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Background: Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is the only treatment approved by the US Food and Drug Administration for hallucinations and delusions associated with Parkinson's disease (PD) psychosis. Aim: We aimed to evaluate motor- and cognition-related safety in pimavanserin-treated patients with PD psychosis. Methods: This analysis included patients with PD psychosis treated with pimavanserin 34 mg from a pooled analysis of 3 randomized, double-blind, placebo-controlled, 6-week studies [NCT00477672 (study ACP-103-012), NCT00658567 (study ACP-103-014), and NCT01174004 (study ACP-103-020)] and a subgroup of patients with PD dementia with psychosis from HARMONY (NCT03325556), a randomized discontinuation study that included a 12-week open-label period followed by a randomized double-blind period of up to 26 weeks. Motor- and cognition-related safety were examined. Results: The pooled analysis included 433 randomized patients (pimavanserin, 202; placebo, 231). Least squares mean (standard error [SE]) change from baseline to week 6 Unified Parkinson's Disease Rating Scale (UPDRS) II + III score was similar for pimavanserin [-2.4 (0.69)] and placebo [-2.3 (0.60)] (95% Confidence Interval [CI]:-1.9, 1.6). The change from baseline to week 6 for UPDRS II and UPDRS III scores was similar between groups. In the HARMONY open-label period, 49 patients with PD dementia with psychosis were treated with pimavanserin 34 mg, 36 of whom were randomized in the double-blind period (pimavanserin, 16; placebo, 20). In the open-label period, the mean (SE) change from baseline to week 12 (n = 39) Extra-Pyramidal Symptom Rating Scale (ESRS-A) score was -1.7 (0.74); in the double-blind period, the results were generally comparable between the pimavanserin and placebo arms. The change from baseline in Mini-Mental State Examination (MMSE) score was also comparable between pimavanserin- and placebo-treated patients in HARMONY [open-label (n = 37): mean (SE) change from baseline to week 12, 0.3 (0.66)]. Rates of motor- and cognition-related adverse events were similar between pimavanserin and placebo in both analyses. Conclusions: Pimavanserin 34 mg was well tolerated and did not yield a negative impact on motor- or cognition-related function in patients with PD psychosis.

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BACKGROUND: Minimal/non-response to antipsychotic treatment, and persistent positive symptoms despite treatment, are common among patients with schizophrenia. The aim of this study was to characterize a US treatment-resistant schizophrenia (TRS) population in terms of patient demographics, burden of symptoms, treatment history, and factors influencing therapeutic choice. METHODS: In an online survey, 204 psychiatrists self-selected and completed three patient records: two TRS and one schizophrenia ('non-TRS'). RESULTS: Respondents reported that 29.5% of their schizophrenia caseload had TRS. Selected TRS (n = 408) vs non-TRS (n = 204) patients were more likely to be unemployed (74.5% vs 45.1%, p < 0.001), hospitalized at least once (93.4% vs 74.0%, p < 0.001), and to have physical/psychiatric comorbidities including obesity (40.2% vs 23.5%, p < 0.001) and depression (38.7% vs 25.0%, p = 0.001). Psychiatric symptoms were more frequent and severe in TRS, and interfered more with social and functioning domains. Of positive symptoms, eliminating delusions and hallucinations was considered most important to improve a patient's long-term prognosis. In TRS, clozapine monotherapy was the most common treatment (15.9%), though ranked fifth of ten options to treat TRS. Psychiatrists typically increased the antipsychotic dose or added a second antipsychotic before initiating clozapine or switching antipsychotics. Antipsychotic switches were most commonly due to lack of efficacy (TRS = 71.4% vs non-TRS = 54.3%, p < 0.001) and intolerability (34.4% vs 38.4%, p = 0.22) with the prior antipsychotic. Persistent hallucinatory behavior was the top symptom leading to treatment switches in TRS (63.9% vs 37.1%, p < 0.001). CONCLUSIONS: According to psychiatrists, symptoms have a greater clinical burden on patients with TRS than non-TRS. TRS is commonly managed by antipsychotic dose increases/combinations, with clozapine the fifth preference despite being the only approved TRS medication. New treatments are needed for patients who do not respond to available antipsychotics.

