Schizophrenia In Later Life Research Articles

Air pollutants, genetic susceptibility, and incident schizophrenia in later life: A prospective study in the UK Biobank

ObjectiveAir pollution has been linked to multiple psychiatric disorders, but little is known on its long-term association with schizophrenia. The interaction between air pollution and genetic susceptibility on incident schizophrenia has never been reported. We aimed to explore the associations between long-term air pollution exposure and late-onset schizophrenia and evaluate whether genetic susceptibility could modify the association. MethodsThis population-based prospective cohort study included 437,802 middle-aged and elderly individuals free of schizophrenia at baseline in the UK Biobank. Land use regression models were applied in the estimation of the annual average concentrations of nitrogen dioxide (NO2), nitrogen oxides (NOx), fine particulate matter (PM2.5), and inhalable particulate matter (PM10) at residence. The associations between air pollutants and schizophrenia were evaluated by using Cox proportional hazard models. A polygenic risk score of schizophrenia was constructed for exploring potential interaction of air pollutants with genetic susceptibility. ResultsAn interquartile range increase in PM2.5, PM10, NO2, and NOx was associated with the hazard ratios (HR) for incident schizophrenia at 1.19, 1.16, 1.22, and 1.09, respectively. The exposure-response curves for the association of air pollution with incident schizophrenia were approximately linear. There are additive interactions of air pollution score (APS), PM10, NO2, and NOx with genetic risk. Specifically, compared with participants with low genetic susceptibility and low APS, the HR was 3.23 for individuals with high genetic risk and high APS, among which 0.49 excess risk could be attributed to the additive interaction, accounting for 15 % of the schizophrenia risk. ConclusionThis large-scale, prospective cohort study conveys the first-hand evidence that long-term air pollution exposure could elevate schizophrenia incidence in later life, especially for individuals with higher genetic risks. The findings highlight the importance of improving air quality for preventing the late-onset schizophrenia in an aging era, especially among those with high genetic risks.

Clinical recovery is not a requirement for subjective well-being: a longitudinal study in older Dutch patients living with schizophrenia

IntroductionGrowing old with schizophrenia is a profound challenge. However, impact and course of the disorder vary widely among individuals. The recovery concept has inspired outcome evaluation. In older schizophrenia patients, research on recovery is limited and mainly cross-sectional.ObjectivesTo compare 5-year outcome of clinical recovery (symptomatic remission and adequate community functioning) with outcome of subjective well-being (as a key element of personal recovery).MethodsOur catchment-area based study sample consisted of 73 older Dutch schizophrenia patients (mean age 65.9 years; SD 5.4), including both community living and institutionalized patients regardless of the age of onset of their disorder.ResultsAt baseline (T1) 5.5% of participants qualified for clinical recovery, while at five-year follow-up (T2) this rate was 12.3% (p=0.18, exact McNemar’s test). Subjective well-being was reported by 20.5% of participants at T1, and by 27.4% at T2 (p=0.27, exact McNemar’s test). Concurrent clinical recovery and subjective well-being was exceptional, being present in only one participant at T1 and in two participants at T2. Clinical recovery and subjective well-being were not correlated at T1 (p=0.82; phi=0.027), nor at T2 (p=0.71; phi= -0.044).ConclusionsTransitions over time confirm a dynamic course of schizophrenia in later life, with room for improvement. In our sample, we found no linkage between clinical recovery and subjective well-being. Results suggest that while clinical recovery is relatively rare in older individuals with schizophrenia it is not a prerequisite to experience subjective well-being. In spite of ongoing symptoms a substantial number of older schizophrenia patients report subjective well-being and thus may find ‘wellness within illness’.DisclosureNo significant relationships.

