Jens Richardt Møllegaard Jepsen

Predictors and longitudinal course of cognitive functioning in schizophrenia spectrum disorders, 10 years after baseline: The OPUS study

BACKGROUND Identifying baseline predictors of the long-term course of cognitive functioning in schizophrenia spectrum disorders is important because of associations between cognitive functioning (CF) and functional outcome. Determining whether CF remains stable or change during the course of illness is another matter of interest. METHODS Participants from The Danish OPUS Trial, aged 18-45years, with a baseline ICD-10 schizophrenia spectrum diagnosis, were assessed on psychopathology, social and vocational functioning at baseline, and cognitive functioning 5 (N=298) and 10years (N=322) after baseline. Uni- and multi-variable regression analyses of potential baseline predictors of 10-year CF were performed. Also, changes in CF and symptomatology between 5 and 10years of follow-up were assessed. FINDINGS Baseline predictors of impaired CF after 10years included male gender, unemployment, poor premorbid achievement and later age of onset. Having finished high school and receiving early intervention treatment was associated with better CF. Age, growing up with both parents, number of family and friends, primary caregivers education, premorbid social function, negative symptoms, GAF (symptoms, function) and substance abuse, were associated with CF in univariable analyses. Non-participants generally suffered from more severe dysfunction. Longitudinally, amelioration in negative symptoms was associated with improved speed of processing and executive functions. Symptom scores generally improved with time, while scores for all cognitive tests remained stable. CONCLUSION The current study identifies several robust associations between baseline characteristics and 10-year cognitive outcome. Several other variables were univariably associated with 10-year cognitive outcome. Also, we found evidence for stability of CF over time.

Five years of specialised early intervention versus two years of specialised early intervention followed by three years of standard treatment for patients with a first episode psychosis: randomised, superiority, parallel group trial in Denmark (OPUS II)

Objective To compare the effects of five years of specialised early intervention (SEI) treatment for first episode schizophrenia spectrum disorder with the standard two years of SEI plus three years of treatment as usual. Design Randomised, superiority, parallel group trial with blinded outcome assessment. Randomisation was centralised and computerised with concealed randomisation sequence carried out at an external site. Setting Participants were recruited from six OPUS teams in Denmark between 2009 and 2012. OPUS teams provide SEI treatment to all patients diagnosed with a schizophrenia spectrum disorder in Denmark. Participants 400 participants (51% women) with a mean age of 25.6 (standard deviation 4.3) were randomised to five years of SEI (experimental intervention; n=197) or to two years of SEI plus three years of treatment as usual (control; n=203). Interventions OPUS treatment consists of three core elements—modified assertive community treatment, family involvement, and social skill training—with a patient-case manager ratio of no more than 12:1. For participants randomised to five years of OPUS treatment, the treatment was largely unchanged. Participants randomised to the control group were mostly referred to community health centres after two years of SEI treatment. Main outcomes Follow-up assessments were conducted five years after start of OPUS treatment. Primary outcome was negative symptoms measured on the scale for assessment of negative symptoms (avolition-apathy, anhedonia, alogia, and affective blunting). Secondary outcomes were remission of both negative and psychotic symptoms, psychotic symptoms, suicidal ideation, substance abuse, compliance with medical treatment, adherence with treatment, client satisfaction, days in hospital care, and labour market affiliation. Results Levels of negative symptoms did not differ between the intervention group and control group (1.72 v 1.81 points; estimated mean difference −0.10 (95% confidence interval 0.33 to 0.13), P=0.39). Participants receiving five years of OPUS treatment were more likely to remain in contact with specialised mental health services (90.4% v 55.6%, P<0.001), had higher client satisfaction (estimated mean difference 2.57 points (95% confidence interval 1.36 to 3.79), P<0.001), and had a stronger working alliance (estimated mean difference 5.56 points (95% confidence interval 2.30 to 8.82), P=0.001) than the control group. Conclusions This trial tests SEI treatment for up to five years for patients with first episode schizophrenia spectrum disorder; previous trials have found treatment effects for programmes lasting from one to three years. The prolonged SEI treatment had few effects, which could be due to the high level of treatment provided to control participants and the late start of specialised treatment. Trial registration Clinicaltrial.gov NCT00914238.

