The CHALLENGE trial: the effects of a virtual reality-assisted exposure therapy for persistent auditory hallucinations versus supportive counselling in people with psychosis: study protocol for a randomised clinical trial.

BACKGROUND: Many patients suffering from schizophrenia spectrum disorders continue having distressing auditory hallucinations in spite of treatment with antipsychotic medication. The aim of this trial is to examine the effect of a targeted virtual reality therapy for persistent auditory hallucinations in individuals with psychosis. The trial explores whether this type of therapy can decrease the severity, frequency and distress of auditory hallucinations and, additionally, whether it can reduce clinical symptoms and enhance daily functioning in individuals with psychosis. METHODS: The study is a randomised, assessor-blinded parallel-group superiority clinical trial, allocating a total of 266 patients to either the experimental intervention or supportive counselling. The participants will be randomised to either (1) seven sessions of virtual reality therapy or (2) seven sessions of supportive counselling to be delivered within the first 12 weeks after inclusion in the study. All participants will be assessed at baseline and 12 and 24 weeks post-baseline. Independent assessors blinded to the treatment allocation will evaluate the outcome. The primary outcome is the level of auditory hallucinations measured with the Psychotic Symptoms Rating Scales (PSYRATS-AH) total score at the cessation of treatment at 12 weeks. Secondary outcomes are frequency of auditory hallucinations, the distress caused by auditory hallucinations, perceived voice power, patient acceptance of voices, patients' ability to respond to voices in an assertive way and social and daily function. DISCUSSION: Promising evidence of the efficacy of this immersive virtual reality-based therapy for auditory hallucinations exist, but evidence needs to be established in a large, methodological rigorous trial. If the therapy proves to be beneficial in reducing the severity of refractory auditory hallucinations, a large group of patients with schizophrenia and related disorders could be the target group of this short-term psychotherapeutic intervention.

Baseline measures of cerebral glutamate and GABA levels in individuals at ultrahigh risk for psychosis: Implications for clinical outcome after 12 months.

BACKGROUND: Cerebral glutamate and gamma-aminobutyric acid (GABA) levels might predict clinical outcome in individuals at ultrahigh risk (UHR) for psychosis but have previously primarily been investigated in smaller cohorts. We aimed to study whether baseline levels of glutamate and GABA in anterior cingulate cortex (ACC) and glutamate in thalamus could predict remission status and whether baseline metabolites differed in the remission versus the nonremission group. We also investigated the relationship between baseline metabolite levels and severity of clinical symptoms, functional outcome, and cognitive deficits at follow-up. METHODS: About 124 UHR individuals were recruited at baseline. In this, 74 UHR individuals were clinically and cognitively assessed after 12 months, while remission status was available for 81 (25 remission/56 nonremission). Glutamate and GABA levels were assessed at baseline using 3 T proton magnetic resonance spectroscopy. Psychopathology, symptom severity, and remission were assessed with the Comprehensive Assessment of At-Risk Mental States and Clinical Global Impression and functional outcome with the Social and Occupational Functioning Assessment Scale. Cognitive function was estimated with the Cambridge Neuropsychological Test Automated Battery. RESULTS: There were no differences between baseline glutamate and GABA levels in subjects in the nonremission group compared with the remission group, and baseline metabolites could not predict remission status. However, higher baseline levels of GABA in ACC were associated with clinical global improvement (r = -0.34, N = 51, p = 0.01) in an explorative analysis. CONCLUSIONS: The variety in findings across studies suggests a probable multifactorial influence on clinical outcome in UHR individuals. Future studies should combine multimodal approaches to attempt prediction of long-term outcome.

High suicide rates during psychiatric inpatient stay and shortly after discharge.