Antipsychotic drug treatment of schizophrenia in later life: Results from the European cross-sectional AMSP study

Objectives To investigate the relationship between patient age and the selection and dosage of antipsychotic drugs (APDs) for treatment of schizophrenia. We describe age effects for multiple individual APDs, thus allowing comparisons between drugs. Methods Prescription data of 32,062 inpatients with schizophrenia from 2000 to 2017 were obtained from the Drug Safety Program in Psychiatry (AMSP) database. APD selection and dosage were related to patient age with sex as an influencing variable. Moreover, a systematic search of current guideline recommendations on APD treatment in patients with schizophrenia aged ≥65 years was performed. Results Eighty percentof elderly patients (≥65 years) received a second-generation APD, most commonly risperidone. The dosage of APDs increased with age until about age 40 years, then decreased slowly at first and more steeply beyond age 55 years. The influence of age as well as sex on dosage partly differed between the individual drugs. Only one of eight schizophrenia guidelines systematically addressed specific aspects of pharmacotherapy in older adults. Conclusions In clinical routine, age has a significant impact on selection and dosing of APDs. Information on optimising pharmacotherapy in older adults with schizophrenia from clinical trials is needed. Guidelines should be improved regarding APD therapy specifically for older adults.

Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk

Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) virus or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with recent events. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate Toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4 h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.

Five-year outcome of clinical recovery and subjective well-being in older Dutch patients with schizophrenia.

Outcome of schizophrenia in later life can be evaluated from different perspectives. The recovery concept has moved forward this evaluation, discerning clinical-based and patient-based definitions. Longitudinal data on measures of recovery in older individuals with schizophrenia are scant. This study evaluated the five-year outcome of clinical recovery and subjective well-being in a sample of 73 older Dutch schizophrenia patients (mean age 65.9 years; SD 5.4), employing a catchment-area based design that included both community living and institutionalized patients regardless of the age of onset of their disorder. At baseline (T1), 5.5% of participants qualified for clinical recovery, while at five-year follow-up (T2), this rate was 12.3% (p = 0.18; exact McNemar's test). Subjective well-being was reported by 20.5% of participants at T1 and by 27.4% at T2 (p = 0.27; exact McNemar's test). Concurrence of clinical recovery and subjective well-being was exceptional, being present in only one participant (1.4%) at T1 and in two participants (2.7%) at T2. Clinical recovery and subjective well-being were not correlated neither at T1 (p = 0.82; phi = 0.027) nor at T2 (p = 0.71; phi = -0.044). There was no significant correlation over time between clinical recovery at T1 and subjective well-being at T2 (p = 0.30; phi = 0.122) nor between subjective well-being at T1 and clinical recovery at T2 (p = 0.45; phi = -0.088). These results indicate that while reaching clinical recovery is relatively rare in older individuals with schizophrenia, it is not a prerequisite to experience subjective well-being.

Did the Nazi Holocaust cause schizophrenia?

After centuries of controversy, mental health professionals still cannot agree on the cause or causes of schizophrenia — the most severe form of psychosis. Theories of aetiology range from genetic, biochemical, and neuropathological approaches to those of an environmental or intrafamilial nature. In this contribution, the author considers the impact of massive psychological traumatisation, examining, in particular, the relatively neglected literature on the role of the Nazi Holocaust in the development of psychotic states. Reviewing the work of such pioneering clinicians as Bruno Bettelheim and William Niederland, each of whom observed acute schizophrenic reactions among survivor patients, the author then surveys the more methodologically sophisticated work of Udo Reulbach and his colleagues who have provided strong evidence that those survivors of concentration camps who endured the most objectively traumatising of experiences, including the death of both parents, would be far more likely, statistically, to receive a diagnosis of schizophrenia in later life. The author argues that the literature on the Holocaust provides important data for an understanding of the role of disrupted attachments and extreme traumatisation in the development of schizophrenic psychoses.

