Paralytic ileus in a patient on clozapine therapy showing an inverted clozapine/norclozapine ratio after switching valproic acid to carbamazepine: a case report.

This case report examines the possible correlation between the clozapine/norclozapine ratio and the occurrence of constipation and paralytic ileus. We present the case of a 42-year-old patient diagnosed with schizoaffective disorder undergoing clozapine therapy. Despite intensive treatment with clozapine, haloperidol, valproic acid and biweekly electroconvulsive therapy sessions for over a year, florid psychotic symptoms and fluctuating mood swings persisted. Therefore, valproic acid was replaced by carbamazepine, a potent inducer of several CYP450-enzymes. To maintain clozapine plasma levels, fluvoxamine, a CYP1A2-inhibitor, was introduced at a dose of 25 mg before this switch. After addition of carbamazepine, there was a significant decline in clozapine levels, necessitating an increase in fluvoxamine dosage to 50 mg. Five weeks later the patient was admitted to a general hospital with a diagnosis of paralytic ileus. Treatment with enemas proved effective. Drug concentration analysis revealed a 2.5-fold increase in norclozapine levels in the weeks preceding hospital admission, resulting in an inverted clozapine/norclozapine ratio. Treatment with clozapine, carbamazepine and fluvoxamine was continued as the patient demonstrated clinical improvement on carbamazepine. Concurrently, an intensive laxative regimen was initiated. Two weeks later, the patient was readmitted to the general hospital due to suspected paralytic ileus and faecal vomiting, once again displaying an inverted clozapine/norclozapine ratio. We discuss potential mechanisms contributing to the occurrence of the paralytic ileus in this patient, including the antagonism of muscarinic M3 receptors by both clozapine and norclozapine, as well as the agonism of delta-opioid receptors by norclozapine. This case highlights the potential significance of both the clozapine/norclozapine ratio and absolute norclozapine levels as risk factors for constipation and paralytic ileus in patients on clozapine therapy.

Acceptance and Commitment Therapy for individuals at risk for psychosis or with a first psychotic episode: A qualitative study on patients' perspectives.

AIM: The aim of this qualitative study is to explore patients' perspectives on Acceptance and Commitment Therapy for early stages of psychosis. Therefore, we interviewed participants of the INTERACT study, that quantitatively investigated Acceptance and Commitment Therapy in Daily Life (ACT-DL) in combination with treatment as usual, for early stages of psychosis, comparing it to treatment as usual. METHODS: Within 6 months after finishing ACT-DL, we conducted semi-structured, individual interviews with 19 participants. All interviews were audio-recorded and transcribed. Thematic analysis was used for coding and analysis. RESULTS: Two overarching themes were formed: 'the meaning of ACT' and 'what to improve'. Considering the first, participants generally understood and connected with the meaning of ACT, noticing more awareness and acceptance of their thoughts and feelings, and living more in line with their personal values. The second theme included comments on the protocol not being personal or psychosis specific enough and some elements of ACT being too difficult to understand when having active psychotic symptoms. CONCLUSIONS: This study suggests that ACT is an acceptable and promising new form of treatment for early stages of psychosis, and it provides relevant information to further develop ACT for this group.

"As a psychiatry resident I am invited to explore my identity. But when I accept that invitation, I still encounter a wall." A qualitative study on inclusion experienced by psychiatry residents with a migration background, sexual minority identity and/or working-class background.