Exploring 'The autisms' at a cognitive level

The autism spectrum is characterized by genetic and behavioral heterogeneity. However, it is still unknown whether there is a universal pattern of cognitive impairment in autism spectrum disorder (ASD) and whether multiple cognitive impairments are needed to explain the full range of behavioral symptoms. This study aimed to determine whether three widely acknowledged cognitive abnormalities (Theory of Mind (ToM) impairment, Executive Function (EF) impairment, and the presence of a Local Processing Bias (LB)) are universal and fractionable in autism, and whether the relationship between cognition and behavior is dependent on the method of behavioral assessment. Thirty‐one high‐functioning children with ASD and thirty‐seven children with neurotypical development (NTD), comparable in age, gender and Intelligence Quotient (IQ), completed several tasks tapping into ToM, EF, and LB, and autistic symptomatology was assessed through parental and teacher questionnaires, parental interview and direct observation. We found that ToM and EF deficits differentiated the groups and some ToM and EF tasks were related to each other. ToM and EF were together able to correctly classify more than three‐quarters of the children into cases and controls, despite relating to none of the specific behavioral measures. Only a small subgroup of individuals displayed a LB, which was unrelated to ToM and EF, and did not aid diagnostic classification, most likely contributing to non‐diagnostic symptoms in a subgroup. Despite the characteristic heterogeneity of the autism spectrum, it remains a possibility therefore that a single cognitive cause may underlie the range of diagnostic symptoms in all individuals with autism. Autism Res 2016, 9: 1328–1339.

Effects of an obesity intervention program on cognitive function in children: A randomized controlled trial.

Adiposity may be associated with poorer cognitive function in children. The purpose of the study was to examine the effects of an obesity intervention on cognitive function in children.

Normal P50 Gating in Children with Autism, Yet Attenuated P50 Amplitude in the Asperger Subcategory.

Autism spectrum disorders (ASD) and schizophrenia are separate disorders, but there is evidence of conversion or comorbid overlap. The objective of this paper was to explore whether deficits in sensory gating, as seen in some schizophrenia patients, can also be found in a group of ASD children compared to neurotypically developed children. An additional aim was to investigate the possibility of subdividing our ASD sample based on these gating deficits. In a case–control design, we assessed gating of the P50 and N100 amplitude in 31 ASD children and 39 healthy matched controls (8–12 years) and screened for differences between groups and within the ASD group. We did not find disturbances in auditory P50 and N100 filtering in the group of ASD children as a whole, nor did we find abnormal P50 and N100 amplitudes. However, the P50 amplitude to the conditioning stimulus was significantly reduced in the Asperger subgroup compared to healthy controls. In contrast to what is usually reported for patients with schizophrenia, we found no evidence for sensory gating deficits in our group of ASD children taken as a whole. However, reduced P50 amplitude to conditioning stimuli was found in the Asperger group, which is similar to what has been described in some studies in schizophrenia patients. There was a positive correlation between the P50 amplitude of the conditioning stimuli and anxiety score in the pervasive developmental disorder not otherwise specified group, which indicates a relation between anxiety and sensory registration in this group. Autism Res 2015, 8: 371–378.

Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial

BACKGROUND Head-to-head trials to guide antipsychotic treatment choices for paediatric psychosis are urgently needed because extrapolations from adult studies might not be implementable. In this superiority trial with two-sided significance testing, we aimed to compare the efficacy and safety of quetiapine-extended release (quetiapine-ER) versus aripiprazole in children and adolescents with first-episode psychosis, to determine whether differences between the two treatments were sufficient to guide clinicians in their choice of one drug over the other. METHODS In this multicentre, double-blind, randomised trial in seven Danish university clinics, we recruited children and adolescents aged 12-17 years with a diagnosis of ICD-10 schizophrenia-spectrum disorder, delusional disorder, or affective-spectrum psychotic disorder, and psychotic symptoms scoring at least 4 on at least one of the following Positive and Negative Syndrome Scale (PANSS) items: P1 (delusions), P2 (conceptual disorganisation), P3 (hallucinations), P5 (grandiosity), P6 (suspiciousness/persecution), and G9 (unusual thought content), and a total PANSS score greater than 60. Patients were randomly assigned (1:1) to 12 weeks of treatment with target doses of 600 mg/day of quetiapine-ER (starting from 50 mg/day) or 20 mg/day of aripiprazole (starting from 2·5 mg/day). The assigned drug was titrated over five levels, with 2 days at each dose, and the final dose achieved on day 9. Randomisation was done using a computer-generated concealed sequence with a block size of 8, and stratified by baseline PANSS positive score (≤20 points or >20 points) and age (12-14 years or 15-17 years). Study drugs were administered in identical capsules, and interventions, assessments, and data analysis were done masked. The primary outcome was PANSS positive score. Key adverse outcomes were bodyweight, homoeostatic model of insulin resistance (HOMA-IR), akathisia, and sedation. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01119014. FINDINGS Between June 10, 2010, and Jan 29, 2014, 231 participants were assessed for elegibility, of whom 113 were randomly assigned to quetiapine-ER (n=55) or aripiprazole (n=58). PANSS positive score did not differ between groups after 12 weeks (adjusted mean change -5·05 [5·46] for quetiapine-ER, -6·21 [5·42] for aripiprazole; p=0·98), but decreased over time in both groups (p<0·0001). Weight gain was more rapid with quetiapine-ER (p=0·0008), with an adjusted mean weight group difference at week 12 of 3·33 kg (SD 7·23; effect size 0·64; p<0·0001). The HOMA-IR group difference at week 12 favoured aripiprazole (adjusted mean log-transformed group difference 0·259 [SD 0·906]; effect size 0·35; p=0·0060). Akathisia was more common with aripiprazole at week 2 (observed in 34 [60%] of 57 patients; estimated 63·5%) than with quetiapine-ER (15 [30%] of 50; estimated 31·3%; p=0·0021), but not at other timepoints. Sedation proportions did not change significantly over time with either intervention (observed at weeks 2, 4, and 12, respectively, for quetiapine-ER in 43 [83%] of 52, 40 [83%] of 48, and 34 [72%] of 47 patients and for aripiprazole in 49 [89%] of 55, 52 [96%] of 54, and 44 [92%] of 48 patients), and the overall estimated probability combining all timepoints was significantly higher for aripiprazole (97·1%) than for quetiapine-ER (89·2%; p=0·012). In addition to sedation and akathisia, the most common adverse events were tremor (42 [79%] patients in the quetiapine-ER group vs 52 [91%] patients in the aripiprazole group), increased duration of sleep (47 [92%] vs 39 [71%]), orthostatic dizziness (42 [78%] vs 46 [81%]), depression (43 [80%] vs 44 [77%]), tension/inner unrest (37 [69%] vs 50 [88%]), failing memory (41 [76%] vs 44 [77%]), and weight gain (46 [87%] vs 38 [68%]). INTERPRETATION This first head-to-head comparison of quetiapine-ER versus aripiprazole in early-onset psychosis showed no significant group differences in severity of psychopathology after 12 weeks of treatment. Quetiapine-ER was associated with more metabolic adverse events and aripiprazole with more initial akathisia and, unexpectedly, more sedation. The limited antipsychotic efficacy and high level of adverse events were noticeable. This trial provides novel information for the treatment of early-onset psychosis and highlights the importance of adverse event profiles when choosing among antipsychotics for children and adolescents who often require chronic treatment. FUNDING The National Research Council for Health and Disease Foundation for Health Promotion, AP Møller Foundation, Rosalie Petersens Foundation, Stevn and Rindom Foundation, Foundation for the Promotion of Medical Science, The Capital Region Psychiatric Research Foundation, Tryg Foundation, Region of Southern Denmark Research Foundation, Danish Psychiatric Research Educational Fund, Psychiatry Foundation, Foundation of 17-12-1981, Psychiatric Research Foundation Region Zealand, Capital Region Strategic Research Foundation, Knud og Dagny Andresens Foundation, Psychiatric Research Foundation of 1967, The Capital Region Research Foundation, Dr Sofus Carl Emil Friis and Hustru Olga Friis Scholarship, Tømrerhandler Johannes Fogs Foundation, Brdr Hartmanns Foundation DKK, Aase and Ejnar Danielsens Foundation, Jacob Madsen and wife Olga Madsens Foundation, CC Klestrup and wife Scholarship, Lundbeck Foundation Scholarship, and Tømrermester Jørgen Holm and wife Elisas Scholarship.