The effect of 17β-estradiol on maternal immune activation-induced changes in prepulse inhibition and dopamine receptor and transporter binding in female rats

Maternal immune activation (MIA) during pregnancy is associated with an increased risk of development of schizophrenia in later life. 17β-estradiol treatment may improve schizophrenia symptoms, but little is known about its efficacy on MIA-induced psychosis-like behavioural deficits in animals. Therefore, in this study we used the poly(I:C) neurodevelopmental model of schizophrenia to examine whether MIA-induced psychosis-like behavioural and neurochemical changes can be attenuated by chronic treatment (2–6 weeks) with 17β-estradiol. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15 and adult female offspring were tested for changes in prepulse inhibition (PPI) and density of dopamine D1 and D2 receptors and dopamine transporters in the forebrain compared to control offspring. Poly(I:C)-treated offspring exhibited significantly disrupted PPI, an effect which was reversed by chronic treatment with 17β-estradiol. In control offspring, but not poly(I:C) offspring, PPI was significantly reduced by acute treatment with either the dopamine D1/D2 receptor agonist, apomorphine, or dopamine releaser, methamphetamine. 17β-estradiol restored the effect of apomorphine, but not methamphetamine, on PPI in poly(I:C) offspring. There was a strong trend for a dopamine D2 receptor binding density increase in the nucleus accumbens core region in poly(I:C) offspring, and this was reversed by chronic 17β-estradiol treatment. No changes were found in the nucleus accumbens shell, caudate putamen or frontal cortex or in the density of dopamine D1 receptors or transporters. These findings suggest that 17β-estradiol may improve some symptoms of schizophrenia, an effect that may be mediated by selective changes in dopamine D2 receptor density.

Academic achievement and schizophrenia: a systematic meta-analysis.

Cognitive impairments in childhood are associated with increased risk of schizophrenia in later life, but the extent to which poor academic achievement is associated with the disorder is unclear. Major databases were searched for articles published in English up to 31 December 2019. We conducted random-effects meta-analyses to: (1) compare general academic and mathematics achievement in youth who later developed schizophrenia and those who did not; (2) to examine the association between education level achieved and adult-onset schizophrenia; and, (3) compare general academic achievement in youth at-risk for schizophrenia and typically developing peers. Meta-regression models examined the effects of type of academic assessment, educational system, age at assessment, measurement of educational level attained, school leaving age, and study quality on academic achievement and education level among individuals with schizophrenia. Meta-analyses, comprising data of over four million individuals, found that: (1) by age 16 years, those who later developed schizophrenia had poorer general academic (Cohen's d = -0.29, p ⩽ 0.0001) and mathematics achievement (d = -0.23, p = 0.01) than those who did not; (2) individuals with schizophrenia were less likely to enter higher education (odds ratio = 0.49, p ⩽ 0.0001); and, (3) youth reporting psychotic-like experiences and youth with a family history of schizophrenia had lower general academic achievement (d = -0.54, p ⩽ 0.0001; d = -0.39, p ⩽ 0.0001, respectively). Meta-regression analyses determined no effect modifiers. Despite significant heterogeneity across studies, various routinely collected indices of academic achievement can identify premorbid cognitive dysfunction among individuals who are vulnerable for schizophrenia, potentially aiding the early identification of risk in the population.

Sex differences in the effect of maternal immune activation on cognitive and psychosis‐like behaviour in Long Evans rats

Maternal immune activation during pregnancy is associated with increased risk of development of schizophrenia in later life. There are sex differences in schizophrenia, particularly in terms of age of onset, course of illness and severity of symptoms. However, there is limited and inconsistent literature on sex differences in the effects of maternal immune activation on behaviour with relevance to schizophrenia. The aim of this study was therefore to investigate sex differences in the effects of maternal immune activation by treating Long Evans rats with poly(I:C) on gestational day 15. We compared adult male and female offspring on spatial working memory in the touchscreen trial-unique nonmatching-to-location task, pairwise discrimination and reversal learning, as well as on prepulse inhibition and psychotropic drug-induced locomotor hyperactivity. Male, but not female poly(I:C) offspring displayed a deficit in spatial working memory, particularly at the longer delay. Neither pairwise discrimination nor reversal learning showed an effect of poly(I:C), but female controls outperformed male controls in the reversal learning task. Significant reduction of prepulse inhibition and enhancement of acute methamphetamine-induced locomotor hyperactivity was found similarly in male and female poly(I:C) offspring. These results show that maternal immune activation induces a range of behavioural effects in the offspring, with sex specificity in the effects of maternal immune activation on some aspects of cognition, but not psychosis-like behaviour.