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Background: Previous qualitative studies indicate high caregiver burden associated with providing care for people with treatment-resistant schizophrenia (TRS). In this study, we report the first quantitative data to characterize the burdens of caring for a person living with TRS. To better understand the potential added burdens of persistent positive symptoms, we compared the self-reported burdens of caregiving for people living with TRS versus caregiving for those whose positive schizophrenia symptoms respond to treatment (comparator group). Methods: Non-professional adult caregivers providing ≥20 h/week of care to individuals with schizophrenia completed an online survey. Allocation to the TRS or comparator groups was based on caregiver report. TRS was defined as failure of ≥2 separate antipsychotics and at least moderate severity in two of four persistent core positive symptoms despite medication adherence. Care recipients in the comparator schizophrenia group had no clinically significant positive symptoms. Results: One hundred seventy seven caregivers (n = 100 TRS group, n = 77 comparator group) completed the online survey. Caregivers in both groups reported high levels of every day involvement in most aspects of daily life, including assistance with basic tasks, housekeeping, and in providing emotional support. There were no significant differences between groups on overall social life or health. However, caregivers of people living with TRS were significantly more likely to be experiencing stress (76% vs. 53%) and anxiety (58% vs. 43%). Relevant differences between caregiver groups were also noted for mean number of hours spent per week on direct care (TRS group vs. comparator group: 61.1 h/week vs. 39.7 h/week, respectively) and time spent "on call" (162.8 h/week vs. 121.6 h/week). Amongst the caregivers in the TRS group, correlation analyses revealed moderate positive correlations between the reported burden of individual persistent positive symptoms with overall caregiver burden. Conclusion: Our findings show that caring for a person living with TRS places considerable burden on caregivers' lives, with the severity of the disease (and especially severity of positive symptoms) driving further burden, as highlighted by a number of quantitative differences between the TRS and comparator groups.

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OBJECTIVES: Treatment-resistant schizophrenia (TRS) is clinically defined as failure to respond to two antipsychotics of adequate dose and duration. An algorithm (registry TRS) was developed, for identifying patients with TRS in claim datasets from Sweden and the United States. METHODS: Schizophrenia (SZ) patients aged ≥13 years were identified in both datasets and matched to controls. Patients were identified as having TRS by use of the registry TRS or ≥1 prescription for clozapine or use of other published criteria. The algorithm was compared for sensitivity, and patients with and without TRS were compared for psychiatric and hospital burden and Global Assessment of Functioning (GAF) scores. TRS prevalence was not assessed due to lack of clinically validated data to test the specificity of the algorithm. RESULTS: Swedish registry TRS patients ≤45 years at first SZ diagnosis had significantly lower GAF scores and earlier disease onset than non-TRS patients. SZ patients with higher psychiatric comorbidity and hospital burden were more likely identified as TRS by all algorithms. The registry algorithm was significantly more sensitive to multiple inpatient stays and all psychiatric comorbidities at identifying TRS. CONCLUSION: The registry algorithm appeared more sensitive at identifying patients with TRS, who had greater psychiatric and hospital burden.

