DEPERROR: Risks of systematic errors in drug and non-drug randomized clinical trials assessing intervention effects in patients with unipolar depression.

BACKGROUND: Systematic errors in randomized clinical trials (RCTs) overestimate treatment effects. We systematically assessed the risks of bias in RCTs assessing the effects of drug and non-drug interventions for patients with unipolar depression. METHODS: We searched bibliographic databases for drug and non-drug RCTs including patients with depression. We assessed the following risk of bias domains: sequence generation, allocation concealment, baseline imbalance, blinding, intention-to-treat analysis, selective outcome reporting, and funding. Risks of bias were compared for drug and non-drug trials and according to year of publication (before 1990; from 1990 to 1999; and 2000 to 2010). RESULTS: Comparing drug trials (N=775) to non-drug trials (N=73), the proportion of drug trials with low risk of bias seemed superior regarding blinding of participants (p<0.001), blinding of health-care providers (p<0.001), and blinded outcome assessment (p<0.001). Non-drug trials were superior regarding sequence generation (p<0.001), allocation concealment (p=0.002), intention-to-treat analysis (p<0.001), and baseline imbalance (p=0.006). Adequate blinding of data managers (p=0.45), blinding of statisticians (p=0.69), and selective outcome reporting (p=0.55) did not differ. 41.5% of drug trials were funded by for-profit organizations compared to 12.3% of non-drug trials (p<0.001). In drug trials, the risk of bias decreased significantly over time. This did not reach statistical significance in non-drug trials. LIMITATIONS: This study only included trials published before 2010. CONCLUSIONS: Included trials were associated with high risks of bias which may distort effect estimates. The risks of bias decreased with time for drug trials.

Ten-year follow-up of the OPUS specialized early intervention trial for patients with a first episode of psychosis.

INTRODUCTION: Specialized early intervention programs such as The Danish OPUS treatment are efficient in treating patients with a first episode of psychosis (FEP) at least after 2 and 5 years. Few studies have examined long-term outcomes of these interventions. AIM: To examine the effect of 2 years of OPUS vs treatment as usual (TAU) within an FEP cohort, 10 years after inclusion into the OPUS trial. METHODS: From 1998 to 2000, participants were randomized to OPUS or TAU. Ten years later, we conducted comprehensive interviews and performed register-based follow-up on all participants in national Danish registers. We analyzed participants according to the intention-to-treat principle. RESULTS: Of the 547 participants included in the study, 347 (63.4%) took part in this follow-up. While there was evidence of a differential 10-year course in the development of negative symptoms, psychiatric bed days, and possibly psychotic symptoms in favor of OPUS treatment, differences were driven by effects at earlier follow-ups and had diminished over time. Statistically significant differences in the course of use of supported housing were present even after 8-10 years. There were no differences between OPUS and TAU regarding income, work-related outcomes, or marital status. CONCLUSION: Most of the positive short-term effects of the OPUS intervention had diminished or vanished at this long-term follow-up. We observed a clear tendency that OPUS treatment leads to fewer days in supported housing. There is a need for further studies investigating if extending the intervention will improve outcomes more markedly at long-term follow-ups.

Prevention of depression in patients with acute coronary syndrome (DECARD) randomized trial: effects on and by self-reported health.

AIM: Escitalopram may prevent depression following acute coronary syndrome. We sought to estimate the effects of escitalopram on self-reported health and to identify subgroups with higher efficacy. METHODS: This is a secondary analysis of a 12-month double-blind clinical trial randomizing non-depressed acute coronary syndrome patients to escitalopram (n = 120) or matching placebo (n = 120). The main outcomes were mean scores on Short Form 36 Health Survey (SF-36) domains, and diagnosis of depression was adjusted for baseline SF-36 scores. RESULTS: Escitalopram did not yield different SF-36 trajectories on any scale compared with placebo (P > 0.28). Efficacy of escitalopram may have been better among those scoring at least the normative score on general health perceptions (hazard ratio (HR) for depression 0.17 (95% confidence interval 0.02-1.42) ) or social functioning (HR = 0.12 (0.02-0.99) ) than in the full sample of patients (HR = 0.20 (0.04-0.90) ), although not statistically significant. CONCLUSIONS: The SF-36 may be too broad an outcome measure in trials or treatments that seek to prevent depression following acute coronary syndrome. The SF-36 may, however, indicate who is more likely to benefit from treatment.