Diversity in terms of class, sexual identity and migration background among medical students in high income countries has increased greatly in recent decades. Some research into the experiences of these new groups of doctors has been performed. However, no previous research into the experiences of psychiatry residents specifically, is known. This qualitative study investigates how psychiatry residents, from these minoritized groups, experience their training regarding inclusion. Inclusion is defined as the degree to which one's needs for connection and for being valued in one's uniqueness, is satisfied. In-depth interviews with 16 psychiatry residents were conducted. These interviews were transcribed and coded using MaxQDA software. Initial themes that were constructed, were explored further in subsequent interviews and linked to literature. Finally, the developed themes were ordered in a model conceptualizing inclusion. Participants reported high belongingness within psychiatry training. Their experienced value in uniqueness, however, was generally quite low. Participants reported to experience little interest in and sensitivity for their perspectives and lived experiences from their co-workers. When faced with stigmatization and discrimination, participants reported lack of support from their colleagues. Assimilation was found to be the most frequently used coping strategy in dealing with diversity. Participants seemed to conform to the 'neutral' norm and experienced barriers in expressing themselves. Through this mechanism of assimilation, the added value that participants might bring with their unique knowledge and lived experiences was not used, both in patient care and in creating an inclusive climate within the organization. Moreover, assimilation is associated with psychological strain.

Patients' and volunteer coaches' experiences with an informal social network intervention in forensic psychiatric care: a qualitative analysis.

BACKGROUND: Improving supportive social networks in forensic psychiatric patients is deemed important due to the protective effects of such networks on both mental health problems and criminal recidivism. Informal interventions targeted at social network enhancement by community volunteers showed positive effects in various patient and offender populations. However, these interventions have not specifically been studied in forensic psychiatric populations. Therefore, forensic psychiatric outpatients' and volunteer coaches' experiences with an informal social network intervention were explored in this study. METHODS: This qualitative study was based on semi-structured interviews conducted alongside an RCT. Forensic outpatients allocated to the additive informal social network intervention, and volunteer coaches, were interviewed 12 months after baseline assessment. Interviews were audio-recorded and transcribed verbatim. Reflexive thematic analysis was used to identify and report patterns in the data. RESULTS: We included 22 patients and 14 coaches in the study. The analysis of interviews revealed five main themes reflecting patients' and coaches' experiences: (1) dealing with patient receptivity, (2) developing social bonds, (3) receiving social support, (4) achieving meaningful change, and (5) using a personalized approach. Patient receptivity, including willingness, attitudes, and timing, was a common reported barrier affecting patients' engagement in the intervention. Both patients' and coaches' experiences confirmed that the intervention can be meaningful in developing new social bonds between them, in which patients received social support. Despite, experiences of meaningful and sustainable changes in patients' social situations were not clearly demonstrated. Coaches' experiences revealed broadened worldviews and an enhanced sense of fulfillment and purpose. Finally, a personalized, relationship-oriented rather than goal-oriented approach was feasible and preferable. CONCLUSION: This qualitative study showed positive experiences of both forensic psychiatric outpatients and volunteer coaches with an informal social network intervention in addition to forensic psychiatric care. Notwithstanding the limitations, the study suggests that these additive interventions provide an opportunity for forensic outpatients to experience new positive social interactions with individuals in the community, which can initiate personal development. Barriers and facilitators to engagement are discussed to improve further development and implementation of the intervention. TRIAL REGISTRATION: This study is registered at the Netherlands Trial Register (NTR7163, registration date: 16/04/2018).

Medication strategies in first episode psychosis patients: A survey among psychiatrists.

AIM: There is an ongoing debate regarding the optimal timing of discontinuation of antipsychotic drugs for patients with first episode psychosis. Although most guidelines recommend maintenance therapy for at least 1 or 2 years after reaching remission, study results indicate that early discontinuation may be beneficial for at least a subsample of patients. To date, little is known about which medication strategies are applied in patients recovering from a first psychotic episode. In this study, we examined the beliefs and practices of clinicians on medication discontinuation. METHODS: We performed a survey among 50 experienced Dutch psychiatrists to assess how often specific treatment strategies have been applied in the past 12 months, as well as their knowledge and expectations with respect to medication discontinuation. RESULTS: Psychiatrists estimated that, after remission, they continued medication at the same dose for at least 12 months in 51.2% of cases, continued in a reduced dose in 33.8% of cases and discontinued medication in 9.1% of cases after 4.4 months of remission on average. Although the medication is discontinued in only a relatively small proportion of patients, almost half of all clinicians (45.9%) used this strategy at least once in the past 12 months. CONCLUSIONS: There is substantial practice variation in antipsychotic medication strategies after remission from a first psychotic episode. Future research on long-term effects of early medication discontinuation can guide clinicians in making evidence-based decisions when treating first-episode patients.