The association between neonatal vitamin D status and risk of schizophrenia

Clues from the epidemiology of schizophrenia, such as the increased risk in those born in winter/spring, have led to the hypothesis that prenatal vitamin D deficiency may increase the risk of later schizophrenia. We wish to explore this hypothesis in a large Danish case-control study (n = 2602). The concentration of 25 hydroxyvitamin D (25OHD) was assessed from neonatal dried blood samples. Incidence rate ratios (IRR) were calculated when examined for quintiles of 25OHD concentration. In addition, we examined statistical models that combined 25OHD concentration and the schizophrenia polygenic risk score (PRS) in a sample that combined the new sample with a previous study (total n = 3464; samples assayed and genotyped between 2008-2013). Compared to the reference (fourth) quintile, those in the lowest quintile (<20.4 nmol/L) had a significantly increased risk of schizophrenia (IRR = 1.44, 95%CI: 1.12–1.85). None of the other quintile comparisons were significantly different. There was no significant interaction between 25OHD and the PRS. Neonatal vitamin D deficiency was associated with an increased risk for schizophrenia in later life. These findings could have important public health implications related to the primary prevention of schizophrenia.

Perinatal Hypoxia and Ischemia in Animal Models of Schizophrenia.

Intrauterine or perinatal complications constitute a major risk for psychiatric diseases. Infants who suffered from hypoxia–ischemia (HI) are at twofold risk to develop schizophrenia in later life. Several animal models attempt to reproduce these complications to study the yet unknown steps between an insult in early life and outbreak of the disease decades later. However, it is very challenging to find the right type and severity of insult leading to a disease-like phenotype in the animal, but not causing necrosis and focal neurological deficits. By contrast, too mild, repetitive insults may even be protective via conditioning effects. Thus, it is not surprising that animal models of hypoxia lead to mixed results. To achieve clinically translatable findings, better protocols are urgently needed. Therefore, we compare widely used models of hypoxia and HI and propose future directions for the field.

Role of Vitamin D in schizophrenia in elderly patient

Vitamin D deficiency is common in the patient with mental illness such as schizophrenia; several environmental risk factors for schizophrenia, such as season of birth, latitude, and migration, have been linked to Vitamin D deficiency. Recent studies have suggested a potential role of Vitamin D in the development of schizophrenia, for example, neonatal Vitamin D status is associated with the risk of developing schizophrenia in later life. Here, we report a case of Vitamin D deficiency presenting with schizophrenia. Vitamin D supplementation is promising treatment strategy to prevent relapse to improve psychotic symptoms, and physical health in patients with schizophrenia should be further explored in future studies.

BBOX1 is down-regulated in maternal immune-activated mice and implicated in genetic susceptibility to human schizophrenia

Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorders such as bipolar disorder, autism, and schizophrenia in later life. Gamma-butyrobetaine hydroxylase (BBOX 1) is an enzyme responsible for the biosynthesis of l-carnitine, a key molecule in fatty acid metabolism. This cytosolic dimeric protein belongs to the dioxygenase family. In this study, we investigated whether BBOX 1 expression was related to psychiatric disorder in an animal model. We also conducted a case–control study using 284 schizophrenia patients and 409 controls with single-nucleotide polymorphisms (SNPs) in the 5′-near region of BBOX 1. BBOX 1 expression was increased in the medial frontal cortex of a mouse model of schizophrenia induced by maternal immune activation. Furthermore, the genotype and allele frequencies of two SNPs (rs7939644 and rs10767592) were significantly associated with schizophrenia susceptibility. Our results suggest that BBOX 1 might be associated with maternal immune activation and schizophrenia susceptibility. Therefore, it might be involved in the pathophysiology of schizophrenia.