From research to practice: how OPUS treatment was accepted and implemented throughout Denmark.

BACKGROUND: The early phases of psychosis have been hypothesized to constitute a critical period, a window of opportunity. At the same time, the early phases of psychosis are associated with increased risk of unwanted outcome, such as suicidal behaviour and social isolation. This was the background for the emergence of early intervention services, and in Denmark, the OPUS trial was initiated as part of that process. METHODS: Modified assertive community treatment, together with family involvement and social skills training, constituted the core elements in the original programme. A total of 547 patients with first-episode psychosis were included in the trial. RESULTS: To summarize briefly the results of the OPUS trial: the OPUS treatment was superior to standard treatment in reducing psychotic and negative symptoms and substance abuse, in increasing user satisfaction and adherence to treatment, and in reducing use of bed days and days in supported housing. Moreover, relatives included in the OPUS treatment were less strained and had a higher level of knowledge about schizophrenia and higher user satisfaction. DISCUSSION: The OPUS treatment was implemented throughout Denmark. Training courses were developed and manuals and books were published. Regional health authorities had access to national grants for implementing early intervention services; as a result, OPUS teams were disseminated throughout the country. The content of the treatment is now further developed, and new elements are being tried out - such as individual placement and support, lifestyle changes, cognitive remediation, specialized treatment for substance abuse and different kinds of user involvement.

Risk of suicide according to level of psychiatric treatment: a nationwide nested case-control study.

PURPOSE: Knowledge of the epidemiology of suicide is a necessary prerequisite of suicide prevention. We aimed to conduct a nationwide study investigating suicide risk in relation to level of psychiatric treatment. METHODS: Nationwide nested case-control study comparing individuals who died from suicide between 1996 and 2009 to age-, sex-, and year-matched controls. Psychiatric treatment in the previous year was graded as "no treatment," "medicated," "outpatient contact," "psychiatric emergency room contact," or "admitted to psychiatric hospital." RESULTS: There were 2,429 cases and 50,323 controls. Compared with people who had not received any psychiatric treatment in the preceding year, the adjusted rate ratio (95 % confidence interval) for suicide was 5.8 (5.2-6.6) for people receiving only psychiatric medication, 8.2 (6.1-11.0) for people with at most psychiatric outpatient contact, 27.9 (19.5-40.0) for people with at most psychiatric emergency room contacts, and 44.3 (36.1-54.4) for people who had been admitted to a psychiatric hospital. The gradient was steeper for married or cohabiting people, those with higher socioeconomic position, and possibly those without a history of attempted suicide. CONCLUSIONS: Psychiatric admission in the preceding year was highly associated with risk of dying from suicide. Furthermore, even individuals who have been in contact with psychiatric treatment but who have not been admitted are at highly increased risk of suicide.

Intervention efficacy in trials targeting cannabis use disorders in patients with comorbid psychosis systematic review and meta-analysis.

INTRODUCTION: Cannabis use disorders are highly prevalent in patients with schizophrenia and other psychoses, and are probably associated with a range of poor outcomes. Several trials have been conducted on this population, the results of which have been summarized in several systematic reviews but never in meta-analyses specifically regarding cannabis use. METHODS: PubMed, PsycINFO, EMBASE, and The Cochrane Central Register of Controlled Trials were searched using predefined search terms. We included randomized trials of all types of interventions targeting cannabis use disorders in patients with schizophrenia spectrum disorders. We extracted information on intervention types, efficacy, trial characteristics, and risk of bias. RESULTS: There was no evidence of an effect on frequency of cannabis use, but intervention effects of motivational intervention with or without cognitive behavior therapy were observed on quantity of use and on positive symptoms of schizophrenia. Psychosocial intervention did not have an appreciable effect on negative symptoms. Longer interventions appear to be more efficacious, and efficacy may be better in trials with comparatively few women. Larger trials may be better at establishing effects on positive symptoms. CONCLUSION: Psychosocial interventions appear moderately efficacious in reducing quantity of cannabis-use and positive symptoms.