Subjective Medication Satisfaction With Antipsychotic Polypharmacy in a Naturalistic Inpatient and Outpatient Sample.

Objective: The aim of this study was to examine satisfaction with pharmacologic treatment in patients who received antipsychotic polypharmacy compared to antipsychotic monotherapy.Methods: This longitudinal cohort study was conducted in two mental health care institutes in Amsterdam, the Netherlands, among a randomly selected sample of in- and outpatients with a severe mental illness. Analyses were performed on data collected in 2011 for 185 patients who were diagnosed with schizophrenia or unspecified psychosis according to DSM-IV criteria. The outcome measure was the Treatment Satisfaction Questionnaire for Medication, version II. One-way analyses of covariance were performed to examine differences in treatment satisfaction between patients who received antipsychotic polypharmacy compared to antipsychotic monotherapy while controlling for the effects of clozapine, antipsychotic dose, and use of long-acting injectable antipsychotics.Results: Twenty percent of patients in this sample received 2 antipsychotic agents; in half of those patients, this involved a combination with clozapine. Polypharmacy resulted in less satisfaction with side effects compared to monotherapy (P = .002). No difference was found in perceived effectiveness (P = .168) or overall medication satisfaction (P = .379).Conclusions: These results confirm that antipsychotic polypharmacy is common in a random in- and outpatient sample. Patients who receive 2 antipsychotic agents are just as positive about the effectiveness and ease of use of and overall satisfaction with their medication compared to those who receive antipsychotic monotherapy. They are, however, less satisfied with perceived side effects of their medication, which may indicate that side effect profiles of antipsychotic combinations are less favorable.

Individualized prediction of three- and six-year outcomes of psychosis in a longitudinal multicenter study: a machine learning approach.

Schizophrenia and related disorders have heterogeneous outcomes. Individualized prediction of long-term outcomes may be helpful in improving treatment decisions. Utilizing extensive baseline data of 523 patients with a psychotic disorder and variable illness duration, we predicted symptomatic and global outcomes at 3-year and 6-year follow-ups. We classified outcomes as (1) symptomatic: in remission or not in remission, and (2) global outcome, using the Global Assessment of Functioning (GAF) scale, divided into good (GAF ≥ 65) and poor (GAF < 65). Aiming for a robust and interpretable prediction model, we employed a linear support vector machine and recursive feature elimination within a nested cross-validation design to obtain a lean set of predictors. Generalization to out-of-study samples was estimated using leave-one-site-out cross-validation. Prediction accuracies were above chance and ranged from 62.2% to 64.7% (symptomatic outcome), and 63.5-67.6% (global outcome). Leave-one-site-out cross-validation demonstrated the robustness of our models, with a minor drop in predictive accuracies of 2.3% on average. Important predictors included GAF scores, psychotic symptoms, quality of life, antipsychotics use, psychosocial needs, and depressive symptoms. These robust, albeit modestly accurate, long-term prognostic predictions based on lean predictor sets indicate the potential of machine learning models complementing clinical judgment and decision-making. Future model development may benefit from studies scoping patient's and clinicians' needs in prognostication.

The bumpy road to achieve reliability of clinical profile characteristics in psychosis and related disorders.

