Hallucinations as a risk marker for suicidal behaviour in individuals with a history of sexual assault: a general population study with instant replication.

BACKGROUND: Research has shown a strong relationship between hallucinations and suicidal behaviour in general population samples. Whether hallucinations also index suicidal behaviour risk in groups at elevated risk of suicidal behaviour, namely in individuals with a sexual assault history, remains to be seen. AIMS: We assessed whether hallucinations were markers of risk for suicidal behaviour among individuals with a sexual assault history. METHODS: Using the cross-sectional 2007 (N = 7403) and 2014 (N = 7546) Adult Psychiatric Morbidity Surveys, we assessed for an interaction between sexual assault and hallucinations in terms of the odds of suicide attempt, as well as directly comparing the prevalence of suicide attempt in individuals with a sexual assault history with v. without hallucinations. RESULTS: Individuals with a sexual assault history had increased odds of hallucinations and suicide attempt compared to individuals without a sexual assault history in both samples. There was a significant interaction between sexual assault and hallucinations in terms of the odds of suicide attempt. In total, 14-19% of individuals with a sexual assault history who did not report hallucinations had one or more suicide attempt. This increased to 33-52% of individuals with a sexual assault history who did report hallucinations (2007, aOR = 2.85, 1.71-4.75; 2014, aOR = 4.52, 2.78-7.35). CONCLUSIONS: Hallucinations are a risk marker for suicide attempt even among individuals with an elevated risk of suicidal behaviour, specifically individuals with a sexual assault history. This finding highlights the clinical significance of hallucinations with regard to suicidal behaviour risk, even among high-risk populations.

Hallucinations in the general population across the adult lifespan: prevalence and psychopathologic significance.

BACKGROUND: Community studies have found a relatively high prevalence of hallucinations, which are associated with a range of (psychotic and non-psychotic) mental disorders, as well as with suicidal ideation and behaviour. The literature on hallucinations in the general population has largely focused on adolescents and young adults. AIMS: We aimed to explore the prevalence and psychopathologic significance of hallucinations across the adult lifespan. METHOD: Using the 1993, 2000, 2007 and 2014 cross-sectional Adult Psychiatric Morbidity Survey series (N = 33 637), we calculated the prevalence of past-year hallucinations in the general population ages 16 to ≥90 years. We used logistic regression to examine the relationship between hallucinations and a range of mental disorders, suicidal ideation and suicide attempts. RESULTS: The prevalence of past-year hallucinations varied across the adult lifespan, from a high of 7% in individuals aged 16-19 years, to a low of 3% in individuals aged ≥70 years. In all age groups, hallucinations were associated with increased risk for mental disorders, suicidal ideation and suicide attempts, but there was also evidence of significant age-related variation. In particular, hallucinations in older adults were less likely to be associated with a cooccurring mental disorder, suicidal ideation or suicide attempt compared with early adulthood and middle age. CONCLUSIONS: Our findings highlight important life-course developmental features of hallucinations from early adulthood to old age.

Prevalence and psychopathologic significance of hallucinations in individuals with a history of seizures.