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OBJECTIVE: To explore and describe potential subgroups within the treatment-resistant schizophrenia (TRS) population, using data from a survey of US psychiatrists. METHODS: Psychiatrists completed an online survey of demographic/clinical characteristics and treatment history for two of their patients with TRS. Patients were stratified according to number of suicide attempts, number of hospitalizations, employment status, and TRS onset time frame. RESULTS: Of the 408 patients with TRS described by psychiatrists, 37.5% had ≥1 suicide attempt, 78.9% had ≥2 hospitalizations, 74.5% were unemployed, 45.0% had TRS onset within 5 years of first treatment (a further 8.0% had TRS from first treatment), and 31.5% had TRS onset after 5 years (15.5% unknown). Patients with ≥1 (vs 0) suicide attempts had statistically significantly more psychiatric (3.6 vs 2.2) and physical (2.2 vs 1.6) comorbidities. Patients with ≥2 (vs ≤1) hospitalizations were statistically significantly more likely to have hallucinations, conceptual disorganization, social withdrawal, and cognitive dysfunction, and had more psychiatric (3.0 vs 1.9) and physical (2.0 vs 1.1) comorbidities. Unemployed (vs employed) patients were statistically significantly more likely to have delusions, hallucinations, blunted affect, social withdrawal, and cognitive dysfunction, and had more psychiatric (2.9 vs 2.3) and physical (2.1 vs 1.2) comorbidities. Patients with TRS onset ≤5 (vs >5) years were statistically significantly younger (35.0 vs 43.7 years), less likely to have hallucinations and social withdrawal, and had fewer psychiatric (2.6 vs 3.3) and physical (1.7 vs 2.3) comorbidities. CONCLUSIONS: Greater clinical burden in TRS is associated with greater illness severity and chronicity markers, suggesting a dimensional gradient from non-TRS to mild-moderate and more severe forms of TRS. Time to onset of TRS may have implications for outcomes, with data indicating greater burden in those with late-onset TRS. Accumulation of illness over time may be more important than time to onset.

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BACKGROUND: Treatment-resistant schizophrenia (TRS) affects about one-third of individuals with schizophrenia. People with TRS do not experience sustained symptom relief and at the same time have the most severe disease-related disability and associated costs among individuals with severe mental disorders. Like caregivers of people with treatment-responsive schizophrenia, caregivers of individuals with TRS experience the disease burden along with their care recipients; however, for those providing care for individuals with TRS, the stress of the burden is unrelenting due to uncontrolled symptoms and a lack of effective treatment options. The objective of this study is to better understand the burden of TRS from the caregiver perspective and to explore their perception of available treatments. METHODS: Eight focus groups with non-professional, informal caregivers of individuals with TRS were conducted in 5 US locations. TRS was defined as failure of ≥2 antipsychotics and persistent moderate-to-severe positive symptoms of schizophrenia, per caregiver report. RESULTS: The 27 caregivers reported an average of 37 h/week providing direct care, and 21 reported being on call "24/7." Caregivers commonly reported that their care recipients exhibited symptoms of auditory hallucinations (89%), agitation/irritability/hostility (81%), suspiciousness (78%), tangentiality (74%), and cognitive impairment (74%); 70% of caregivers ranked suspiciousness/persecution as the most challenging symptom category. Caring for an individual with TRS impacted many caregivers' finances, career prospects, social relationships, and sense of freedom. Additionally, multiple medication failures led to a sense of hopelessness for many caregivers. CONCLUSIONS: Persistent positive symptoms caused significant perceived burden, feelings of being overwhelmed and having no relief, and substantial negative impacts on caregivers' emotional and physical health. To address these substantial unmet needs, policy makers should be aware of the need for practical, social, and emotional support for these caregivers and their families. Additionally, new treatment options for TRS should be developed.

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OBJECTIVE: The aim was to apply a structured questionnaire, the Inventory of Stigmatizing Experiences (ISE), to study experiences of stigma (associated stigma) among relatives of persons with schizophrenia who attended outpatient clinics, using an approach based on assertive community treatment in a Swedish major city. A second aim was to explore the relationship between associated stigma and overall burden among these relatives. METHODS: Relatives (N=65) of persons taking oral antipsychotics who attended outpatient clinics completed a mailed questionnaire that included the ISE and the Burden Inventory for Relatives of Persons with Psychotic Disturbances. Associations were analyzed with ordinal logistic regression. RESULTS: More than half of the relatives (53%) stated that their ill relative had been stigmatized, but only 18% (N=11) reported that they themselves had been stigmatized (responses of sometimes, often, or always). One-fifth of the relatives (23%) acknowledged that they avoided situations that might elicit stigma. Neither experienced stigma nor anticipated stigma was associated with overall burden level in ordinal logistic regression models. The impact of stigma on both the relative's personal quality of life and the family's quality of life were both significantly associated with overall burden after adjustment for patient age and level of functioning. CONCLUSIONS: Stigma had an impact on quality of life at the personal and family levels, and this was associated with overall burden. Increased awareness among service providers may decrease the impact of stigma on relatives, but associations need to be examined in larger studies in diverse cultures and treatment settings.

