HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry.

The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.

De-escalation techniques used, and reasons for seclusion and restraint, in a forensic psychiatric hospital.

In Finland, the Mental Health Act determines the legal basis for seclusion and restraint. Restrictive measures are implemented to manage challenging situations and should be used as a last resort in psychiatric inpatient care. In the present study, we examined the reasons for seclusion and restraint, as well as whether any de-escalation techniques were used to help patients calm down. Seclusion and restraint files from a 4-year period (1 June 2009-31 May 2013) were retrospectively investigated and analysed by content analysis. Descriptive statistics were calculated. A total of 144 episodes of seclusion and restraint were included to analyse the reasons for seclusion and restraint, and 113 episodes were analysed to examine unsuccessful de-escalation techniques. The most commonly-used techniques were one-to-one interaction with a patient (n = 74, 65.5% of n = 113) and administration of extra medication (n = 37, 32.7% of n = 113). The reasons for seclusion and restraint were threatening harmful behaviour (n = 51, 35.4% of n = 144), direct harmful behaviour (n = 43, 29.9%), indirect harmful behaviour (n = 42, 29.1%), and other behaviours (n = 8, 5.6%). In general, the same de-escalation techniques were used with most patients. Most episodes of seclusion or restraint were due to threats of violence or direct violence. Individual means of self-regulation and patient guidance on these techniques are needed. Additionally, staff should be educated on a diverse range of de-escalation techniques. Future studies should focus on examining de-escalation techniques for the prevention of seclusion.

Seasonal variation of hospital violence, seclusion and restraint in a forensic psychiatric hospital.

Several epidemiological studies have reported seasonal patterns in both violent and self-destructive behaviour. However, a few studies on hospital violence have found contradictory results. The aim of this study was to investigate whether there was any seasonal variation of violence in a forensic psychiatric hospital providing care for persons suffering from psychotic disorders and violent or self-destructive behaviour. Seasonal variation of the prevalence of seclusion and restraint was also investigated. Reports of violent incidents and seclusion and restraint statistics from between 2007 and 2012 were examined with Poisson regression analysis. There was significant variation in the prevalence of seclusion and restraint between months (p<0.001), and between seasons (p<0.001). Monthly prevalence of seclusion and restraint was the lowest in January compared to other months. In comparison, the prevalence of seclusion and restraint was lower in winter than in other seasons. In a hospital with persons suffering from psychotic disorders, no significant variation of violence or self-destructive behaviour was found, similarly as in the society. By contrast, the prevalence of seclusion and restraint showed marked seasonality. Variation in the prevalence of seclusion and restraint was not consistent with the variance in violence, which implies that the use of coercive measures is related to seasonal variation among staff.

Multinational experiences in reducing and preventing the use of restraint and seclusion.

Restraint and seclusion (R/S) have been used in many countries and across service sectors for centuries. With the recent and increasing recognition of the harm associated with these procedures, efforts have been made to reduce and prevent R/S. Following a scathing media exposé in 1998 and congressional scrutiny, the United States began a national effort to reduce and prevent R/S use. With federal impetus and funding, an evidence-based practice, the Six Core Strategies to Prevent Conflict, Violence and the Use of Seclusion and Restraint, was developed. This model was widely and successfully implemented in a number of U.S. states and is being adopted by other countries, including Finland, Australia, and the United Kingdom. Recently, the first cluster randomized controlled study of the Six Core Strategies in Finland provided the first evidence-based data of the safety and effectiveness of a coercion prevention methodology. Preliminary findings of some of the international efforts are discussed. Reduction in R/S use and other positive outcomes are also reported.

Cluster-randomized controlled trial of reducing seclusion and restraint in secured care of men with schizophrenia.

OBJECTIVE: This randomized controlled trial studied whether seclusion and restraint could be prevented in the psychiatric care of persons with schizophrenia without an increase of violence. METHODS: Over the course of a year, 13 wards of a secured national psychiatric hospital in Finland received information about seclusion and restraint prevention. Four high-security wards (N=88 beds) for men with psychotic illness were then stratified by coercion rates and randomly assigned to two equal groups. In the intervention wards, staff, patients, and doctors were trained for six months in applying six core strategies to prevent seclusion-restraint; six months of supervised intervention followed. Poisson's regression analyses compared monthly incidence rate ratios (IRRs) of coercion and violence (per 100 patient-days). RESULTS: The proportion of patient-days with seclusion, restraint, or room observation declined from 30% to 15% for intervention wards (IRR=.88, 95% confidence interval [CI]=.86-.90, p<.001) versus from 25% to 19% for control wards (IRR=.97, CI=.93-1.01, p=.056). Seclusion-restraint time decreased from 110 to 56 hours per 100 patient-days for intervention wards (IRR=.85, CI=.78-.92, p<.001) but increased from 133 to 150 hours for control wards (IRR=1.09, CI=.94-1.25, p=.24). Incidence of violence decreased from 1.1% to .4% for the intervention wards and from .1% to .0% for control wards. Between-groups differences were significant for seclusion-restraint-observation days (p=.001) and seclusion-restraint time (p=.001) but not for violence (p=.91). CONCLUSIONS: Seclusion and restraint were prevented without an increase of violence in wards for men with schizophrenia and violent behavior. A similar reduction may also be feasible under less extreme circumstances.

Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia.

Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors.