OBJECTIVE: A relationship between seizure activity and hallucinations is well established. The psychopathologic significance of hallucinations in individuals with seizures, however, is unclear. In this study, we assessed the prevalence of auditory and visual hallucinations in individuals who reported a seizure history and investigated their relationship with a number of mental disorders, suicidal ideation, and suicide attempts. METHODS: Data were from the "Adult Psychiatric Morbidity Survey," a population-based cross-sectional survey. Auditory and visual hallucinations were assessed using the Psychosis Screening Questionnaire. Mental health disorders were assessed using the Clinical Interview Schedule. Logistic regressions assessed relationships between hallucinatory experiences and mental disorders, suicidal ideation, and suicide attempts. RESULTS: A total of 14 812 adults (58% female; mean [standard error of the mean; SEM] age 51.8 [0.15]) completed the study; 1.39% reported having ever had seizures (54% female), and 8% of individuals with a seizure history reported hallucinatory experiences (odds ratio [OR] 2.05, 95% confidence interval [CI] 1.24-3.38). Individuals with seizures had an increased odds of having any mental disorder (OR 2.34, 95% CI 1.73-3.16), suicidal ideation (OR 2.38, 95% CI 1.77-3.20), and suicide attempt (OR 4.15, 95% CI 2.91-5.92). Compared to individuals with seizures who did not report hallucinatory experiences, individuals with seizures who reported hallucinatory experiences had an increased odds of any mental disorder (OR 3.47, 95% CI 1.14-10.56), suicidal ideation (OR 2.58, 95% CI 0.87-7.63), and suicide attempt (OR 4.61, 95% CI 1.56-13.65). Overall, more than half of individuals with a seizure history who reported hallucinatory experiences had at least one suicide attempt. Adjusting for psychopathology severity did not account for the relationship between hallucinatory experiences and suicide attempts. SIGNIFICANCE: Hallucinatory experiences in individuals with seizures are markers of high risk for mental health disorders and suicidal behavior. There is a particularly strong relationship between hallucinations and suicide attempts in individuals with seizures. Clinicians working with individuals with seizures should routinely ask about hallucinatory experiences.

Sensitivity of the familial high-risk approach for the prediction of future psychosis: a total population study.

Children who have a parent with a psychotic disorder present an increased risk of developing psychosis. It is unclear to date, however, what proportion of all psychosis cases in the population are captured by a familial high-risk for psychosis (FHR-P) approach. This is essential information for prevention research and health service planning, as it tells us the total proportion of psychosis cases that this high-risk approach would prevent if an effective intervention were developed. Through a prospective cohort study including all individuals born in Finland between January 1, 1987 and December 31, 1992, we examined the absolute risk and total proportion of psychosis cases captured by FHR-P and by a transdiagnostic familial risk approach (TDFR-P) based on parental inpatient hospitalization for any mental disorder. Outcomes of non-affective psychosis (ICD-10: F20-F29) and schizophrenia (ICD-10: F20) were identified in the index children up to December 31, 2016. Of the index children (N=368,937), 1.5% (N=5,544) met FHR-P criteria and 10.3% (N=38,040) met TDFR-P criteria. By the study endpoint, 1.9% (N=6,966) of the index children had been diagnosed with non-affective psychosis and 0.5% (N=1,846) with schizophrenia. In terms of sensitivity, of all non-affective psychosis cases in the index children, 5.2% (N=355) were captured by FHR-P and 20.6% (N=1,413) by TDFR-P approaches. The absolute risk of non-affective psychosis was 6.4% in those with FHR-P, and 3.7% in those with TDFR-P. There was notable variation in the sensitivity and total proportion of FHR-P and TDFR-P cases captured based on the age at which FHR-P/TDFR-P were determined. The absolute risk for psychosis, however, was relatively time invariant. These metrics are essential to inform intervention strategies for psychosis risk requiring pragmatic decision-making.

Risk of Psychosis Among Individuals Who Have Presented to Hospital With Self-harm: A Prospective Nationwide Register Study in Sweden.

BACKGROUND AND HYPOTHESIS: Recent research showed that young people who presented to hospital with self-harm in Finland had a significantly elevated risk of later psychosis. We investigated the prospective relationship between hospital presentation for self-harm and risk of psychosis in an unprecedentedly large national Swedish cohort. STUDY DESIGN: We used inpatient and outpatient healthcare registers to identify all individuals born between 1981 and 1993 who were alive and living in Sweden on their 12th birthday and who presented to hospital one or more times with self-harm. We compared them with a matched cohort, followed up for up to 20 years, and compared the cumulative incidence of psychotic disorders. Furthermore, we examined whether the strength of the relationship between hospital presentation for self-harm and later psychosis changed over time by examining for cohort effects. STUDY RESULTS: In total, 28 908 (2.0%) individuals presented to hospital with self-harm without prior psychosis diagnosis during the follow-up. For individuals who presented to hospital with self-harm, the cumulative incidence of diagnosed psychosis was 20.7% at 20 years follow-up (hazard radio = 13.9, 95% CI 13.3-14.6, P-value <5 × 10-308). There was no evidence of a dilution of the effect over time: while the incidence of hospital self-harm presentation increased, this did not result in an attenuation over time of the strength of the relationship between hospital self-harm presentation and subsequent psychosis. CONCLUSIONS: Individuals who present to hospital with self-harm in their teens and 20s represent an important risk group for psychosis prediction and prevention.