Comparison of neurocognitive function in major depressive disorder, bipolar disorder, and schizophrenia in later life: A cross-sectional study of euthymic or remitted, non-demented patients using the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J)

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are associated with cognitive dysfunction both in adulthood and in later life. In this study, we directly compared neurocognitive function between these three conditions in later life, employing stringent definitions of euthymia and symptomatic remission. Cognitive function in 60 elderly outpatients with MDD, BD, or SZ (20 patients per group) was assessed using the Japanese version of the Brief Assessment of Cognition in Schizophrenia. Patients with MDD had significantly higher z scores than both the other groups with large or moderately large effect sizes, for verbal fluency, attention and speed of information processing, and composite scores. In contrast, there were no significant differences in the degree of neurocognitive impairment between patients with BD and SZ. In later life, patients with BD and SZ showed a similar degree of neurocognitive impairment, while patients with MDD showed smaller impairments in several neurocognitive domains compared to patients with either of the other two disorders.

Early Life Bereavement and Schizophrenia: A Nationwide Cohort Study in Denmark and Sweden.

We aimed to examine whether early life bereavement, as indicator of severe stress, was associated with an increased risk of schizophrenia later in life.Based on population registers, we established a cohort of all children born in Denmark (N = 1 686 416) and Sweden (N = 2 563 659) from 1973 to 1997. Children were categorized as exposed if they lost a first-degree relative during the first 18 years of life. Outcome is the first diagnosis of schizophrenia as either inpatient or outpatient. Log-linear Poisson regression models were used to estimate incidence rate ratios (IRRs).A total of 188,850 children (4.6%) experienced death of a first-degree relative from birth to 18 years of age. Compared with unexposed children, those exposed had overall a 39% higher risk of schizophrenia (= 1.39, 95% CI [confidence interval]: 1.32-1.47). The IRR was particularly high if the family member committed suicide (aIRR = 2.11, 95% CI: 1.90-2.34) or died due to an injury or accident (aIRR = 1.44, 95% CI: 1.27-1.63). The IRR of schizophrenia decreased with increasing child's age at bereavement (P < 0.0001). Children who experienced >1 death during the first 18 years of life (aIRR = 1.79, 95% CI: 1.46-2.19) had a higher risk than those with a single death (aIRR = 1.37, 95% CI: 1.30-1.45).The study suggested that exposure to death of a first-degree relative before 18 years was associated with an increased risk of schizophrenia in later life. The complex mechanisms behind these associations remain to be elucidated.

Current Concepts in the Diagnosis and Treatment of Schizophrenia in Later Life

Caring for patients with schizophrenia in later life is emerging as a major concern as well as a challenge for practicing psychiatrists. The clinical presentation and course of this disorder in older patients differ from that of younger patients with unresolved cognitive and social issues often being prominent. It is hard to establish a definite age of onset for schizophrenia in later life. However, based on research evidence, symptomatology, brain imaging studies, family history, and cognitive issues observed in older patients with schizophrenia, the International Late-Onset Schizophrenia Group proposed to retain the term schizophrenia for both early (before age 40) and late-onset, but further divided the late-onset schizophrenia into late-onset (onset after age 40) and very-late-onset (onset after age 60). The group also proposed that patients with onset of schizophrenia after age 60 should be called as very-late-onset-schizophrenia-like psychosis. This paper is an attempt to share current concepts relative to diagnosis and treatment options, based on bio-psycho-social model, for patients with schizophrenia in later life.

A Longitudinal Study of the Outcome and Associated Factors of Subsyndromal and Syndromal Depression in Community-Dwelling Older Adults with Schizophrenia Spectrum Disorder.