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AIM: To record and measure the nature and severity of stigma and discrimination experienced by people during a first episode of schizophrenia and those with a first episode of major depressive disorder. METHODS: The Discrimination and Stigma Scale (DISC-12) was used in a cross-sectional survey to elicit service user reports of anticipated and experienced discrimination by 150 people with a diagnosis of first-episode schizophrenia and 176 with a diagnosis of first-episode major depressive disorder in seven countries (Austria, Croatia, Czech Republic, Poland, Romania, Sweden and Turkey). RESULTS: Participants with a diagnosis of major depressive disorder reported discrimination in a greater number of life areas than those with schizophrenia, as rated by the total DISC-12 score (p = .03). With regard to specific life areas, participants with depression reported more discrimination in regard to neighbours, dating, education, marriage, religious activities, physical health and acting as a parent than participants with schizophrenia. Participants with schizophrenia reported more discrimination with regard to the police compared to participants with depression. CONCLUSION: Stigma and discrimination because of mental illness change in the course of the mental diseases. Future research may take a longitudinal perspective to better understand the beginnings of stigmatisation and its trajectory through the life course and to identify critical periods at which anti-stigma interventions can most effectively be applied.

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The aims of this naturalistic non-interventional study were to quantify the level of stigma and discrimination in persons with schizophrenia and to test for potential associations between different types of stigma and adherence to antipsychotics. Antipsychotic medication use was electronically monitored with a Medication Event Monitoring System (MEMS®) for 12 months in 111 outpatients with schizophrenia and schizophrenia-like psychosis (DSM-IV). Stigma was assessed at endpoint using the Discrimination and Stigma Scale (DISC). Single DISC items that were most frequently reported included social relationships in making/keeping friends (71%) and in the neighborhood (69%). About half of the patients experienced discrimination by their families, in intimate relationships, regarding employment and by mental health staff. Most patients (88%) wanted to conceal their mental health problems from others; 70% stated that anticipated discrimination resulted in avoidance of close personal relationships. Non-adherence (MEMS® adherence≤0.80) was observed in 30 (27.3%). When DISC subscale scores (SD) were entered in separate regression models, neither experienced nor anticipated stigma was associated with adherence. Our data do not support an association between stigma and non-adherence. Further studies in other settings are needed as experiences of stigma and levels of adherence and their potential associations might vary by a healthcare system or cultural and sociodemographic contexts.

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Nonadherence with medication occurs in all chronic medical disorders. It is a particular challenge in schizophrenia due to the illness's association with social isolation, stigma, and comorbid substance misuse, plus the effect of symptom domains on adherence, including positive and negative symptoms, lack of insight, depression, and cognitive impairment. Nonadherence lies on a spectrum, is often covert, and is underestimated by clinicians, but affects more than one third of patients with schizophrenia per annum. It increases the risk of relapse, rehospitalization, and self-harm, increases inpatient costs, and lowers quality of life. It results from multiple patient, clinician, illness, medication, and service factors, but a useful distinction is between intentional and unintentional nonadherence. There is no gold standard approach to the measurement of adherence as all methods have pros and cons. Interventions to improve adherence include psychoeducation and other psychosocial interventions, antipsychotic long-acting injections, electronic reminders, service-based interventions, and financial incentives. These overlap, all have some evidence of effectiveness, and the intervention adopted should be tailored to the individual. Psychosocial interventions that utilize combined approaches seem more effective than unidimensional approaches. There is increasing interest in electronic reminders and monitoring systems to enhance adherence, eg, Short Message Service text messaging and real-time medication monitoring linked to smart pill containers or an electronic ingestible event marker. Financial incentives to enhance antipsychotic adherence raise ethical issues, and their place in practice remains unclear. Simple pragmatic strategies to improve medication adherence include shared decision-making, regular assessment of adherence, simplification of the medication regimen, ensuring that treatment is effective and that side effects are managed, and promoting a positive therapeutic alliance and good communication between the clinician and patient. These elements remain essential for all patients, not least for the small minority where vulnerability and risk issue dictate that compulsory treatment is necessary to ensure adherence.