Factor and network analysis of psychosis-like experiences and depressive symptoms in a sample of Finnish adolescents entering psychiatric services.

AIM: Psychosis-Like Experiences (PLEs) and depressive symptoms are correlated in clinical adolescent populations. However, symptom-level associations between the two phenomena are not clear. METHODS: We analysed factor structures of a PLE instrument, the Prodromal Questionnaire-Brief (PQ-B), based on dimensions of positive symptoms of schizophrenia, and a depression measurement instrument, the Beck Depression Inventory (BDI-21A) and performed a network analysis of item-level associations between the two measures. The sample consisted of 417 adolescents (range 13-18 years of age, mean 14.9 years, 72.4% females) entering secondary psychiatric services at Helsinki metropolitan area, Finland. RESULTS: Confirmatory factor analysis resulted in adequately fitting 2-factor solution, one for PQ-B and one for BDI-21, with a strong correlation coefficient of 0.605 between the two factors. In the network analysis, PQ-B and BDI-21 both formed their own clusters, and two significant pathways were estimated between PQ-B and BDI-21 clusters: 1. the association between paranoid thinking and distorted body image, and 2. the association between somatic preoccupation and worry about problems of one's mind. CONCLUSIONS: Even though on a general, factor level, PLEs and depressive symptoms were strongly correlated, unique associations between symptoms of the two constructs were sparse. These findings should be considered in the psychiatric assessment and in the care of adolescents.

Dr. Lång et al. Reply.

We thank our respected colleagues, Fusar-Poli and Salazar de Pablo,1 for their interest in our recent systematic review and meta-analysis on psychosis risk in children and adolescents diagnosed with an at-risk mental state (ARMS).2 Fusar-Poli and Salazar de Pablo agreed with our call for developmentally sensitive approaches when considering psychosis risk in children and adolescents, recognizing that psychotic experiences (the basis of ARMS assessments) are more prevalent in childhood and adolescence than they are in adulthood,3 with age-varying pathological significance.4,5 This, however, appears to be contradicted by the authors' suggestion that we should have included adults (age >18 years) in our pediatric analysis.

Systematic Review and Meta-analysis: Psychosis Risk in Children and Adolescents With an At-Risk Mental State.

OBJECTIVE: The "At Risk Mental State" (ARMS) approach to psychosis, also called "Clinical/Ultra High Risk," has had a major impact on psychosis services internationally. Despite well-established developmental differences in the prevalence and expression of psychotic symptoms from childhood into adulthood, there has been no systematic review of psychosis transitions specifically in children and adolescents up to age of 18 years. Evidence for this age group is crucial for developmentally appropriate clinical decisions by child and adolescent psychiatrists. METHOD: Systematic review and meta-analysis of psychosis risk among children diagnosed with ARMS up to age 18 years, with pooled transition rates after 1-year, 2-year and ≥5-year follow-up. RESULTS: We retrieved 1,107 records and identified 16 articles from 9 studies reporting transition rates on 436 individuals with ARMS aged 9 to 18 years. The pooled transition rate to psychosis at 1 year was 9.5% (95% CI = 5.5%-14.2%, 7 studies included), at 2-years 12.1% (95% CI = 6.7%-18.6%, 4 studies included), and at ≥5 years 16.1% (95% CI = 5.6%-30.0%, 4 studies included). We did not find evidence that the diagnosis of ARMS was associated with increased risk of psychosis once risk-enriching recruitment strategies were taken into account. CONCLUSION: At 5-year follow-up, 1 in 6 youths diagnosed with an ARMS had transitioned to psychosis, but we did not find evidence that this risk was related to ARMS diagnosis as opposed to sampling/recruitment strategies. Our findings indicate a need for caution in applying ARMS methodology to children and adolescents. and highlight the need for developmentally sensitive approaches when considering psychosis risk.