[Restrictions during psychiatric hospitalization]. / Potilaan rajoittaminen psykiatrisessa sairaalahoidossa.

The Finnish Constitution affirms that everyone has the right to remain private and undisturbed. During the course of involuntary psychiatric treatment, only the exemptions stipulated in the Mental Health Act are allowed. The Act on the Status and Rights of Patients states that cooperation with the patient must also be attempted during involuntary treatment. The orders for restraints are different in psychiatric hospitals. For decades, restrictions were derived from early 19th century regulations, when all mentally ill individuals were considered to be incompetent. Nowadays, a patient's mental competence is based on functional disabilities, which should also apply to psychiatric treatment.

Transmission of violent offending and crime across three generations.

BACKGROUND: We previously reported 24-fold risk (OR) of violent crime and 17-fold risk for criminal offending among adult children of homicide recidivistic offenders (HR). However, there exist neither published data on the quantitative risk for crime or violent offending among parents of violent offenders, nor data on the transmission of the increased prevalence of crime across three generations. METHODS: In this naturalistic case-control cohort study all HR subjects (G2, n = 35) were extracted from the total of 1584 homicide offenders who were convicted in Finland during 1981-1993. The criminal records and prison documents from their parents (G1, n = 68), and the matched controls (n = 136), were studied, and compared with the previously published data from their children (G3, n = 11) and the controls (n = 220). RESULTS: Among the G1 parents of HR, the odds ratio (OR) for committing any crime was 5.0 (95% CI = 1.3-23.1) but the risk for violent offending was not significantly increased (OR = 3.1, 95% CI = 0.3-37.6). The prevalence of index persons convicted for any crime (versus controls) was 13.2% (versus 2.9%) in G1 and 36.4% (versus 3.2%) in G3. Only 4.4% (versus 1.5%) of G1 index parents, as compared to 18.2% (versus 0.9%) of G3 had convictions for violent crimes. The disparity of the proportions of criminal offenders between index versus control groups had increased across generations (P = 0.0023). This was also the case with violent offenders (P = 0.0019). CONCLUSIONS: The homicide recidivistic offenders had parents with 5-fold risk for any crime but, without significant risk for violent offending. The results provide the first evidence of transmission of crime across three generations, and also of the increased risk of crime among parents of violent offenders.

Comorbid personality disorders and substance use disorders of mentally ill homicide offenders: a structured clinical study on dual and triple diagnoses.

Comorbid substance use disorders (SUDs) increase the risk of homicide by persons with major mental disorders (MMDs). However, there are no published data from clinical interviews or lifetime objective documents on the prevalence of lifetime personality disorder (PD) or SUD among a comprehensive sample of mentally ill homicide offenders. Therefore, a nationally representative sample of men with MMD (n = 90) who had committed or attempted homicide was assessed using the research version of the Structured Clinical Interview for DSM-IV Axis I and Axis II Disorders. Lifetime documents, records, and questionnaires from persons who knew the subjects since childhood were used. Seventy-eight percent of the mentally ill homicide offenders were diagnosed with schizophrenia, 17 percent with schizoaffective disorder, and 5 percent with other psychosis. A lifetime SUD was detected in 74 percent and alcohol use disorder in 72 percent. PD accounted for 51 percent, in 47 percent as antisocial personality disorder (APD). All subjects diagnosed with PD had SUD. Only 25 percent of the subjects had neither SUD nor PD. Among persons with dual diagnoses (MMD and SUD), about two-thirds had PD or APD. These results indicated that there were two-thirds major diagnostic categories of psychotic homicide offenders: about one-half had triple diagnosis (APD + SUD + MMD), one-quarter had "pure" dual diagnosis (SUD + MMD), and one-quarter had "pure" MMD. The fourth possible category, "APD + MMD but no SUD," was not found. The prevention of severe violence by persons with MMD necessitates effective treatments for those with dual diagnosis who also have a history of APD.

Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial.

BACKGROUND: There is no evidence from randomized, controlled trials that demonstrate effectiveness for any pharmacological treatment in clozapine-resistant schizophrenia. Since the introduction of chlorpromazine, all antipsychotics with proven efficacy on positive symptoms have been dopamine antagonists, but recent experimental data suggest that ketamine-induced positive schizophreniform symptoms in healthy subjects can be controlled by a glutamate antagonist lamotrigine. The hypothesis tested was that lamotrigine is more effective than placebo in the treatment of positive schizophrenic symptoms when combined with clozapine. METHODS: Thirty-four hospitalized treatment-resistant patients having chronic schizophrenia participated in a double-blind, placebo-controlled, 14-week, crossover trial where 200 mg/day lamotrigine was gradually added to their ongoing clozapine treatment. Clinical assessments were made by the Positive and Negative Syndrome Scale at the beginning and end of each treatment period. RESULTS: In intention-to-treat analysis, lamotrigine treatment was more effective in reducing positive (effect size.7, p =.009) and general psychopathological (effect size.6, p =.030) symptoms, whereas no improvement was observed in negative symptoms. CONCLUSIONS: These results provide the first evidence from a randomized controlled trial of an effective pharmacological treatment with an anticonvulsant agent in treatment-resistant schizophrenia and indicate that both positive and general psychopathological symptoms in patients with schizophrenia can be controlled by a drug that is not a dopamine antagonist. The results are in line with previous experimental data suggesting that excessive glutamate neurotransmission contributes to the positive symptoms of schizophrenia.