigate the progression of fMMN between childhood and adolescence, a vulnerable period for brain maturation. We measured evoked potentials to auditory oddball stimuli in the same sample of 16 patients with 22q11.2 DS and 14 age-matched controls in childhood and adolescence. In addition, we cross-sectionally compared an increased sample of 51 participants with 22q11.2 DS and 50 controls divided into two groups (8–14 and 14–20 years). The reported results are obtained using the fMMN difference waveforms. In the longitudinal design, the 22q11.2 deletion carriers exhibit a significant reduction in amplitude and a change in topographic patterns of the mismatch negativity response from childhood to adolescence. The same effect, reduced mismatch amplitude in adolescence, while preserved during childhood, is observed in the cross-sectional study. These results point towards functional changes within the brain network responsible for the fMMN. In addition, the adolescents with 22q11.2 DS displayed a significant increase in amplitude over central electrodes during the auditory N1 component. No such differences, reduced mismatch response nor increased N1, were observed in the typically developing group. These findings suggest different developmental trajectories of early auditory sensory processing in 22q11.2 DS and functional changes that emerge during the critical period of increased risk for schizophrenia spectrum disorders

Action sequence learning, habits, and automaticity in obsessive-compulsive disorder

Peer reviewed: TrueFunder: Mental Health Research UK; FundRef: http://dx.doi.org/10.13039/100009981Enhanced habit formation, greater automaticity and impaired goal/habit arbitration in obsessive-compulsive disorder (OCD) are key hypotheses from the goal/habit imbalance theory of compulsion which have not been directly investigated. This article tests these hypotheses using a combination of newly developed behavioral tasks. First, we trained patients with OCD and healthy controls, using a novel smartphone app, to perform chunked action sequences, previously shown to engage habit brain circuitry. The motor training was daily over one month period. There was equivalent procedural learning and attainment of habitual performance (measured with an objective criteria of automaticity) in both groups, despite greater subjective habitual tendencies in patients with OCD, self-reported via a recently developed questionnaire. We then used a combination of follow-up behavioral tasks to further assess the arbitration between previous automatic and new goal-directed action sequences. We found no evidence for impairments of goal/habit arbitration in OCD following re-evaluation based on monetary feedback, although there was a greater preference for engaging in the trained habitual sequence under certain conditions which may have derived from its intrinsic value. These findings may lead to a reformulation of the goal/habit imbalance hypothesis in OCD. Finally, OCD patients with higher compulsivity scores and habitual tendencies showed more engagement with the motor habit-training app and reported symptom alleviation, with implications for its potential use as a form of habit reversal therapy

Excessive Checking in Obsessive-Compulsive Disorder: Neurochemical Correlates Revealed by 7T Magnetic Resonance Spectroscopy

Background Compulsive checking, a common symptom of obsessive-compulsive disorder (OCD), has been difficult to capture experimentally. Therefore, determination of its neural basis remains challenging, despite some evidence suggesting it is linked to dysfunction of cingulo-striatal systems. This study introduces a novel experimental paradigm to measure excessive checking and its neurochemical correlates. Methods Thirty-one OCD and twenty-nine healthy volunteers performed a decision-making task requiring them to decide whether two perceptually similar visual representations were the same or different under a high uncertainty condition without feedback. Both groups underwent magnetic resonance spectroscopy scans at 7-Tesla on the same day. Correlations between out-of-scanner experimental measures of checking and the Glutamate/GABA ratio in the anterior cingulate cortex (ACC), supplementary motor area (SMA) and occipital cortex (OCC) were assessed. Their relationship with subjective ratings of doubt, anxiety and confidence was also investigated. Results OCD patients exhibited excessive and dysfunctional checking, which significantly correlated with changes in the Glutamate/GABA ratio within the ACC. No behavioral/neurochemical relationships were evident for either the SMA or OCC. Excessive checking observed in patients negatively correlated with their confidence levels and positively related to doubt, anxiety and compulsivity traits. Conclusions We conclude that experimental measures of excessive and dysfunctional checking in OCD, linked to increased doubt, anxiety and lack of confidence, are related to an imbalance between excitatory and inhibitory neural activity within the ACC. This study adds to our understanding of the role of this region in OCD in providing a laboratory model of the possible development of compulsive checking

Clozapine-related obsessive-compulsive symptoms and their impact on wellbeing: a naturalistic longitudinal study.

BACKGROUND: Obsessive-compulsive symptoms (OCS) are commonly associated with clozapine treatment but are frequently overlooked by clinicians despite their potential impact on patients' quality of life. In this study, we explored whether OCS severity impacted subjective wellbeing and general functioning, independently of depressive and psychotic symptoms. METHODS: We used anonymised electronic healthcare records from a large cohort of patients who were treated with clozapine and assessed annually for OCS, wellbeing, general functioning, and psychopathology using standardised scales as part of routine clinical practice. We used statistical mixed linear model techniques to evaluate the longitudinal influence of OCS severity on wellbeing and general functioning. RESULTS: A total of 184 patients were included, with 527 face-to-face assessments and 64.7% evaluated three or more times. Different linear mixed models demonstrated that OCS in patients treated with clozapine were associated with significantly worse wellbeing scores, independently of depression and psychotic symptoms, but OCS did not impair general functioning. Obsessional thinking and hoarding behaviour, but not compulsions, were significantly associated with the impact on wellbeing, which may be attributable to the ego-syntonic nature of the compulsions. CONCLUSIONS: Given the frequent occurrence of OCS and their negative impact on wellbeing, we encourage clinicians to routinely assess and treat OCS in patients who are taking clozapine.This research was supported in part by the NIHR Cambridge Biomedical Research Centre (BRC) and the Wellcome Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Wellcome Trust, or the Department of Health and Social Care