Potential for prediction of psychosis and bipolar disorder in Child and Adolescent Mental Health Services: a longitudinal register study of all people born in Finland in 1987.

Current strategies to predict psychosis identify only a small proportion of individuals at risk. Additional strategies are needed to increase capacity for pre-diction and prevention of serious mental illness, ideally during childhood and adolescence. One possible approach would be to investigate systems in which psychosis risk factors are concentrated during childhood. One notable such system is represented by Child and Adolescent Mental Health Services (CAMHS). Although psychotic disorders are uncommon in CAMHS, many risk factors for psychosis are highly prevalent in young people who enter this system. We hypothesized, therefore, that youth attending CAMHS would be a high-risk group for psychosis if followed into adulthood and, furthermore, that CAMHS systems would capture a substantial proportion of future psychosis cases. We constructed a total population cohort study of all Finns born in 1987 (N=55,875), linking together extensive register data on health care contacts from birth through age 28 years. We identified all individuals diagnosed with a psychotic or bipolar disorder by age 28 (N=1,785). The risk of psychosis/bipolar disorder by age 28 years was 1.8% for individuals who had not attended CAMHS during childhood or adolescence, whereas it was 12.8% for those with a history of any outpatient CAMHS contact (odds ratio, OR=7.9, 95% CI: 7.2-8.7). Furthermore, the risk of psychosis/bipolar disorder by age 28 years was 2.3% for individuals without a history of inpatient CAMHS admission, whereas it was 24.0% for those with a history of inpatient CAMHS admission (OR=13.3, 95% CI: 11.9-14.9), and 36.5% for those with a history of inpatient CAMHS admission in adolescence (age 13-17 years) (OR=24.2, 95% CI: 21.2-27.6). Individuals who attended CAMHS but received no mental disorder diagnosis had an equally high risk of subsequently developing a psychosis/bipolar disorder as individuals who did receive a diagnosis (OR=0.9, 99.5% CI: 0.7-1.1). Compared to other CAMHS attendees, individuals who developed psychosis or bipolar disorder were more likely to have had an initial CAMHS diagnosis of depressive or other mood disorder (OR=2.3, 99.5% CI: 1.6-3.0) and disruptive behaviour disorder (OR=1.7, 99.5% CI: 1.2-2.5). Of all psychosis/bipolar diagnoses by age 28 years, 50.2% occurred in individuals who had, at some point in childhood or adolescence, attended CAMHS, indicating that CAMHS represent not only a high-risk but also a high-capacity system for prediction of psychosis/bipolar disorder. These findings suggest an enormous, untapped potential for large-scale psychosis/bipolar disorder prediction and prevention research within existing specialist CAMHS.

Sexual assault and psychosis in two large general population samples: Is childhood and adolescence a developmental window of sensitivity?

BACKGROUND: Research has shown a strong relationship between psychosis and sexual assault. Theories on developmental trauma as a causal factor for psychosis suggest that exposure to sexual trauma in childhood would have a stronger association with psychosis than sexual trauma in adulthood. We hypothesized that exposure to sexual trauma earlier in childhood and adolescence would be more strongly associated with hallucinations, delusional beliefs and psychotic disorder than sexual trauma that occurred later in life. METHODS: Using the 2007 and 2014 Adult Psychiatric Morbidity Surveys (N = 14,949) we calculated the prevalence of sexual assault, hallucinations, delusional beliefs, and psychotic disorder. We used logistic regression to examine the relationship between age of exposure to sexual assault (first exposure <16 vs first exposure ≥16) and odds of hallucinations, delusions, and psychotic disorder. RESULTS: Sexual assault at any age was associated with an increased odds of hallucinations (aOR = 2.00, 95%CI = 1.63-2.46), delusional beliefs (aOR = 2.55, 95%CI = 2.24-2.89) and psychotic disorder (aOR = 5.28, 95%CI = 3.59-7.76). There was no significant difference, however, in the prevalence of hallucinations, delusional beliefs or psychotic disorders in individuals first exposed to sexual assault <16 and individuals first exposed ≥16. CONCLUSIONS: Contrary to our hypothesis, we did not find evidence that exposure to sexual assault in childhood and adolescence was more strongly associated with hallucinations, delusional beliefs or psychotic disorder than exposure to sexual assault age >16. Our findings do not support the idea that childhood and adolescence are uniquely sensitive periods for the emergence of psychotic experiences or psychotic disorder in relation to sexual trauma.