OBJECTIVE: Over recent decades, intense efforts to address suicides in psychiatric admitted people have been initiated. The aim was to calculate suicide rates, rate ratios, population attributable risks (PAR) and trends among people admitted to or recently discharged from psychiatric wards. METHODS: Using a cohort design, we obtained nationwide register data on 6 292 932 individuals aged 15+ living in Denmark during 1995-2016. Of these, 178 703 (5.73%) males and 201 033 females (6.33%) had been admitted to psychiatric hospital. Incidence rate ratios (IRR) were obtained using Poisson regression analyses while adjusting for age and calendar period. Trends were assessed using joinpoint analyses. RESULTS: In total, 15 075 persons died by suicide, of which 6174 had been psychiatrically admitted. Among males, the suicide rate during the first week of admission and after discharge was 3409 and 3148 per 100 000 person-years, respectively. The corresponding values for females were 1267 and 1631. Generally, estimated suicide rates were highest in those with affective or anxiety stress disorders. During first week of hospitalization, the IRR was 237 for males and of 322 for females when compared with those never hospitalized. In first week after discharge, the IRR was 225 and 425 for males and females, respectively. PAR estimates indicated 6% of male suicides and 13% of female suicides attributes to first week of admission and discharge. The inpatient suicide rate decreased annually 2.5% until 2009 followed by a 7.5% annual percentage increase. The suicide rate after discharge decreased steadily annually over the study period. CONCLUSION: Despite finding declining post-discharge suicide rates, the period surrounding a psychiatric admission was still associated with extremely high suicide rates.

Basic symptoms influence real-life functioning and symptoms in individuals at high risk for psychosis.

OBJECTIVE: To investigate potential clinical differences in high-risk profiles presenting with and without basic symptoms, and additionally investigate the association between basic symptoms and clinical symptoms, functioning, and cognition. METHODS: High-risk individuals (n = 133) were stratified into individuals fulfilling ultra-high-risk (UHR) criteria (n = 59) and individuals fulfilling UHR+ basic symptoms criteria (BS) (n = 74). Group differences were assessed on clinical symptoms, real-life functioning, and cognition. Regression analyses were conducted to elucidate on the relationship between BS and clinical symptoms, functioning, neurocognition, and social cognition. RESULTS: The group fulfilling both UHR+ BS criteria had significantly more symptoms and lower real-life functioning and quality of life but not more cognitive deficits. BS influenced on attenuated psychotic, depressive, and general symptoms, but only modestly on negative symptoms. No relationship between BS and neuro- and social cognition was established except for an association with emotion recognition processing speed. BS influenced real-life functioning, and this finding was sustained when controlling for the effect of negative symptoms. CONCLUSIONS: Our findings indicate that BS contribute highly to the distress and symptom load of clinical high-risk individuals. Longitudinal findings are needed to establish the predictive validity of BS on high-risk individuals' clinical and functional prognosis.

Risk of homelessness after discharge from psychiatric wards in Denmark: a nationwide register-based cohort study.

OBJECTIVE: To examine the absolute and relative risk of homelessness following discharge from psychiatric wards in Denmark. METHODS: A nationwide, register-based, cohort study including people aged 18+ years discharged from psychiatric wards in Denmark between 1 January 2001 and 31 December 2015. We analysed associations between psychiatric diagnoses and risk of homelessness using survival analysis. RESULTS: A total of 126 848 psychiatric in-patients were included accounting for 94 835 person-years. The incidence of homelessness one year following discharge was 28.18 (95% CI 26.69-29.75) and 9.27 (95% CI 8.45-10.16) per 1000 person-years at risk in men and women respectively. The one-year cumulative probability of first homelessness after discharge from psychiatric wards was 1.58% (95% CI 1.48-1.68) in males and 0.55% (95% CI 0.50-0.61) in females. Substance use disorders increased the risk of homelessness after discharge with adjusted incidence rate ratios of 6.60 (95% CI 5.19-8.40) (men) and 13.06 (95% CI 9.31-18.33) (women), compared with depressive disorders. Prior history of homelessness was an important predictor for homelessness following discharge. CONCLUSIONS: The first year following discharge from psychiatric wards is a high-risk period of homelessness, especially when having a substance use disorder or a prior history of homeless shelter contact. Improved efforts to prevent homelessness are needed.

Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials.

BACKGROUND: No study has gathered evidence from all randomized clinical trials (RCTs) with anti-inflammatory drugs measuring antidepressant effects including a detailed assessment of side-effects and bias. METHODS: We performed a systematic review identifying RCTs published prior to January 1, 2018, studying antidepressant treatment effects and side-effects of pharmacological anti-inflammatory intervention in adults with major depressive disorder (MDD) or depressive symptoms. Outcomes were depression scores after treatment, remission, response, and side-effects. Pooled standard mean differences (SMD) and risk ratios (RR) including 95% confidence intervals (95%-CI) were calculated. RESULTS: We identified 36 RCTs, whereof 13 investigated NSAIDs (N = 4214), 9 cytokine inhibitors (N = 3345), seven statins (N = 1576), 3 minocycline (N = 151), 2 pioglitazone (N = 77), and 2 glucocorticoids (N = 59). Anti-inflammatory agents improved depressive symptoms compared to placebo as add-on in patients with MDD (SMD = -0.64; 95%-CI = -0.88, -0.40; I2  = 51%; N = 597) and as monotherapy (SMD = -0.41; 95%-CI = -0.60, -0.22; I2  = 93%, N = 8825). Anti-inflammatory add-on improved response (RR = 1.76; 95%-CI = 1.44-2.16; I2  = 16%; N = 341) and remission (RR = 2.14; 95%-CI = 1.03-4.48; I2  = 57%; N = 270). We found a trend toward an increased risk for infections, and all studies showed high risk of bias. CONCLUSION: Anti-inflammatory agents improved antidepressant treatment effects. Future RCTs need to include longer follow-up, identify optimal doses and subgroups of patients that can benefit from anti-inflammatory intervention.

Stability and development of psychotic symptoms and the use of antipsychotic medication - long-term follow-up.

BACKGROUND: Few studies have evaluated the development in the use of antipsychotic medication and psychotic symptoms in patients with first-episode psychosis on a long-term basis. Our objective was to investigate how psychotic symptoms and the use of antipsychotic medication changed over a 10-year period in a cohort of patients with first-episode psychosis. METHOD: The study is a longitudinal prospective cohort study over 10 years with follow-ups at years 1, 2, 5 and 10. A total of 496 patients with first-episode psychosis were included in a multi-centre study initiated between 1998 and 2000 in Copenhagen and Aarhus, Denmark. RESULTS: At all follow-ups, a large proportion (20-30%) of patients had remission of psychotic symptoms without use of antipsychotic medication at the time of the follow-up. Patients who were in this group at the 5-year follow-up had an 87% [95% confidence interval (CI) 77-96%] chance of being in the same group at the 10-year follow-up. This stability was also the case for patients who had psychotic symptoms and were treated with antipsychotic medication at year 5, where there was a 67% (95% CI 56-78%) probability of being in this group at the consecutive follow-up. CONCLUSIONS: A large group of patients with psychotic illness were in remission without the use of antipsychotic medication, peaking at year 10. Overall there was a large degree of stability in disease courses over the 10-year period. These results suggest that the long-term outcome of psychotic illness is heterogeneous and further investigation on a more individualized approach to long-term treatment is needed.

Association between alcohol, cannabis, and other illicit substance abuse and risk of developing schizophrenia: a nationwide population based register study.