The Danish High Risk and Resilience Study – VIA 7 - a cohort study of 520 7-year-old children born of parents diagnosed with either schizophrenia, bipolar disorder or neither of these two mental disorders

BackgroundSevere mental illnesses like schizophrenia and bipolar disorder are known to be diseases that to some extent, but not entirely can be understood genetically. The dominating hypothesis is that these disorders should be understood in a neurodevelopmental perspective where genes and environment as well as gene-environment-interactions contribute to the risk of developing the disease. We aim to analyse the influences of genetic risk and environmental factors in a population of 520 7-year-old children with either 0, 1 or 2 parents diagnosed with schizophrenia spectrum psychosis or bipolar disorder on mental health and level of functioning. We hypothesize that a larger proportion of children growing up with an ill parent will display abnormal or delayed development, behavioural problems or psychiatric symptoms compared to the healthy controls.Methods/designWe are establishing a cohort of 520 7-year-old children and both their parents for a comprehensive investigation with main outcome measures being neurocognition, behaviour, psychopathology and neuromotor development of the child. Parents and children are examined with a comprehensive battery of instruments and are asked for genetic material (saliva or blood) for genetic analyses. The participants are recruited via Danish registers to ensure representativity. Data from registers concerning social status, birth complications, somatic illnesses and hospitalization are included in the database. Psychological and relational factors like emotional climate in the family, degree of stimulation and support in the home and attachment style are also investigated.DiscussionData collection started January 1, 2013, and is successfully ongoing. By Aug 2015 424 families are included. About 20 % of the invited families decline to participate, equal for all groups.

Pretreatment Cardiometabolic Status in Youth With Early-Onset Psychosis: Baseline Results From the TEA Trial.