Hospital Presentation for Self-Harm in Youth as a Risk Marker for Later Psychotic and Bipolar Disorders: A Cohort Study of 59 476 Finns.

Expanding clinical strategies to identify high risk groups for psychotic and bipolar disorders is a research priority. Considering that individuals diagnosed with psychotic and bipolar disorder are at high risk of self-harm, we hypothesised the reverse order relationship would also be true (ie, self-harm would predict psychotic/bipolar disorder). Specifically, we hypothesised that hospital presentation for self-harm would be a marker of high risk for subsequent development of psychotic/bipolar disorder and sought to test this hypothesis in a large population sample. This prospective register-based study included everyone born in Finland in 1987, followed until age 28 years (N = 59 476). We identified all hospital records of self-harm presentations, as well as all ICD-10 healthcare registrations of first diagnoses of psychotic and bipolar disorders. Cox proportional hazards models were used to assess the relationship between self-harm and psychotic/bipolar disorders. Of all individuals who presented to hospital with self-harm (n = 481), 12.8% went on to receive a diagnosis of psychosis (hazard ratio [HR] = 6.03, 95% confidence interval [CI] 4.56-7.98) and 9.4% a diagnosis of bipolar disorder (HR = 7.85, 95% CI 5.73-10.76) by age 28 years. Younger age of first self-harm presentation was associated with higher risk-for individuals who presented before age 18 years, 29.1% developed a psychotic or bipolar disorder by age 28 years. Young people who present to hospital with self-harm are at high risk of future psychotic and bipolar disorders. They represent an important cohort for the prevention of serious mental illness.

Measurement Invariance of Psychotic-Like Symptoms as Measured With the Prodromal Questionnaire, Brief Version (PQ-B) in Adolescent and Adult Population Samples.

Valid measurement of group differences in self-reported psychotic-like experiences (PLEs) requires knowing any group-specific measurement properties of the instruments. We investigated the measurement invariance of the 21-item Prodromal Questionnaire-Brief (PQ-B) questionnaire across gender, ethnic minority/majority status, and presence of depressive symptoms in two different US non-clinical undergraduate samples (N = 1,099). For each item, endorsement of the experience and the associated distress were combined for analysis. A unidimensional model of the PQ-B fit the data well. Across genders, the PQ-B showed configural and metric, but not full scalar invariance; there were statistically significant differences in eight thresholds of six items, most being higher endorsement thresholds for self-identified females. Partial scalar invariance was also found for ethnic status, with five thresholds of three items being higher for the minority participants. For depressive symptomatology, defined as the top quintile by the Beck Depression Inventory-II, partial scalar invariance required dropping one item, after which there were statistically significant differences only in two response thresholds. Overall, a wide range of PLE questionnaire items were found to be robust to gender and ethnicity effects, strengthening confidence in found group differences in PLEs. Although full scalar invariance could not be ascertained for any of the group comparisons, the few found scalar differences across groups were small, with minimal impact on group PLE estimates. However, since PLEs are easily conceptually entangled with depression symptoms, similar items should be considered for exclusion if separable constructs are the target of investigation.

Association of Psychotic Experiences With Subsequent Risk of Suicidal Ideation, Suicide Attempts, and Suicide Deaths: A Systematic Review and Meta-analysis of Longitudinal Population Studies.