OBJECTIVES: Profile characteristics are factors that are relevant for diagnosis, prognosis or treatment. The present study aims to develop a set of clinically relevant profile characteristics. Moreover, our goal is to determine the inter-rater reliability (IRR) of the selected profile characteristics. METHODS: Potential profile characteristics were determined by literature review. Assessment of IRR was done by comparing scores on profile characteristics determined by two researchers. We conducted three subsequent studies: (1) assessment of pre-training IRR, (2) IRR following implementation of an instruction manual, (3) IRR after optimizing scoring methods. IRR was measured with the Intraclass Correlation Coefficient (ICC). RESULTS: IRR scores of profile characteristic Illegal activities were high across the three studies (ICC ≥ 0.75). Following training procedures in study 2 and 3, reliability estimates remained low to moderate (ICC < 0.75) for the profile characteristics Support of relatives, Aggression recent and lifetime, substance use and insight recent. IRR scores of the other eight profile characteristics varied from low, moderate to high across studies. CONCLUSION: IRR scores of profile characteristics were highly variable, and mostly inadequate in all three studies. Consequently, further research should focus on specification of severity scores of profile characteristics, optimizing scoring methods and re-evaluation of IRR.

Association between cognitive phenotype in unaffected siblings and prospective 3- and 6-year clinical outcome in their proband affected by psychosis.

BACKGROUND: Cognitive alterations are a central and heterogeneous trait in psychotic disorders, driven by environmental, familial and illness-related factors. In this study, we aimed to prospectively investigate the impact of high familial risk for cognitive alterations, unconfounded by illness-related factors, on symptomatic outcomes in patients. METHODS: In total, 629 probands with non-affective psychosis and their sibling not affected by psychosis were assessed at baseline, 3- and 6-year follow-up. Familial cognitive risk was modeled by three cognitive subtypes ('normal', 'mixed' and 'impaired') in the unaffected siblings. Generalized linear mixed models assessed multi-cross-sectional associations between the sibling cognitive subtype and repeated measures of proband symptoms across all assessments. Between-group differences over time were assessed by adding an interaction effect of time and sibling cognitive subtype. RESULTS: Probands affected by psychosis with a sibling of the impaired cognitive subtype were less likely to be in symptomatic remission and showed more disorganization across all time points. When assessing differences over time, probands of siblings with the impaired cognitive subtype showed less remission and less improvement of disorganization after 3 and 6 years relative to the other subtypes. They also showed less reduction of positive, negative and excitement symptoms at 6-year follow-up compared to probands with a sibling of the normal cognitive subtype. CONCLUSIONS: Cross-sibling pathways from higher levels of familial cognitive vulnerability to worse long-term outcomes may be informative in identifying cognition-related environmental and genetic risks that impact psychotic illness heterogeneity over time.

The impact of affective symptoms on personal recovery of patients with severe mental illness.

BACKGROUND: Clinical recovery is often defined as remission of symptoms. Personal recovery is described as growing beyond the catastrophic effects of mental illness, sometimes despite ongoing symptoms. AIMS: To examine the relationship between the severity of clinical symptom domains and personal recovery in patients with severe mental illness (SMI). METHODS: Symptom severity and personal recovery of 105 outpatients with SMI at Mentrum, part of Arkin Institute for Mental Health in Amsterdam, the Netherlands, were assessed using the Brief Psychiatric Rating Scale-Expanded Version (BPRS-E) and the Mental Health Recovery Measure (MHRM). Correlation and regression analyses were used to investigate the associations. RESULTS: The multiple regression analysis showed that only affective symptoms significantly predicted personal recovery, whereas neither positive nor negative symptom severity added to the explained variance in the model. CONCLUSION: The association between affective symptoms and personal recovery in patients with SMI implies that treatment of affective symptoms may advance personal recovery, and/or support of personal recovery may improve mood, whereas focussing on treatment of psychotic symptoms might not be the key to personal recovery. More research is needed to elucidate causal interrelations.

Dopamine in high-risk populations: A comparison of subjects with 22q11.2 deletion syndrome and subjects at ultra high-risk for psychosis.