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The primary aim was to compare objective and subjective measures of adherence in a naturalistic cohort of schizophrenia outpatients over 12 months between October 2008 and June 2011. Antipsychotic medication adherence was monitored in 117 outpatients diagnosed with schizophrenia or schizophrenia-like psychosis according to DSM-IV criteria in a naturalistic prospective study. Adherence was determined by the Medication Event Monitoring System (MEMS®), pill count, plasma levels and patient, staff, psychiatrist and close informant ratings. The plasma level adherence measure reflects adherence to medication and to lab visits. Relationships between MEMS® adherence and other measures were expressed as a concordance index and kappa (K). Non-adherence (MEMS® ≤0.80) was observed in 27% of the patients. MEMS® adherence was highly correlated with pill count (concordance= 89% and K=0.72, p<0.001). Concordance and K were lower for all other adherence measures and very low for the relationship between MEMS® adherence and plasma levels (concordance=56% and K=0.05, p=0.217). Adherence measures were also entered into a principal component analysis that yielded three components. MEMS® recordings, pill count and informant ratings had their highest loadings in the first component, plasma levels alone in the second and patient, psychiatrist and staff ratings in the third. The strong agreement between MEMS® and pill count suggests that structured pill count might be a useful tool to follow adherence in clinical practice. The large discrepancy between MEMS® and the adherence measure based on plasma levels needs further study in clinical settings.

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The aim was to investigate clinical predictors of adherence to antipsychotics. Medication use was electronically monitored with a Medication Event Monitoring System (MEMS(®)) for 12 months in 112 outpatients with schizophrenia and schizophrenia-like psychosis according to DSM-IV. Symptom burden, insight, psychosocial function (PSP) and side effects were rated at baseline. A comprehensive neuropsychological test battery was administered and a global composite score was calculated. The Drug Attitude Inventory (DAI-10) was filled in. A slightly modified DAI-10 version for informants was distributed as a postal questionnaire. Non-adherence (MEMS(®) adherence ≤0.80) was observed in 27%. In univariate regression models low scores on DAI-10 and DAI-10 informant, higher positive symptom burden, poor function, psychiatric side effects and lack of insight predicted non-adherence. No association was observed with global cognitive function. In multivariate regression models, low patient-rated DAI-10 and PSP scores emerged as predictors of non-adherence. A ROC analysis showed that DAI-10 had a moderate ability to correctly identify non-adherent patients (AUC=0.73, p<0.001). At the most "optimal" cut-off of 4, one-third of the adherent would falsely be identified as non-adherent. A somewhat larger AUC (0.78, p<0.001) was observed when the ROC procedure was applied to the final regression model including DAI-10 and PSP. For the subgroup with informant data, the AUC for the DAI-10 informant version was 0.68 (p=0.021). Non-adherence cannot be properly predicted in the clinical setting on the basis of these instruments alone. The DAI-10 informant questionnaire needs further testing.

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PURPOSE: Stigma is the most powerful obstacle to the development of mental health care. Numerous activities aiming to reduce the stigma of mental illness and the consequent negative discrimination of the mentally ill and their families have been conducted in Europe. Descriptions of many of these activities are not easily available, either because there are no publications that describe them, or because descriptions exist only in local languages. This supplement aims to help in overcoming this imbalance by providing a description of anti-stigma activities in 14 countries in Europe regardless of the language in which they were published and regardless whether they were previously published. METHODS: The review was undertaken by experts who were invited to describe anti-stigma activities in the countries in which they reside. It was suggested that they use all the available evidence and that they consult others in their country to obtain a description of anti-stigma activities that is as complete as possible. RESULTS: The anti-stigma activities undertaken in the countries involved are presented in a tabular form. The texts contributed by the authors focus on their perception of the stigma of mental illness and of activities undertaken to combat it in their country. CONCLUSIONS: Although much has been done against the stigmatization and discrimination of the mentally ill, fighting stigma remains an essential task for mental health programs and for society. The descriptions summarized in this volume might serve as an inspiration for anti-stigma work and as an indication of potential collaborators in anti-stigma programs.

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