Importance: Recent research has highlighted that psychotic experiences are far more prevalent than psychotic disorders and associated with the full range of mental disorders. A particularly strong association between psychotic experiences and suicidal behavior has recently been noted. Objective: To provide a quantitative synthesis of the literature examining the longitudinal association between psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide deaths in the general population. Data Sources: We searched PubMed, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO from their inception until September 2017 for longitudinal population studies on psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide death. Study Selection: Two authors searched for original articles that reported a prospective assessment of psychotic experiences and suicidal ideation, suicide attempts, or suicide death in general population samples, with at least 1 follow-up point. Data Extraction and Synthesis: Two authors conducted independent data extraction. Authors of included studies were contacted for information where necessary. We assessed study quality using the Newcastle-Ottawa Quality Assessment Scale. We calculated pooled odds ratios using a random-effects model. A secondary analysis assessed the mediating role of co-occurring psychopathology. Main Outcomes and Measures: Psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide death. Results: Of a total of 2540 studies retrieved, 10 met inclusion criteria. These 10 studies reported on 84 285 participants from 12 different samples and 23 countries. Follow-up periods ranged from 1 month to 27 years. Individuals who reported psychotic experiences had an increase in the odds of future suicidal ideation (5 articles; n = 56 191; odds ratio [OR], 2.39 [95% CI,1.62-3.51]), future suicide attempt (8 articles; n = 66 967; OR, 3.15 [95% CI, 2.23-4.45]), and future suicide death (1 article; n = 15 049; OR, 4.39 [95% CI, 1.63-11.78]). Risk was increased in excess of that explained by co-occurring psychopathology: suicidal ideation (adjusted OR, 1.59 [95% CI, 1.09-2.32]) and suicide attempt (adjusted OR, 2.68 [95% CI, 1.71-4.21]). Conclusions and Relevance: Individuals with psychotic experiences are at increased risk of suicidal ideation, suicide attempts, and suicide death. Psychotic experiences are important clinical markers of risk for future suicidal behavior.

High-fidelity DNA replication in Mycobacterium tuberculosis relies on a trinuclear zinc center.

High-fidelity DNA replication depends on a proofreading 3'-5' exonuclease that is associated with the replicative DNA polymerase. The replicative DNA polymerase DnaE1 from the major pathogen Mycobacterium tuberculosis (Mtb) uses its intrinsic PHP-exonuclease that is distinct from the canonical DEDD exonucleases found in the Escherichia coli and eukaryotic replisomes. The mechanism of the PHP-exonuclease is not known. Here, we present the crystal structure of the Mtb DnaE1 polymerase. The PHP-exonuclease has a trinuclear zinc center, coordinated by nine conserved residues. Cryo-EM analysis reveals the entry path of the primer strand in the PHP-exonuclease active site. Furthermore, the PHP-exonuclease shows a striking similarity to E. coli endonuclease IV, which provides clues regarding the mechanism of action. Altogether, this work provides important insights into the PHP-exonuclease and reveals unique properties that make it an attractive target for novel anti-mycobacterial drugs.The polymerase and histidinol phosphatase (PHP) domain in the DNA polymerase DnaE1 is essential for mycobacterial high-fidelity DNA replication. Here, the authors determine the DnaE1 crystal structure, which reveals the PHP-exonuclease mechanism that can be exploited for antibiotic development.

DNA replication fidelity in Mycobacterium tuberculosis is mediated by an ancestral prokaryotic proofreader.

The DNA replication machinery is an important target for antibiotic development in increasingly drug-resistant bacteria, including Mycobacterium tuberculosis. Although blocking DNA replication leads to cell death, disrupting the processes used to ensure replication fidelity can accelerate mutation and the evolution of drug resistance. In Escherichia coli, the proofreading subunit of the replisome, the ɛ exonuclease, is essential for high-fidelity DNA replication; however, we find that the corresponding subunit is completely dispensable in M. tuberculosis. Rather, the mycobacterial replicative polymerase DnaE1 itself encodes an editing function that proofreads DNA replication, mediated by an intrinsic 3'-5' exonuclease activity within its PHP domain. Inactivation of the DnaE1 PHP domain increases the mutation rate by more than 3,000-fold. Moreover, phylogenetic analysis of DNA replication proofreading in the bacterial kingdom suggests that E. coli is a phylogenetic outlier and that PHP domain-mediated proofreading is widely conserved and indeed may be the ancestral prokaryotic proofreader.