Striatal dopamine (DA) dysfunction has been consistently reported in psychotic disorders. Differences and similarities in the pathogenesis between populations at clinical and genetic risk for developing psychosis are yet to be established. Here we explored markers of dopamine (DA) function in subjects meeting clinically ultra-high risk criteria for psychosis (UHR) and in subjects with 22q11.2 deletion syndrome (22q11DS), a genetic condition associated with significant risk for developing psychotic disorders. Single Photon Emission Computed Tomography (SPECT) with 123I-labelled iodobenzamide ([123I]IBZM) was used to measure striatal DA D2/3 receptor binding potential (D2R BPND). Also, peripheral DAergic markers were assessed in serum and urine (plasma prolactin (pPRL), plasma homovanillic acid (pHVA) and urine DA(uDA)). No significant difference in striatal D2R BPND was found between UHR and 22q11DS subjects. Compared to UHR subjects, pPRL and pHVA were lower and uDA levels were higher in the 22q11DS subjects. However, after correcting for age and gender, only pPRL as significantly lower in the 22q11DS patients. These results may suggest that there are differences in DAergic markers between subjects with UHR and with 22q11DS that may reflect differences in the pathways to psychosis. However, bigger samples are needed to replicate these findings.

Homesick: residential and care patterns in patients with severe mental illness.

BACKGROUND: Changes in the residential and care settings of patients with severe mental illness (SMI) are a concern because of the large variety of possible negative consequences. This study describes patterns of changes in the residential and care settings of SMI patients and explores associations between these changes, sociodemographics, and clinical characteristics. METHODS: From January 2006 to January 2012, all data relating to changes in residential and/or care setting by SMI patients (N = 262) were collected from electronic case files. Data covering psychopathology, substance use, and medication adherence were assessed in 2006. RESULTS: There were more changes in the residential than in the care setting. In 6 years, only 22% of our sample did not move, 23% changed residence once, 19% twice, 10% three times, and 26% four or more times. Substance use predicted changes of care and/or residential setting and rehospitalisation. The severity of negative symptoms predicted rehospitalisation and duration of hospitalisation. Disorganisation symptoms predicted the duration of hospitalisation. CONCLUSIONS: A majority of patients with SMI changed residential and/or care settings several times in 6 years. Patients with substance use or severe negative and disorganisation symptoms may need more intensive and customised treatment. Further research is needed to investigate prevention programmes for highly-frequent movers.

Cortical Morphology Differences in Subjects at Increased Vulnerability for Developing a Psychotic Disorder: A Comparison between Subjects with Ultra-High Risk and 22q11.2 Deletion Syndrome.

INTRODUCTION: Subjects with 22q11.2 deletion syndrome (22q11DS) and subjects with ultra-high risk for psychosis (UHR) share a risk of approximately 30% to develop a psychotic disorder. Studying these groups helps identify biological markers of pathophysiological processes involved in the development of psychosis. Total cortical surface area (cSA), total cortical grey matter volume (cGMV), cortical thickness (CT), and local gyrification index (LGI) of the cortical structure have a distinct neurodevelopmental origin making them important target markers to study in relation to the development of psychosis. MATERIALS AND METHODS: Structural T1-weighted high resolution images were acquired using a 3 Tesla Intera MRI system in 18 UHR subjects, 18 22q11DS subjects, and 24 matched healthy control (HC) subjects. Total cSA, total cGMV, mean CT, and regional vertex-wise differences in CT and LGI were assessed using FreeSurfer software. The Positive and Negative Syndrome Scale was used to assess psychotic symptom severity in UHR and 22q11DS subjects at time of scanning. RESULTS: 22q11DS subjects had lower total cSA and total cGMV compared to UHR and HC subjects. The 22q11DS subjects showed bilateral lower LGI in the i) prefrontal cortex, ii) precuneus, iii) precentral gyrus and iv) cuneus compared to UHR subjects. Additionally, lower LGI was found in the left i) fusiform gyrus and right i) pars opercularis, ii) superior, and iii) inferior temporal gyrus in 22q11DS subjects compared to HC. In comparison to 22q11DS subjects, the UHR subjects had lower CT of the insula. For both risk groups, positive symptom severity was negatively correlated to rostral middle frontal gyrus CT. CONCLUSION: A shared negative correlation between positive symptom severity and rostral middle frontal gyrus CT in UHR and 22q11DS may be related to their increased vulnerability to develop a psychotic disorder. 22q11DS subjects were characterised by widespread lower degree of cortical gyrification linked to early and postnatal neurodevelopmental pathology. No implications for early neurodevelopmental pathology were found for the UHR subjects, although they did have distinctively lower insula CT which may have arisen from defective pruning processes during adolescence. Implications of these findings in relation to development of psychotic disorders are in need of further investigation in longitudinal studies.