BACKGROUND: Several studies have examined whether use of substances can cause schizophrenia. However, due to methodological limitations in the existing literature (e.g. selection bias and lack of adjustment of co-abuse) uncertainties still remain. We aimed to investigate whether substance abuse increases the risk of developing schizophrenia, addressing some of these limitations. METHOD: The longitudinal, nationwide Danish registers were linked to establish a cohort of 3 133 968 individuals (105 178 673 person-years at risk), identifying 204 505 individuals diagnosed with substance abuse and 21 305 diagnosed with schizophrenia. Information regarding substance abuse was extracted from several registers and did not include psychotic symptoms caused by substance abuse in the definition. This resulted in a large, generalizable sample of exposed individuals. The data was analysed using Cox regression analyses, and adjusted for calendar year, gender, urbanicity, co-abuse, other psychiatric diagnosis, parental substance abuse, psychiatric history, immigration and socioeconomic status. RESULTS: A diagnosis of substance abuse increased the overall risk of developing schizophrenia [hazard ratio (HR) 6.04, 95% confidence interval (CI) 5.84-6.26]. Cannabis (HR 5.20, 95% CI 4.86-5.57) and alcohol (HR 3.38, 95% CI 3.24-3.53) presented the strongest associations. Abuse of hallucinogens (HR 1.86, 95% CI 1.43-2.41), sedatives (HR 1.68, 95% CI 1.49-1.90), and other substances (HR 2.85, 95% CI 2.58-3.15) also increased the risk significantly. The risk was found to be significant even 10-15 years subsequent to a diagnosis of substance abuse. CONCLUSION: Our results illustrate robust associations between almost any type of substance abuse and an increased risk of developing schizophrenia later in life.

Negative symptoms mediate the relationship between neurocognition and function in individuals at ultrahigh risk for psychosis.

OBJECTIVE: Neurocognition is known to impact functioning in individuals at ultrahigh risk (UHR) for psychosis, but studies investigating potential mediators of this relationship are scarce. Building on evidence from schizophrenia spectrum disorders, the study tested whether negative symptoms and social skills act as mediators between neurocognition and functional outcome in UHR individuals. METHODS: Ultrahigh risk participants (N = 84) underwent neurocognitive testing using the Brief Assessment of Cognition in Schizophrenia. Social skills and negative symptoms were assessed using the High-Risk Social Challenge task and the Scale for the Assessment of Negative Symptoms respectively. Four instruments were used to assess overall functioning, and one instrument assessed quality of life encompassing social functioning. RESULTS: The cross-sectional analyses revealed that neurocognition was related to the measures of functioning. Negative symptoms mediated the relationship between neurocognition and four of the five measures of functioning. We did not find social skills to mediate between neurocognition and functioning. CONCLUSION: Negative symptoms appear to mediate the relationship between neurocognition and functional outcome in UHR individuals, but the finding needs to be confirmed and extended to longitudinal studies. This underscores the importance of focusing on both neurocognition and negative symptoms when aiming at improving the functional outcome of UHR individuals.

High loading of polygenic risk in cases with chronic schizophrenia.

Genomic risk profile scores (GRPSs) have been shown to predict case-control status of schizophrenia (SCZ), albeit with varying sensitivity and specificity. The extent to which this variability in prediction accuracy is related to differences in sampling strategies is unknown. Danish population-based registers and Neonatal Biobanks were used to identify two independent incident data sets (denoted target and replication) comprising together 1861 cases with SCZ and 1706 controls. A third data set was a German prevalent sample with diagnoses assigned to 1773 SCZ cases and 2161 controls based on clinical interviews. GRPSs were calculated based on the genome-wide association results from the largest SCZ meta-analysis yet conducted. As measures of genetic risk prediction, Nagelkerke pseudo-R(2) and variance explained on the liability scale were calculated. GRPS for SCZ showed positive correlations with the number of psychiatric admissions across all P-value thresholds in both the incident and prevalent samples. In permutation-based test, Nagelkerke pseudo-R(2) values derived from samples enriched for frequently admitted cases were found to be significantly higher than for the full data sets (Ptarget=0.017, Preplication=0.04). Oversampling of frequently admitted cases further resulted in a higher proportion of variance explained on the liability scale (improvementtarget= 50%; improvementreplication= 162%). GRPSs are significantly correlated with chronicity of SCZ. Oversampling of cases with a high number of admissions significantly increased the amount of variance in liability explained by GRPS. This suggests that at least part of the effect of common single-nucleotide polymorphisms is on the deteriorative course of illness.

