CLEAR - clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings.

BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.

Attrition in longitudinal studies among patients with schizophrenia and other psychoses; findings from the STRATA collaboration.

A major problem with longitudinal studies is the bias generated due to attrition, particularly apparent amongst patients suffering from psychotic disorders. Factors associated with study-participation were investigated as part of a larger research collaboration (STRATA). Out of 479 eligible participants, only 50 (10,4%) were successfully followed up. The present study investigated whether study participation differed depending on baseline characteristics. Results indicated that individuals who did not participate were more likely to report an alcohol use disorder while those who did respond were more likely to have been in full-time education for longer and be of white ethnicity. Participation did not differ depending on diagnosis, symptoms, GAF, age of onset or depression.

Predictors of treatment resistant schizophrenia: a systematic review of prospective observational studies.

Treatment-resistant schizophrenia, affecting approximately 20-30% of patients with schizophrenia, has a high burden both for patients and healthcare services. There is a need to identify treatment resistance earlier in the course of the illness, in order that effective treatment, such as clozapine, can be offered promptly. We conducted a systemic literature review of prospective longitudinal studies with the aim of identifying predictors of treatment-resistant schizophrenia from the first episode. From the 545 results screened, we identified 12 published studies where data at the first episode was used to predict treatment resistance. Younger age of onset was the most consistent predictor of treatment resistance. We discuss the gaps in the literature and how future prediction models can identify predictors of treatment response more robustly.

Effect of age on the relative efficacy of clozapine in schizophrenia.

OBJECTIVE: Early treatment of schizophrenia improves outcomes. Clozapine appears to have unique benefit when other antipsychotic medication has failed. This systematic review and meta-analysis aims to assess clozapine's superiority over alternative antipsychotic medication and examine whether earlier use is associated with additional benefit. METHOD: Systematic retrieval of blinded, randomized controlled trials comparing clozapine with alternative antipsychotics in adults with schizophrenia. The effect of mean age on relative clozapine response was examined using random effects meta-regression, and multiple linear regression on available patient data. RESULTS: A total of 276 studies were retrieved. Thirty-four studies were included in the meta-analysis. Clozapine was significantly more effective than alternative antipsychotics in reducing psychotic symptoms and increasing response. However, meta-regression failed to show a more significant effect in younger patients (age on effect size (total psychotic symptoms) 0.00, P = 0.79 CI -0.03 to 0.03). Individual patient data were available for two studies, the larger of which showed a significant interaction between younger age and superiority of clozapine. CONCLUSION: The results support clozapine's superiority over other antipsychotics. A convincing effect of age on this effect was not demonstrated, although this was suggested in one study. In view of the age of many of the included studies, and changes in reporting practice over time, new clozapine RCTs, which include age of illness onset as well as age at trial time, would be welcome in order to provide meta-analysable data for future use.

The impact of clozapine initiation and cessation on psychiatric hospital admissions and bed days: a mirror image cohort study.

BACKGROUND: Clozapine is the most effective medication for the positive symptoms of treatment-refractory schizophrenia. Although clozapine use is associated with fewer admissions, less is known about the impact of clozapine cessation on hospitalisation. AIMS: The aims of this study were to investigate whether clozapine-reduced psychiatric inpatient admissions and bed days, and investigate patient factors associated with these changes from a sample of 1906 people commenced on clozapine. METHODS: All people commencing clozapine during an acute hospitalisation over a 10-year period in Queensland, Australia, were included in this retrospective cohort study. A mirror image design was used to compare psychiatric bed days and hospitalisations 2 years before and after clozapine treatment, and the impact of clozapine continuation or early cessation. Changes in psychiatric bed days and hospitalisations were analysed using linear regression, adjusting for the duration on clozapine, sex, age, indigenous status, country of origin and time to clozapine commencement. RESULTS/OUTCOMES: There was a significant reduction in bed days (29.55 days vs 24.46 days, p < 0.001) and admissions (2.27 vs 1.87 < 0.001) associated with clozapine commencement. This remained significant among clozapine continuers, but not among those with early cessation. Longer duration on clozapine was associated with greater reductions in psychiatric bed days and admissions. Age, sex and time to clozapine commencement, indigeneity and country of origin did not impact outcomes. CONCLUSION/INTERPRETATION: Longer clozapine therapy led to a greater reduction in psychiatric bed days and hospitalisations. Early cessation was associated with a return to pre-clozapine levels of bed days and admissions.