Glutamatergic markers, age, intellectual functioning and psychosis in 22q11 deletion syndrome.

RATIONALE: Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of intellectual disabilities and psychiatric disorders, including psychosis. Haplo-insufficiency of genes in the deleted region may offer a partial explanation for the increased vulnerability for psychosis and intellectual disability. One gene of particular interest is the gene coding for proline dehydrogenase (PRODH), an enzyme responsible for the conversion of proline into glutamate. OBJECTIVES: Because abnormalities in glutamatergic signaling are thought to be responsible for cognition and psychosis in the general population, we hypothesized that PRODH haplo-insufficiency may underlie some of the cognitive and psychotic features seen in 22q11DS. METHODS: In this explorative study, we investigated the relation between plasma proline, glutamate, and glutamine and age, intelligence, and psychosis in 64 adults with 22q11DS. RESULTS: Hyperprolinemia was found in 31.3% of subjects with 22q11DS. A relation between glutamine, glutamate, proline, and presence of psychosis was not observed. Regression analysis revealed a positive relation between plasma glutamate and age, a positive relation of glutamate with antipsychotic drugs, a relation of glutamine and gender, and a positive relation of glutamine and mood stabilizing drugs, and a negative relation of the ratio glutamine/glutamate and age. The group with relatively lower IQ had higher glutamate levels compared to the group with relatively higher IQ. CONCLUSIONS: Our results suggest that 22q11DS is accompanied by abnormalities in glutamatergic metabolism. Future longitudinal studies are needed to further investigate the glutamatergic system in 22q11DS and how this affects the development of cognitive problems and psychopathology.

PRODH rs450046 and proline x COMT Val¹58 Met interaction effects on intelligence and startle in adults with 22q11 deletion syndrome.

RATIONALE: 22q11 deletion syndrome (22q11DS) is associated with an increased risk for psychotic disorders, suggesting a relationship between genotypes and the pathophysiology of psychotic disorders. Two genes in the deleted region, catechol-O-methyl-transferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH), contain polymorphisms associated with neuropsychiatric phenotypes. OBJECTIVES: Here, we explored the association between polymorphisms and full-scale intelligence (FSIQ), startle reactivity (SR) and prepulse inhibition (PPI) in adults with 22q11DS. METHODS: Forty-five adults with 22q11DS were genotyped for PRODH rs450046, rs372055 and COMT Val(158)Met. Plasma proline levels, FSIQ, SR and PPI were measured. RESULTS: Thirty-five percent of the subjects were hyperprolinemic with a median proline value of 456 µmol/L. C allele carriers of PRODH rs450046 had a lower FSIQ compared to T allele carriers, indicating the C allele to be a risk allele (C allele: mean FSIQ 60.2 (sd 8.7); T allele: mean FSIQ 73.7 (sd 11.5); F 1,43 = 7.59; p = 0.009; partial η (2) = 0.15). A significant interaction effect of proline levels and COMT Val(158)Met genotype was found for SR (F 1,16 = 7.9; p = 0.01; partial η (2) = 0.33), but not for PPI and FSIQ. In subjects with hyperprolinemia, the COMT Val(158)Met genotype effect on SR was stronger than in subjects with normal proline levels. CONCLUSIONS: Overall, these data provide further evidence for the risk effect of elevated proline levels combined with the COMT Met allele and support the possibilities of using 22q11DS as a model to investigate genotype effects on psychiatric disorders.

Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis.

