Wijnand Laan

Adjuvant Aspirin Therapy Reduces Symptoms of Schizophrenia Spectrum Disorders: Results From a Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE Inflammatory processes may play a role in the pathophysiology of schizophrenia. The aim of this study was to determine the efficacy of adjuvant treatment with aspirin (acetylsalicylic acid) in schizophrenia spectrum disorders. METHOD This randomized, double-blind, placebo-controlled study was conducted between May 2004 and August 2007. Seventy antipsychotic-treated inpatients and outpatients from 10 psychiatric hospitals in The Netherlands with a DSM-IV-diagnosed schizophrenia spectrum disorder were included. Patients were randomized to adjuvant treatment with aspirin 1000 mg/d or placebo. During a 3-month follow-up, psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). Other assessments included cognitive tests and immune function. The primary efficacy outcome was the change in total PANSS score. Secondary outcomes were changes in the PANSS subscales and cognitive test results. RESULTS Mixed-effect models showed a 4.86-point (95% CI, 0.91 to 8.80) and 1.57-point (95% CI, 0.06 to 3.07) larger decrease in the aspirin group compared to the placebo group on the total and positive PANSS score, respectively. Similar but not statistically significant results were observed for the other PANSS subscale scores. Treatment efficacy on total PANSS score was substantially larger in patients with the more altered immune function (P = .018). Aspirin did not significantly affect cognitive function. No substantial side effects were recorded. CONCLUSION Aspirin given as adjuvant therapy to regular antipsychotic treatment reduces the symptoms of schizophrenia spectrum disorders. The reduction is more pronounced in those with the more altered immune function. Inflammation may constitute a potential new target for antipsychotic drug development. TRIAL REGISTRATION controlled-trials.com Identifier: ISRCTN27745631.

Effect of Treatment of Subclinical Neonatal Seizures Detected With aEEG: Randomized, Controlled Trial

OBJECTIVES: The goals were to investigate how many subclinical seizures in full-term neonates with hypoxic-ischemic encephalopathy (HIE) would be missed without continuous amplitude-integrated electroencephalography (aEEG) and whether immediate treatment of both clinical and subclinical seizures would result in a reduction in the total duration of seizures and a decrease in brain injury, as seen on MRI scans. METHODS: In this multicenter, randomized, controlled trial, term infants with moderate to severe HIE and subclinical seizures were assigned randomly to either treatment of both clinical seizures and subclinical seizure patterns (group A) or blinding of the aEEG registration and treatment of clinical seizures only (group B). All recordings were reviewed with respect to the duration of seizure patterns and the use of antiepileptic drugs (AEDs). MRI scans were scored for the severity of brain injury. RESULTS: Nineteen infants in group A and 14 infants in group B were available for comparison. The median duration of seizure patterns in group A was 196 minutes, compared with 503 minutes in group B (not statistically significant). No significant differences in the number of AEDs were seen. Five infants in group B received AEDs when no seizure discharges were seen on aEEG traces. Six of 19 infants in group A and 7 of 14 infants in group B died during the neonatal period. A significant correlation between the duration of seizure patterns and the severity of brain injury in the blinded group, as well as in the whole group, was found. CONCLUSIONS: In this small group of infants with neonatal HIE and seizures, there was a trend for a reduction in seizure duration when clinical and subclinical seizures were treated. The severity of brain injury seen on MRI scans was associated with a longer duration of seizure patterns.

Paternal age and psychiatric disorders: findings from a Dutch population registry.

BACKGROUND We measured the association between paternal age and schizophrenia (SCZ), autism spectrum disorders (ASD), major depressive disorder (MDD), and bipolar disorder (BPD) in the Dutch population. METHODS In total, 14231 patients and 56924 matched controls were collected and analyzed for an association with paternal age by logistic regression. RESULTS ASD is significantly associated with increased paternal age: Older fathers >40 years of age have a 3.3 times increased odds of having a child with ASD compared to young fathers <20 years of age. SCZ has significant associations for fathers aged >35 years (OR=1.27, 95% Confidence Interval: 1.05 and 1.53). For MDD, both younger and older fathers have increased odds. No association was found for BPD. CONCLUSIONS The effects of paternal age as a risk factor are different for ASD and SCZ on one hand, and the affective disorders on the other hand. Different types of association might indicate different biological or psychosocial mechanisms. Late paternity (associated with predispositions to psychiatric disorders) seems the most probable explanation for the association with paternal age.