Suicide and unintentional injury mortality among homeless people: a Danish nationwide register-based cohort study.

BACKGROUND: Homeless people have elevated mortality, especially due to external causes. We aimed to examine suicide and unintentional injury mortality levels and identify predictors in the homeless population. METHODS: A nationwide, register-based cohort study of homeless people aged 16 years and older was carried out using the Danish Homeless Register, 1999-2008. RESULTS: In all, 32 010 homeless people (70.5% men) were observed. For men, the mortality rate was 174.4 [95% confidence interval (CI) = 150.6-198.1] per 100 000 person-years for suicide and 463.3 (95% CI = 424.6-502.0) for unintentional injury. For women, the corresponding rates were 111.4 (95% CI = 81.7-141.1) for suicide and 241.4 (95% CI = 197.6-285.1) for unintentional injury. Schizophrenia spectrum, affective, personality and substance use disorders were strongly associated with increased risk of suicide; the highest risk estimates were found for schizophrenia spectrum disorders among both men [hazard ratio (HR) = 3.1, 95% CI = 2.0-4.9] and women (HR = 15.5, 95% CI = 4.5-54.0). Alcohol and drug use disorders were predictors of death by unintentional injury for both men and women, whereas schizophrenia spectrum disorders and personality disorders were only significant predictors among men; the highest risk estimates were found for drug use disorders among men (HR = 2.2, 95% CI = 1.8-2.8) and women (HR = 3.1, 95% CI = 1.8-5.4). A history of psychiatric admission and emergency room contact were predictors for dying by suicide and unintentional injury. CONCLUSION: People in the homeless shelter population with a history of a psychiatric disorder constitute a high-risk group regarding the elevated suicide and unintentional injury mortality.

Psychiatric treatment following participation in the CapOpus randomized trial for patients with comorbid cannabis use disorder and psychosis.

BACKGROUND: Randomized trials targeting cannabis use disorders in patients with psychosis have generally been unsuccessful. One of the largest such trials was the CapOpus trial, which had an impact on the number of monthly joints used, but not on the number of days with cannabis use or positive or negative symptoms. OBJECTIVE: To investigate the effects of CapOpus on psychiatric treatment. METHODS: Six-month randomized trial on participants meeting ICD-10 criteria for cannabis use disorder and schizophrenia-spectrum psychosis. Participants were randomized to treatment as usual (TAU, n=51) alone versus TAU plus CapOpus (n=52) consisting of motivational interviewing and cognitive behavior therapy. Data regarding psychiatric treatment was obtained from complete nationwide registers. Analyses were intention-to-treat. Cox and poisson regression were used as appropriate. RESULTS: Compared with treatment as usual, participants in the CapOpus group had an overall higher risk of having a psychiatric emergency room contact (hazard ratio 2.02, 95% confidence interval 1.22-3.34). Participants in CapOpus also had more contacts with psychiatric emergency rooms (incidence rate ratio 3.47 (2.64-4.57)) and more admissions to psychiatric hospitals (incidence rate ratio 2.24 (1.65-3.03)); conversely, CapOpus-participants spent fewer days admitted to psychiatric hospitals than treatment-as-usual participants (incidence rate ratio 0.72 (0.68-0.75)). CONCLUSIONS: CapOpus led to earlier and more psychiatric emergency room contacts and admissions that, however, were of fewer days. This pattern could indicate that participants receiving treatment as usual were inadequately treated. However, it cannot be excluded that the differences might be an adverse reaction to the psychosocial intervention.

Test-retest reliability of the Danish Adult Reading Test in patients with comorbid psychosis and cannabis-use disorder.