Childhood abuse and psychotic experiences - evidence for mediation by adulthood adverse life events.

AIMS: We have previously reported an association between childhood abuse and psychotic experiences (PEs) in survey data from South East London. Childhood abuse is related to subsequent adulthood adversity, which could form one pathway to PEs. We aimed to investigate evidence of mediation of the association between childhood abuse and PEs by adverse life events. METHODS: Data were analysed from the South East London Community Health Study (SELCoH, n = 1698). Estimates of the total effects on PEs of any physical or sexual abuse while growing up were partitioned into direct (i.e. unmediated) and indirect (total and specific) effects, mediated via violent and non-violent life events. RESULTS: There was strong statistical evidence for direct (OR 1.58, 95% CI: 1.19-2.1) and indirect (OR 1.51, 95% CI: 1.32-1.72) effects of childhood abuse on PEs after adjustment for potential confounders, indicating partial mediation of this effect via violent and non-violent life events. An estimated 47% of the total effect of abuse on PEs was mediated via adulthood adverse life events, of which violent life events made up 33% and non-violent life events the remaining 14%. CONCLUSIONS: The association between childhood abuse and PEs is partly mediated through the experience of adverse life events in adulthood. There is some evidence that a larger proportion of this effect was mediated through violent life events than non-violent life events.

Clozapine and all-cause mortality in treatment-resistant schizophrenia: a historical cohort study.

OBJECTIVE: Large-scale epidemiological studies have demonstrated a protective effect of clozapine on mortality in people with schizophrenia. Clozapine is reserved for use in patients with treatment-resistant schizophrenia (TRS), but evidence of clozapine's effect on mortality exclusively within TRS samples is inconclusive. Hence, we aimed to investigate the effect of clozapine use on all-cause mortality in TRS patients. METHODS: A historical patient cohort sample of 2837 patients, who met criteria for TRS between 1 Jan 2008 and 1 Jan 2016, were selected from the South London and Maudsley NHS Foundation Trust (SLAM) electronic health records (EHR). The national Zaponex Treatment Access System (ZTAS) mandatory monitoring system linked to the SLAM EHR was used to distinguish which patients were initiated on clozapine (n = 1025). Cox proportional hazard models were used, adjusting for sociodemographics, clinical monitoring, mental and physical illness severity and functional status. RESULTS: After controlling for potential confounders, the protective effect of clozapine on all-cause mortality was significant (adjusted hazard ratio 0.61; 95% confidence interval 0.38-0.97; P = 0.04). CONCLUSIONS: Clozapine reduces the risk of mortality in patients who meet criteria for TRS. We provide further evidence that improving access to clozapine in TRS is likely to reduce the mortality gap in schizophrenia.

Psychiatric symptoms and risk of victimisation: a population-based study from Southeast London.

AimsAlthough violence is a vital public health problem, no prospective studies have tested for subsequent vulnerability to violence, as a victim or witness, in members of the general population with a range of psychiatric symptoms, or evaluated the importance of higher symptom burden on this vulnerability. METHODS: We used successive waves of a household survey of Southeast London, taken 2 years apart, to test if association exists between psychiatric symptoms (symptoms of psychosis, common mental disorders, post-traumatic stress disorder and personality disorder) and later victimisation, in the form of either witnessing violence or being physically victimised, in weighted logistic regression models. Statistical adjustment was made for prior violence exposure, sociodemographic confounders, substance/alcohol use and violence perpetration. Sensitivity analyses were stratified by violence perpetration, sex and history of mental health service use. RESULTS: After adjustments, psychiatric symptoms were prospectively associated with reporting any subsequent victimisation (odds ratio (OR) 1.88, 95% confidence interval (CI) 1.25-2.83), a two times greater odds of reporting witnessed violence (OR 2.24, 95% CI 1.33-3.76) and reporting physical victimisation (OR 1.76, 95% CI 1.01-3.06). One more symptom endorsed was accompanied by 47% greater odds of subsequent victimisation (OR 1.47, 95% CI 1.16-1.86). In stratified analyses, statistical associations remained evident in non-perpetrators, and among those without a history of using mental health services, and were similar in magnitude in both men and women. CONCLUSIONS: Psychiatric symptoms increase liability to victimisation compared with those without psychiatric symptoms, independently of a prior history of violence exposure and irrespective of whether they themselves are perpetrators of violence. Clinicians should be mindful of the impact of psychiatric symptoms on vulnerability to victimisation, including among those with common psychiatric symptoms and among those who are not considered at risk of perpetrating violence.