Reduced prepulse inhibition (PPI) of the acoustic startle response is thought to represent a robust biomarker in schizophrenia. Reduced PPI has been demonstrated in subjects at ultra high risk (UHR) for developing psychosis. Imaging studies report disruption of striatal dopaminergic neurotransmission in patients with schizophrenia. First, we compared the PPI of the acoustic startle response in UHR subjects versus healthy controls, to see if we could replicate previous findings of reduced PPI; secondly, we investigated our hypothesis that PPI would be negatively correlated with striatal synaptic dopamine (DA) concentration. We measured the startle reactivity and PPI of the acoustic startle response in 14 UHR subjects, and 14 age- and gender-matched healthy controls. Imaging of 11 UHR subjects and 11 healthy controls was completed by an [(123)I]-IBZM (radiotracer for dopamine D2/3 receptors) SPECT, at baseline and again after DA depletion with alpha-methyl-para-tyrosine (AMPT). The percentage change in striatal [(123)I]-IBZM radiotracer binding potential is a proxy of striatal synaptic DA concentration. UHR subjects showed reduced PPI, compared to control subjects. In both UHR and control subjects, there were no significant correlations between striatal synaptic DA concentration and PPI. We provide further evidence for the hypothesis that these two biomarkers are measuring different aspects of pathophysiology.

Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at Ultra High Risk for psychosis.

Altered striatal dopaminergic neurotransmission is thought to be fundamental to schizophrenia. Increased presynaptic dopaminergic activity ([18F]-DOPA PET) may predate the onset of psychotic symptoms and correlates to clinical symptoms in subjects at Ultra High Risk (UHR) for developing psychosis. Postsynaptic dopaminergic neurotransmission has not been investigated yet in UHR patients. We hypothesized that synaptic dopamine concentration would be increased in UHR patients, and that synaptic dopamine concentration would be related to symptom severity. 14 UHR patients and 15 age and IQ matched controls completed an [123I]-IBZM SPECT scan at baseline and again after dopamine depletion with alpha-methyl-para-tyrosine (AMPT). We measured changes in radiotracer binding potential, compared these between UHR patients and controls, and correlated these to symptom severity. The UHR group as a whole did not differ significantly from controls. AMPT significantly reduced symptom severity in the UHR group (p=0.014). Higher synaptic dopamine concentration predicted larger reduction of positive symptoms following depletion in the UHR group (p=0.01). In UHR patients, positive symptoms responded to dopamine depletion, comparable to observations in schizophrenia, suggesting a similar mechanism. Higher synaptic dopamine concentration was associated with more severe positive symptoms and a greater reduction of these symptoms following depletion.

Startle reactivity and prepulse inhibition of the acoustic startle response are modulated by catechol-O-methyl-transferase Val(158) Met polymorphism in adults with 22q11 deletion syndrome.

22q11 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22, which includes the gene coding for catechol-O-methyl-transferase (COMT). High dopamine (DA) levels due to COMT haplo-insufficiency may be associated with the increased risk of developing schizophrenia in adults with 22q11DS. Reduced prepulse inhibition (PPI) of the acoustic startle response has been associated with schizophrenia and with disrupted DAergic transmission in the prefrontal cortex (PFC). COMT Val(158)Met polymorphism has been shown to influence PPI. We report the first study in adults with 22q11DS to examine PPI of the acoustic startle response and its modulation by COMT Val(158)Met polymorphism. Startle reactivity (SR) and PPI of the acoustic startle response were measured in 23 adults with 22q11DS and 21 healthy controls. 22q11DS subjects were genotyped for the functional COMT Val(158)Met polymorphism. 22q11DS Met hemizygotes showed reduced SR and PPI compared with 22q11DS Val hemizygotes. The effect of COMT Val(158)Met polymorphism on PPI was no longer significant when controlling for baseline SR. Met hemizygosity in 22q11DS is associated with reduced SR and influences PPI indirectly. Decreased PFC functioning following excessive PFC DA levels may be one of the mechanisms by which the Met genotype in 22q11DS disrupts SR.