BACKGROUND: The New Adult Reading Test is a common instrument for assessing pre-morbid IQ for patients with, for instance, schizophrenia. However, test-retest reliability has not been established for patients dually diagnosed with psychosis and substance use disorder. Furthermore, test-retest reliability of the Danish adaptation has never been established in any population. AIMS: To determine the test-retest reliability of the Danish Adult Reading Test (DART) (adapted from the National Adult Reading Test, NART) for patients dually diagnosed with psychosis and cannabis-use disorder. METHODS: This was a secondary analysis of the CapOpus randomized trial. As part of the trial, 103 patients were randomized, and completed the DART up to three times. Pearson's r and pairwise t-tests were calculated. RESULTS: DART score was independent of randomization, cannabis-use frequency and psychopathology. Scores at the last interview were slightly higher than at the first two. Correlation over time was very strong (0.8 < r <0.9) for all pairwise comparisons of interviews. Variations in DART scores and estimated pre-morbid IQ over time were sometimes of borderline statistical significance but not of clinical relevance. CONCLUSIONS: DART and NART have high test-retest reliability, but apparently non-systematic, clinically irrelevant variation over time does occur. CLINICAL IMPLICATION: The Danish adaptation of the New Adult Reading Test possesses good test-retest reliability, making it an appropriate choice for assessment of pre-morbid IQ, and in patients with dually diagnosed psychosis and cannabis-use disorder.

Health care use by patients with somatoform disorders: a register-based follow-up study.

OBJECTIVE: Studies have shown a greater use of medical than mental health services in patients with somatoform disorders. However, not many studies are based on structured interviews and include the entire somatoform spectrum of diagnoses. We conducted a register-based case-control study to investigate medical care use prior to and three years after diagnosis in patients with somatoform disorders. METHODS: We included 380 patients with somatoform diagnoses (SCID-NP for DSM-IIIR) in a case-control study and compared them with 174 patients with anxiety disorders and 5540 controls from the background population. Data from the Danish National Registers were used to assess health care use in both primary and secondary care. RESULTS: Somatoform patients incurred 2.11 (2.09-2.12) times the primary care visits of controls. They had 3.12 (3.08-3.16) times as many somatic bed-days than controls and 3.94 (3.91-3.97) as many psychiatric bed-days. Primary care use remained stable 3 years after diagnosis (p = 0.14) and the award of disability pension (p = 0.82). However, the number of somatic admissions decreased from 5.64 to 2.76 (p = 0.0004) 3 years after diagnosis. Somatization had an independent effect on health care use when controlling for psychiatric comorbidity. CONCLUSIONS: Patients with somatoform disorders make significantly greater use of health care services than do controls and patients with anxiety. Somatoform patients made more use of psychiatric services than expected. The use of somatic health care was independent of psychiatric comorbidity. Primary care use and disability pension award were not influenced by proper diagnosing of somatoform disorders whereas number of somatic admissions were halved.

Correlations and agreement between delta-9-tetrahydrocannabinol (THC) in blood plasma and timeline follow-back (TLFB)-assisted self-reported use of cannabis of patients with cannabis use disorder and psychotic illness attending the CapOpus randomized clinical trial.

AIMS: To assess correlations and agreement between timeline follow-back (TLFB)-assisted self-report and blood samples for cannabis use. DESIGN: Secondary analysis of a randomized trial. SETTING: Copenhagen, Denmark. PARTICIPANTS: One hundred and three patients from the CapOpus trial with cannabis use disorder and psychosis, providing 239 self-reports of cannabis use and 88 valid blood samples. MEASUREMENTS: Delta-9-tetrahydrocannabinol (THC), 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) detected in plasma using high-performance liquid chromatography with tandem mass spectrometry detection. Self-report of cannabis-use last month by TLFB. Pearson's r, sensitivity and specificity calculated as measures of correlation or agreement. FINDINGS: Correlations were strong; r = 0.75 for number of days and r = 0.83 for number of standard joints in the preceding month when excluding outliers. Including outliers, coefficients were moderate to strong (r = 0.49). There were differences in subgroups, mainly inconsistent, depending on inclusion or exclusion of outliers. Sensitivity and specificity for TLFB detecting the presence or absence of cannabis use were 95.7% [95% confidence interval (CI) 88.0-99.1%) and 72.2% (95% CI 46.5-90.3%), respectively. Using 19 days as cut-off on TLFB, they were 94.3% (95% CI 86.0-98.4%) and 94.4% (95% CI 72.2-99.9%), respectively. Area under the receiver operating characteristic (ROC) curve was 0.96. CONCLUSIONS: Timeline follow-back (TLFB)-assisted self-report of cannabis use correlates highly with plasma-delta-9-tetrahydrocannabinol in patients with comorbid cannabis use disorder and psychosis. Sensitivity and specificity of timeline follow-back appear to be optimized with 19 days as the cut-off point. As such, timeline follow-back may be superior to analysis of blood when going beyond 19 days of recall.