Studies examining depression in older adults with schizophrenia have been limited by cross-sectional data. This study examines longitudinal changes in depression, predictors of depression, and the impact of depression on clinical and psychosocial variables in this population. The sample consisted of 104 community-dwelling persons with schizophrenia spectrum disorder aged 55 and over who developed the disorder before age 45. Mean follow-up was 54 months (range: 12-116 months), mean age was 61 years, 55% were men, and 55% were white. Presence of subsyndromal or syndromal depression (SSSD) was defined as scoring >7 on the Center for Epidemiologic Studies-Depression Scale (CES-D). There were no significant differences in SSSD rates between interviews (61% baseline; 54% follow-up); 44% of the sample had SSSD at both assessments, 30% did not have SSSD at either assessment, 16% went from SSSD to nondepression, and 10% went from nondepression to SSSD. Similarly, 20%, 27%, and 53% of the sample exhibited >0.5 effect size increase, decrease, or no change, respectively, in their CES-D scores between assessments. There were two significant time 1 predictors of SSSD at time 2: SSSD and greater number of psychotropic medications. SSSD at time 1 predicted having higher time 2 anxiety scores. Persistent ("core") depression occurs in about two-fifths of persons, 30% remain persistently nondepressed, and one-fourth may fluctuate between depression and nondepression. No association was found between depression and most predictor variables. This study supports recent findings that schizophrenia in later life is not a quiescent state or one of affective withdrawal.

Late Life Schizophrenia: New Research Findings

The increasing scientific interest in schizophrenia in later life is all but devoid of urgency, as demographic trends will bring about a rapid increase in the number of elderly schizophrenia patients in the next decades, making them the fastest growing segment of the schizophrenia population. The picture emerging from recent research is subtle and diverse, and partially gives rise to cautious optimism. In a substantial number of patients, psychosocial function improves with age, while the intensity of psychotic symptoms tends to diminish.

Evaluating negative-symptom-like behavioural changes in developmental models of schizophrenia

Many lines of evidence suggest that schizophrenia has a major developmental component and that environmental factors that disrupt key stages of development, such as maternal stress during pregnancy as a result of infection or malnutrition, can increase the risk of developing schizophrenia in later life. This review examines how non-clinical neurodevelopmental models pertinent to schizophrenia have been evaluated for their ability to reproduce behavioural deficits related to the negative symptoms of schizophrenia. The more frequently used are the prenatal application of the mitotoxic agent methylazoxymethanol, prenatal immune challenge and the neonatal ventral hippocampus lesion model. In general they have been extensively evaluated in models considered relevant to positive symptoms of schizophrenia. In contrast, very few studies have examined tests related to negative symptoms and, when they have, it has almost exclusively been a social interaction model. Other aspects related to negative symptoms such as anhedonia, affective flattening and avolition have almost never been studied. Further studies examining other components of negative symptomatology are needed to more clearly associate these deficits with a schizophrenia-like profile as social withdrawal is a hallmark of many disorders. Although there are no truly effective treatments for negative symptoms, better characterisation with a broader range of drugs used in schizophrenia will be necessary to better evaluate the utility of these models. In summary, developmental models of schizophrenia have been extensively studied as models of positive symptoms but, given the unmet need in the clinic, the same effort now needs to be made with regard to negative symptoms.

Early childhood infections and risk of schizophrenia

The association between early childhood infections and the risk of schizophrenia is not clear, and this study aimed to investigate the association between childhood infections and the risk of schizophrenia in a population-based Australia male cohort. A population-based cohort of males born between 1980 and 1984 in Western Australia was identified using birth registry records and followed-up until December 31st, 2009 or death using linked health data available through the Western Australian Data Linkage System. The associations between hospitalized infections occurring during 0–3yr of age and risk of schizophrenia were assessed with stratified analysis and multivariate logistic regression models. Analysis was further repeated to assess the effect of hospitalized intestinal infections (gastroenteritis) and respiratory infections. It was observed that male participants with two or more hospitalizations for infections before the age of three had an 80% higher risk of schizophrenia, and these findings remained when the analysis was limited to intestinal infections and acute respiratory infections. These findings support the hypothesis that infections during early childhood may lead to the onset of schizophrenia in later life.