Long-term antipsychotic polypharmacy prescribing in secondary mental health care and the risk of mortality.

OBJECTIVES: To investigate the association between long-term antipsychotic polypharmacy use and mortality; and determine whether this risk varies by cause of death and antipsychotic dose. METHODS: Using data from a large anonymised mental healthcare database, we identified all adult patients with serious mental illness (SMI) who had been prescribed a single antipsychotic or polypharmacy, for six or more months between 2007 and 2014. Multivariable Cox regression models were constructed, adjusting for sociodemographic, socioeconomic, clinical factors and smoking, to examine the association between APP use and the risk of death. RESULTS: We identified 10 945 adults with SMI who had been prescribed long-term antipsychotic monotherapy (76.9%) or APP (23.1%). Patients on long-term APP had a small elevated risk of mortality, which was significant in some but not all models. The adjusted hazard ratios for death from natural and unnatural causes associated with APP were 1.2 (0.9-1.4, P = 0.111) and 1.1 (0.7-1.9, P = 0.619) respectively. The strengths of the associations between APP and mortality outcomes were similar after further adjusting for % BNF antipsychotic dose (P = 0.031) or olanzapine equivalence (P = 0.088). CONCLUSION: The findings suggest that the effect of long-term APP on mortality is not clear-cut, with limited evidence to indicate an association, even after controlling for the effect of dose.

Artistic creativity and risk for schizophrenia, bipolar disorder and unipolar depression: a Swedish population-based case-control study and sib-pair analysis.

BACKGROUND: Many studies have addressed the question of whether mental disorder is associated with creativity, but high-quality epidemiological evidence has been lacking.AimsTo test for an association between studying a creative subject at high school or university and later mental disorder. METHOD: In a case-control study using linked population-based registries in Sweden (N = 4 454 763), we tested for associations between tertiary education in an artistic field and hospital admission with schizophrenia (N = 20 333), bipolar disorder (N = 28 293) or unipolar depression (N = 148 365). RESULTS: Compared with the general population, individuals with an artistic education had increased odds of developing schizophrenia (odds ratio = 1.90, 95% CI = [1.69; 2.12]) bipolar disorder (odds ratio = 1.62 [1.50; 1.75]) and unipolar depression (odds ratio = 1.39 [1.34; 1.44]. The results remained after adjustment for IQ and other potential confounders. CONCLUSIONS: Students of artistic subjects at university are at increased risk of developing schizophrenia, bipolar disorder and unipolar depression in adulthood.Declaration of interestNone.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

This corrects the article DOI: 10.1038/mp.2016.97.

Tobacco smoking is associated with psychotic experiences in the general population of South London.

BACKGROUND: The association between cigarette smoking and psychosis remains unexplained, but could relate to causal effects in both directions, confounding by socioeconomic factors, such as ethnicity, or use of other substances, including cannabis. Few studies have evaluated the association between cigarettes and psychotic experiences (PEs) in diverse, inner-city populations, or relationships with number of cigarettes consumed. METHODS: We assessed associations and dose-response relationships between cigarette smoking and PEs in a cross-sectional survey of household residents (n = 1680) in South East London, using logistic regression to adjust for cannabis use, other illicit substances, and socioeconomic factors, including ethnicity. RESULTS: We found association between any PEs and daily cigarette smoking, which remained following adjustment for age, gender, ethnicity, cannabis and use of illicit stimulant drugs (fully adjusted odds ratio 1.47, 95% confidence interval 1.01-2.15). Fully adjusted estimates for the association, and with number of PEs, increased with number of cigarettes smoked daily, implying a dose-response effect (p = 0.001 and <0.001, respectively). Odds of reporting any PEs in ex-smokers were similar to never-smokers. CONCLUSIONS: In this diverse epidemiological sample, association between smoking and PEs was not explained by confounders such as cannabis or illicit drugs. Daily cigarette consumption showed a dose-response relationship with the odds of reporting PEs, and of reporting a greater number of PEs. There was no difference in odds of reporting PEs between ex-smokers and never-smokers, raising the possibility that the increase in PEs associated with smoking may be reversible.

Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors.

BACKGROUND: We examined longitudinally the course and predictors of treatment resistance in a large cohort of first-episode psychosis (FEP) patients from initiation of antipsychotic treatment. We hypothesized that antipsychotic treatment resistance is: (a) present at illness onset; and (b) differentially associated with clinical and demographic factors. METHOD: The study sample comprised 323 FEP patients who were studied at first contact and at 10-year follow-up. We collated clinical information on severity of symptoms, antipsychotic medication and treatment adherence during the follow-up period to determine the presence, course and predictors of treatment resistance. RESULTS: From the 23% of the patients, who were treatment resistant, 84% were treatment resistant from illness onset. Multivariable regression analysis revealed that diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis predicted treatment resistance from illness onset. CONCLUSIONS: The striking majority of treatment-resistant patients do not respond to first-line antipsychotic treatment even at time of FEP. Clinicians must be alert to this subgroup of patients and consider clozapine treatment as early as possible during the first presentation of psychosis.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

Educational achievement in psychiatric patients and their siblings: a register-based study in 30 000 individuals in The Netherlands.

BACKGROUND: Poor educational achievement is associated with a range of psychiatric disorders. Several studies suggest that this underperformance is due to cognitive deficits that commence before disease onset and reflect a genetic risk for this disorder. However, the specificity and the familial contribution of this cognitive deficit are not clear. We analysed lifetime educational achievement of psychiatric patients diagnosed with schizophrenia, bipolar or depressive disorder and their unaffected siblings. METHOD: In a register-based case-control study, 1561 patients with schizophrenia, 813 patients with bipolar disorder, 8112 patients with depression, and their siblings were each matched with eight population controls. Patients, siblings and controls were compared on the highest educational stream they completed. RESULTS: Lower educational achievement was present in schizophrenia patients from primary school onwards [completing primary school: odds ratio (OR) 0.69; completing secondary school: OR 0.69; completing academic education: OR 0.46], compared to patients with bipolar disorder or depression. Siblings of schizophrenia, bipolar or depressed patients showed no underachievement at primary or secondary school, but siblings of schizophrenia patients as well as siblings of depressed patients were less successful in their educational achievement after secondary school (completing academic education, schizophrenia siblings: OR 0.90; depressive disorder siblings: OR 0.91). CONCLUSIONS: Educational underachievement from primary school onwards is specifically related to schizophrenia and not to bipolar disorder or depression. Moreover, it appears to be a harbinger of the illness, since it is not found in their siblings. These results add to evidence that early cognitive deficits are a distinct feature of the schizophrenia phenotype.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

This corrects the article DOI: 10.1038/mp.2016.97.

Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses.

BACKGROUND: Clozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated. METHOD: This is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010. We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not. RESULTS: Seventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (<20 years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25-4.94] compared to those with non-TR. The relationship between an early age of first contact (<20 years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44-9.56); and patients of male gender (OR 3.13 95% CI 1.35-7.23). CONCLUSIONS: For the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.

Genetic overlap between type 2 diabetes and depression in Swedish and Danish twin registries.

A bidirectional association between type 2 diabetes (T2DM) and depression has been consistently reported. Depression is associated with worse biomedical outcomes and increased mortality. The mechanisms underlying the association of T2DM with depression remain unclear. One possible question we can address is the extent to which the co-occurrence of diabetes and depression is due to correlated genetic and/or environmental risk factors. In this study, we performed structural equation model fitting to population-level data from the Swedish (n=68 606) and Danish (n=95 403) twin registries. The primary outcomes were clinical diagnosis of T2DM and depression using national hospital discharge registries. The phenotypic correlation between T2DM and depression is modest in both samples. In the Swedish sample, unique environmental effects explain a greater proportion of the covariance in males, whereas the association is primarily attributed to genetic effects in females. In the Danish sample, genetic effects account for the majority of the covariance in both males and females. Qualitative genetic sex differences are observed in both samples. We believe this is the first study to demonstrate significant genetic overlap between T2DM and depression.