Change in cannabis use, clinical symptoms and social functioning among patients with first-episode psychosis: a 5-year follow-up study of patients in the OPUS trial.

BACKGROUND: Several studies indicate that cannabis use among patients with psychotic disorders is associated with worse outcome, but only a few studies have controlled for baseline condition and medication. METHOD: At 5-year follow-up, interviews were carried out with 314 first-episode psychosis patients included in the OPUS trial. The patients included were in the age range of 18 to 45 years old and 59% were male. Cannabis use was extracted from the Schedule for Clinical Assessment in Neuropsychiatry. At follow-up, the patients were divided into different groups according to the variable cannabis use: abstainers, stoppers, starters and continuers. Psychotic, negative and disorganized dimensions (ranging from zero to five) were calculated for each of the four groups based on the Schedule for the Assessment of Positive and Negative Symptoms in Schizophrenia. RESULTS: Cannabis users were younger (24.6 years v. 27.4 years, p < 0.001) and had a lower level of education. At the 5-year follow-up, users of cannabis had higher scores on the psychotic dimension [difference 0.97, 95% confidence interval (CI) 0.41-1.53, p = 0.001] and lower levels of the Global Assessment of Functioning (difference 8.26, 95% CI 2.13-14.39, p = 0.01). Those who stopped using cannabis between entry and 5-year follow-up had a significantly lower level of psychotic symptoms at 5-year follow-up even after controlling for baseline level of psychotic symptoms and for insufficient antipsychotic medication (adjusted difference in psychotic dimension -1.04, 95% CI -1.77 to -0.31, p = 0.006). CONCLUSIONS: Continuous cannabis use was associated with higher levels of psychotic symptoms after 5 years, and this association was only partly explained by insufficient antipsychotic medication.

Specialized psychosocial treatment plus treatment as usual (TAU) versus TAU for patients with cannabis use disorder and psychosis: the CapOpus randomized trial.

BACKGROUND: Cannabis abuse in psychotic patients is associated with rehospitalizations, reduced adherence and increased symptom severity. Previous psychosocial interventions have been ineffective in cannabis use, possibly because of low sample sizes and short interventions. We investigated whether adding CapOpus to treatment as usual (TAU) reduces cannabis use in patients with cannabis use disorder and psychosis. Method A total of 103 patients with psychosis and cannabis use disorder were centrally randomized to 6 months of CapOpus plus TAU (n = 52) or TAU (n = 51). CapOpus consisted mainly of motivational interviewing and cognitive behaviour therapy (CBT). TAU was targeted primarily at the psychotic disorder. The primary outcome was self-reported days with cannabis use in the preceding month. RESULTS: Pre-randomization cannabis use frequency was 14.9 [95% confidence interval (CI) 12.7-17.1] days/month. Post-treatment, the ratio of days/month with cannabis use in CapOpus versus TAU was 0.76 (95% CI 0.38-1.50) (p = 0.42), and 0.80 (95% CI 0.21-3.10) (p = 0.75) at the 4-month follow-up. From 46.4 (95% CI 36.4-56.3) monthly joints pre-randomization, consumption fell to 27.3 (95% CI 12.6-41.9) joints in CapOpus and 48.2 (95% CI 31.8-64.6) in TAU (p = 0.06). Follow-up amounts were 28.4 (95% CI 13.5-43.2) and 41.6 (95% CI 25.2-58.0) joints (p = 0.23). Several subgroup analyses suggested benefits of CapOpus. CONCLUSIONS: CapOpus did not reduce the frequency, but possibly the amount, of cannabis use. This is similar to the findings of previous trials in this population. Implementation of CapOpus-type interventions is thus not warranted at present but subgroup analyses call for further trials.