Validity of Timeline Follow-Back for self-reported use of cannabis and other illicit substances--systematic review and meta-analysis.

BACKGROUND: Timeline Follow-Back (TLFB) is a widely used, calendar-based measure of self-reported use of (among other things) illicit substances. We examined agreement between TLFB and biological measures for illicit substances. METHODS: PubMed, PsycINFO, Cochrane CENTRAL, and EMBASE were searched in December 2010. 16,633 papers screened to identify those that measured illicit substance use by both TLFB and biological measures. We extracted data on agreement between TLFB and biological measures, sample size, study type, inclusion criteria of participants, and length of recall of TLFB. RESULTS: Twenty-nine papers were included, almost exclusively in substance-use-disorder populations. Some studies reported several overall agreement rates, e.g. over time. Lowest and highest weighted average agreement rates were: for cannabis, 87.3% (95% confidence interval 86.9% to 87.7%) and 90.9% (90.5% to 91.4%); for cocaine, 79.3% (79.1% to 79.6%) and 84.1% (83.9% to 84.2%); for opiates 94.0% (93.5% to 94.5%) for both weighted averages; and for studies not distinguishing between substances, 88.5% (88.4 to 88.7%) and 91.0% (90.7% to 91.2%). Higher agreement was found in populations without psychiatric comorbidity, and lower agreement in randomized controlled trials. Publication bias or selective outcome reporting bias was not detected. CONCLUSIONS: TLFB validly detects use of illicit substances in populations with substance use disorders. Using TLFB may limit the need for biological samples, making information on illicit substance use easier and less costly to obtain and analyze.

Psychiatric disorders and mortality among people in homeless shelters in Denmark: a nationwide register-based cohort study.

BACKGROUND: The increased mortality of homeless people compared with non-homeless people might be linked to psychiatric disorders. However, homeless people are, because of their insufficient accommodation, difficult to sample and monitor, which has limited previous studies. We aimed to assess registered psychiatric disorders, mortality, and predictors of mortality in the homeless shelter population in Denmark. METHODS: We did a nationwide, prospective, register-based cohort study of homeless people aged 16 years and older who were registered in the Danish Homeless Register between Jan 1, 1999, and Dec 31, 2009. We calculated the proportion of registered psychiatric disorders, overall and cause-specific standardised mortality ratio (SMR), and life expectancy. Hazard ratios (HRs) were used to assess predictors of death. FINDINGS: 32,711 homeless people (23,040 men and 9671 women) were included in the study population. 14,381 men (62·4%) and 5632 women (58·2%) had registered psychiatric disorders, and 11,286 men (49·0%) and 3564 women (36·9%) had a substance abuse diagnosis. During the study period, 3839 men (16·7%) and 951 women (9·8%) died. The overall SMR for men was 5·6 (95% CI 5·4-5·8) and for women was 6·7 (6·2-7·1), and external causes accounted for 1161 (27·9%) of 4161 deaths for which information on the cause was available. Remaining life expectancy at age 15-24 years was 21·6 years (95% CI 21·2-22·1) and 17·4 years (16·4-18·5) lower for homeless men and women, respectively, than the general population. Registered substance abuse disorder was associated with the highest mortality risk compared with no psychiatric contact registered (adjusted HR 1·4, 95% CI 1·3-1·5 for men; 1·7, 1·4-2·1 for women). INTERPRETATION: Health problems are extensive in the homeless shelter population and there is an urgent need for more sustained efforts to reduce the high morbidity and mortality, especially from external causes. Register data is an important resource to supplement existing knowledge on homeless people with more valid and detailed information. FUNDING: The Danish Council for Independent Research.