OBJECTIVE To describe pretreatment cardiometabolic constitution in children and adolescents with first-episode psychosis (FEP). METHODS Baseline cardiometabolic assessment was performed in youths aged 12-17 years with FEP entering the Tolerability and Efficacy of Antipsychotics (TEA) trial and matched healthy controls. Patients were included between June 10, 2010, and January 29, 2014. ICD-10 was used as the diagnostic classification system. Cardiometabolic risk markers were compared between patients versus controls and antipsychotic-naive versus antipsychotic-exposed patients. RESULTS Comparing 113 youths with FEP (age ± SD = 15.74 ± 1.36 years, males = 30.1%, schizophrenia-spectrum disorders = 92.9%, antipsychotic-naive: n = 57) to 60 controls, patients had higher waist circumference (WC) z scores (1.13 ± 1.65 vs 0.42 ± 1.27, P = .018), cholesterol (4.10 ± 0.71 vs 3.79 ± 0.49 mmol/L, P = .014), low-density lipoproteins (2.37 ± 0.56 vs 2.13 ± 0.51, P = .012), and non-high-density lipoproteins (2.58 ± 1.60 vs 2.52 ± 0.52, P = .018). More patients than controls (42.9% vs 20.3%, P = .019) and antipsychotic-naive than antipsychotic-exposed (51.9% vs 34.0%, P = .023) had a WC > 90th percentile. Hypercholesterolemia (34.0% vs 12.5%, P = .015) was more frequent in patients, while decreased high-density lipoprotein cholesterol was more frequent in controls (32.5% vs 19.0%, P = .032). Family history of type 2 diabetes mellitus was associated with increased body mass index (BMI) z score (P < .001), WC z score (P = .001), insulin (P = .038), and homeostatic model assessment of insulin resistance (HOMA-IR; P = .025). Dyslipidemia was associated with significantly increased insulin (P = .041), HOMA-IR (P = .032), and low-density lipoprotein cholesterol (P = .041). Previous antipsychotic exposure was not associated with increased cardiometabolic risk. Early age at onset predicted increased BMI and WC z scores, while diagnosis of schizophrenia and higher Clinical Global Impression-Severity score were associated with increased blood lipids. CONCLUSIONS Youths with FEP had significantly greater WC and lipid abnormalities than matched controls, regardless of antipsychotic exposure. In youths with FEP, elevated metabolic risk predates antipsychotic exposure. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01119014; European Clinical Trials Database (EudraCT): 2009-016715-38​​​.

Auditory processing in autism spectrum disorder : Mismatch negativity deficits

Children with autism spectrum disorders (ASD) often show changes in (automatic) auditory processing. Electrophysiology provides a method to study auditory processing, by investigating event‐related potentials such as mismatch negativity (MMN) and P3a‐amplitude. However, findings on MMN in autism are highly inconsistent, partly due to small sample sizes in the studies and differences in MMN paradigms. Therefore, in the current study, MMN and P3a amplitude were assessed in a relatively large sample of children with ASD, using a more extensive MMN paradigm and compared with that of typically developing children (TDC). Thirty‐five children (aged 8–12 years) with ASD and 38 age and gender matched TDC were assessed with a MMN paradigm with three types of deviants, i.e., frequency, duration and a combination of these two. MMN elicited by duration and frequency‐duration deviants was significantly reduced in the ASD group. P3a‐amplitude elicited by duration deviants was significantly increased in the ASD group. Reduced MMN in children with ASD suggests that children with ASD may be less responsive to environmentally deviant stimuli at an early (sensory) level. P3a‐amplitude was increased in ASD, implying a hyper‐responsivity at the attentional level. In addition, as similar MMN deficits are found in schizophrenia, these MMN results may explain some of the frequently reported increased risk of children with ASD to develop schizophrenia later in life. Autism Res 2017, 10: 1857–1865.

Are Weight Status and Cognition Associated

Abstract Objective The aim of this study was to characterise the association between the cognitive profile and weight restoration in children and adolescents with anorexia nervosa. Methods The study was a longitudinal, matched case–control, multicentre study. An assessment of cognitive functions was conducted by using the Wechsler Intelligence Scale for Children–III/the Wechsler Adult Intelligence Scale–III, the Test of Memory and Learning–second edition, Trail Making Tests A and B, the Rey–Osterrieth Complex Figure Test and the Cambridge Neuropsychological Test Automated Battery. Results One hundred twenty individuals, 60 patients with anorexia nervosa with mean age of 14.65 (SD 1.820) years and 60 healthy controls with mean age of 14.76 (SD 1.704) years, participated. No association was found between weight recovery and cognitive functions. However, a significant increase in motor speed was found in Trail Making Test A (p = 0.004), Reaction Time (RTI) five‐choice movement time (p = 0.002) and RTI simple movement time (p = 0.011), resulting in a normalisation corresponding to that found in healthy controls. Furthermore, a significantly lower score in the perceptual organization index (p = 0.029) was found at follow‐up. Conclusions Weight recovery appears not to be associated with cognition. Copyright