Glucocorticosteroids associated with a decreased risk of psychosis.

The hypothesis that chronic inflammation may play a role in psychosis receives increasing attention. In this study, we aim to investigate whether the use of steroidal anti-inflammatory drugs is associated with a decreased risk of psychosis. A longitudinal nested case-control study was performed investigating the association of glucocorticosteroid (GCS) consumption with a new diagnosis of a psychotic disorder. Significantly reduced odds ratios of 0.52 (95% confidence interval, 0.36-0.75) were found for GCS in men only (odds ratio in women, 0.84 [95% confidence interval, 0.590-1.20]). Similar risk reductions were present for the inhaled and systemic GCSs. A dose-response relationship was present. Our finding of an inverse relation between GCS consumption and new psychotic episodes may promote further research into inflammation in schizophrenia.

A comorbid anxiety disorder does not result in an excess risk of death among patients with a depressive disorder

BACKGROUND Several studies have demonstrated increased mortality associated with depression and with anxiety. Mortality due to comorbidity of two mental disorders may be even more increased. Therefore, we investigated the mortality among patients with depression, with anxiety and with both diagnoses. METHODS By linking the longitudinal Psychiatric Case Register Middle-Netherlands, which contains all patients of psychiatric services in the Utrecht region, to the death register of Statistics Netherlands, hazard ratios of death were estimated overall and for different categories of death causes separately. RESULTS We found an increased risk of death among patients with an anxiety disorder (N=6919): HR=1.45 (95%CI: 1.25-1.69), and among patients with a depression (N=14,778): HR=1.83, (95%CI: 1.72-1.95), compared to controls (N=103,824). The hazard ratios among both disorders combined (N=4260) were similar to those with only a depression: HR=1.91, (95% CI: 1.64-2.23). Among patients with a depression, mortality across all important disease-related categories of death causes (neoplasms, cardiovascular, respiratory, and other diseases) and due to suicide was increased, without an excess mortality in case of comorbid anxiety. LIMITATIONS The presented data are restricted to broad categories of patients in specialist services. No data on behavioral or intermediate factors were available. CONCLUSIONS Although anxiety is associated with an increased risk of death, the presence of anxiety as comorbid disorder does not give an additional increase in the risk of death among patients with a depressive disorder. The increased mortality among patients with depression is not restricted to suicide and cardiovascular diseases, but associated with a broad range of death causes.

Factors associated with increasing functional decline in multimorbid independently living older people

OBJECTIVES With increasing age the levels of activities of daily living (ADL) deteriorate. In this study we aimed to investigate which demographic characteristics and disorders are associated with ADL disabilities in multi-morbid older people. STUDY DESIGN We performed a cross-sectional study with baseline patient data from a large Dutch trial in independently living multi-morbid older people combined with the reimbursed healthcare data for the same subjects. MAIN OUTCOME MEASURES The primary outcome of our study was the level of independence of activities of daily living (ADL) as assessed with the Modified Katz Activities of Daily Living (KATZ-15) scale. RESULTS In our study we were able to include 1187 persons (63.0% female) for whom both questionnaire data and reimbursed healthcare data was available. In total, 59% had a Katz-15 score of 1 or higher. The strongest associations with ADL disabilities in women were psychiatric disorders, with prevalence rate (PR) estimates of 1.37 (95% confidence interval (CI): 1.17-1.60) and transient ischaemic attacks and cerebrovasculair accidents in men, with PR estimates of 1.94 (95% CI: 1.41-2.66). Although univariate analysis seemed to also reveal associations with socio-demographic factors such as living together with a partner or the socio-economic status, these factors were not independently associated with ADL disabilities. CONCLUSIONS In this cross-sectional study we found that 71% of the multi-morbid female elderly had a sub-optimal level of activities of daily living, as assessed with the Katz-15 scale. The results of our study show that multiple disorders are associated with ADL disabilities in multi-morbid older men and women. We found socio-demographic characteristics not to be independently associated ADL disabilities.

An incidence study of diagnosed autism-spectrum disorders among immigrants to the Netherlands

To estimate the risk of developing autism‐spectrum disorder (ASD) in children born to immigrants as compared with children of Dutch‐born parents.

The Psychiatric Case Register Middle Netherlands

BackgroundThe Psychiatric Case Register Middle Netherlands (PCR-MN) registers the mental healthcare consumption of over Dutch 760,000 inhabitants in the centre of the Netherlands. In 2010 the follow-up period was over ten years. In this paper we describe the content, aims and research potential of this case register.DescriptionAll mental healthcare institutions in the middle-western part of the province of Utrecht participate in the PCR-MN case register. All in- and out-patients treated in these institutions have been included in the database from the period 2000 to 2010. Diagnosis according to DSM-IV on axis I to IV, visits to in- and out-patient clinics and basic demographics are recorded. A major advantage of this register is the possibility to link patients anonymously from the PCR-MN cohort to other databases to analyze relationships with determinants and outcomes, such as somatic healthcare consumption, mortality, and demographics, which further increases the research potentialConclusionsThe PCR-MN database has a large potential for scientific research because of its size, duration of follow-up and ability to link with additional databases, and is accessible for academic researchers.

Psychosis and suicide risk by ethnic origin and history of migration in the Netherlands.

BACKGROUND There is an increased incidence of non-affective psychotic disorders (NAPD) among first- and second-generation migrants in Europe. The purpose of this population-based study was to compare the risk of suicide in Dutch natives and immigrants with or without NAPD. METHODS Cases of NAPD (n=12 580) from three Dutch psychiatric registers were linked to the cause of death register of Statistics Netherlands and were compared to matched controls (n=244 792) from the population register, who had no such diagnosis. Hazard ratios (HRs) of suicide were estimated and adjusted for age and gender by Cox regression analysis. RESULTS The presence of NAPD was strongly associated with suicide risk in each ethnic group. However, for all ethnic minority groups the HRs were somewhat lower than among Dutch natives, for whom the HR was 23.4 (95%-CI; 18.5-29.7). A closer examination revealed that suicide risk was influenced by the history of migration. While the risk for immigrants of the first generation, diagnosed with NAPD, was significantly lower than that for native Dutch patients (HR=0.45; 95%-CI: 0.28-0.73), the risk for those of the second generation was more similar to that for the Dutch (HR=0.85; 95%-CI: 0.51-1.40) (P value of history of migration=0.005). CONCLUSION Immigrants diagnosed with NAPD of the first generation appear to be protected against suicide, whereas this protection is waning among those of the second generation. This is the first study worldwide on suicide in migrants with NAPD and the first study of suicide in patients with NAPD in the Netherlands.

A randomised controlled trial on hypnotherapy for irritable bowel syndrome: design and methodological challenges (the IMAGINE study)

BackgroundIrritable Bowel Syndrome (IBS) is a common gastro-intestinal disorder in primary and secondary care, characterised by abdominal pain, discomfort, altered bowel habits and/or symptoms of bloating and distension. In general the efficacy of drug therapies is poor. Hypnotherapy as well as Cognitive Behaviour Therapy and short Psychodynamic Therapy appear to be useful options for patients with refractory IBS in secondary care and are cost-effective, but the evidence is still limited. The IMAGINE-study is therefore designed to assess the overall benefit of hypnotherapy in IBS as well as comparing the efficacy of individual versus group hypnotherapy in treating this condition.Methods/DesignThe design is a randomised placebo-controlled trial. The study group consists of 354 primary care and secondary care patients (aged 18-65) with IBS (Rome-III criteria). Patients will be randomly allocated to either 6 sessions of individual hypnotherapy, 6 sessions of group hypnotherapy or 6 sessions of educational supportive therapy in a group (placebo), with a follow up of 9 months post treatment for all patients. Ten hospitals and four primary care psychological practices in different parts of The Netherlands will collaborate in this study. The primary efficacy parameter is the responder rate for adequate relief of IBS symptoms. Secondary efficacy parameters are changes in the IBS symptom severity, quality of life, cognitions, psychological complaints, self-efficacy as well as direct and indirect costs of the condition. Hypnotherapy is expected to be more effective than the control therapy, and group hypnotherapy is expected not to be inferior to individual hypnotherapy.DiscussionIf hypnotherapy is effective and if there is no difference in efficacy between individual and group hypnotherapy, this group form of treatment could be offered to more IBS patients, at lower costs.Trial registration numberISRCTN: ISRCTN22888906