Joanna Le Noury

Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence

Objectives To reanalyse SmithKline Beecham’s Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine. Design Double blind randomised placebo controlled trial. Setting 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. Participants 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality. Interventions Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo. Main outcome measures The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified. Results The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group. Conclusions Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.

Mortality in schizophrenia and related psychoses: data from two cohorts, 1875–1924 and 1994–2010

Objective To investigate death rates in schizophrenia and related psychoses. Design Data from two epidemiologically complete cohorts of patients presenting for the first time to mental health services in North Wales for whom there are at least 1, and up to 10-year follow-up data have been used to calculate survival rates and standardised death rates for schizophrenia and related psychoses. Setting The North Wales Asylum Denbigh (archived patient case notes) and the North West Wales District General Hospital psychiatric unit. Population Cohort 1: The North Wales Asylum Denbigh (archived patient case notes). Of 3168 patients admitted to the North Wales Asylum Denbigh 1875–1924, 1074 had a schizophrenic or related psychosis. Cohort 2: Patients admitted between 1994 and 2010 to the North West Wales District General Hospital psychiatric unit, of whom 355 had first admissions for schizophrenia or related psychoses. Results We found a 10-year survival probability of 75% in the historical cohort and a 90% survival probability in the contemporary cohort with a fourfold increase in standardised death rates in schizophrenia and related psychoses in both historical and contemporary periods. Suicide is the commonest cause of death in schizophrenia in the contemporary period (SMR 35), while tuberculosis was the commonest cause historically (SMR 9). In the contemporary data, deaths from cardiovascular causes arise in the elderly and deaths from suicide in the young. Conclusions Contemporary death rates in schizophrenia and related psychoses are high but there are particular hazards and windows of risk that enable interventions. The data point to possible interventions in the incident year of treatment that could give patients with schizophrenia a normal life expectancy.

The incidence and prevalence of diabetes in patients with serious mental illness in North West Wales: Two cohorts, 1875–1924 & 1994–2006 compared

BackgroundAgainst a background of interest in rates of diabetes in schizophrenia and related psychoses and claims that data from historical periods demonstrate a link that antedates modern antipsychotics, we sought to establish the rate of diabetes in first onset psychosis and subsequent prevalence in historical and contemporary cohorts.MethodsAnalysis of two epidemiologically complete databases of individuals admitted for mental illness. 3170 individuals admitted to the North Wales Asylum between 1875–1924 and tracked over 18,486 patient years and 394 North West Wales first admissions for schizophrenia and related psychoses between 1994 and 2006 and tracked after treatment.ResultsThe prevalence of Type 2 diabetes among patients with psychoses at time of first admission in both historical and contemporary samples was 0%. The incidence of diabetes remained 0% in the historical sample throughout 15 years of follow-up but rose in the contemporary sample after 3, 5 and 6 years of treatment with an incidence rate double the expected population rate so that the 15 year prevalence is likely to be over 8%.ConclusionNo association was found between diabetes and serious mental illness, but there may be an association between diabetes and treatment.

One hundred and twenty cases of enduring sexual dysfunction following treatment.

BACKGROUND There have been reports for over a decade linking serotonin reuptake inhibitors, finasteride and isotretinoin with enduring sexual dysfunction after treatment stops. OBJECTIVE To explore the clinical pictures linked to all 3 drugs. METHODS We have selected 120 reports to RxISK.org reporting the problem and mined these for data on age, gender, drug of use, and impact of the problem. RESULTS The data make it clear that the three drugs show extensive overlap in symptom profile, regardless of sex or country of origin. CONCLUSIONS The availability of 120 reports from over 20 countries add to the case for the validity of the syndrome. This is severe and enduring condition can result in death. An understanding of its physiology and an approach to treatment are needed.

The incidence of admissions for schizophrenia and related psychoses in two cohorts: 1875–1924 and 1994–2010

Objective To investigate changes in incidence of admissions for schizophrenia and related non-affective psychoses in North Wales. Design Data from two epidemiologically complete cohorts of patients presenting for the first time to mental health services in North Wales between 1875–1924 and 1994–2010 are used in this study to map the incidence of hospital admissions for schizophrenia and non-affective psychoses. Setting The North Wales Asylum Denbigh (archived patient case notes) and the North West Wales District General Hospital psychiatric unit. Population 3168 patients admitted to the North Wales Asylum Denbigh between 1875 and 1924 and 355 patients admitted to the District General Hospital psychiatric unit between 1994 and 2010. Results There was an increasing admission incidence for schizophrenia between 1875 and 1900, a higher admission rate in the 1990s for men, followed by a drop in rates of admission for both genders since 2006. Admission incidences switch from parity between the sexes in the historical period to a doubling of the admission rates for men compared with women in the modern period. This admission pattern differs from the admission patterns for affective psychoses or organic disorders. Conclusion There have been changes in the incidence of admissions for schizophrenia in North Wales.

The morbidity and mortality linked to melancholia: two cohorts compared, 1875–1924 and 1995–2005

For over a century, melancholia has been linked to increased rates of morbidity and mortality. Data from two epidemiologically complete cohorts of patients presenting to mental health services in North Wales (1874–1924 and 1995–2005) have been used to look at links between diagnoses of melancholia in the first period and severe hospitalized depressive disorders today and other illnesses, and to calculate mortality rates. This is a study of the hospitalized illness rather than the natural illness, and the relationship between illness and hospitalization remains poorly understood. These data confirm that melancholia is associated with a substantial increase in the standardized mortality rate both formerly and today, stemming from a higher rate of deaths from tuberculosis in the historical sample and from suicide in the contemporary sample. The data do not link melancholia to cancer or cardiac disease. The comparison between outcomes for melancholia historically and severe mood disorder today argue favourably for the effectiveness of asylum care.

Study 329 continuation phase: Safety and efficacy of paroxetine and imipramine in extended treatment of adolescent major depression.

OBJECTIVE: This is an analysis of the unpublished continuation phase of Study 329, the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The objectives of the continuation phase were to assess safety and relapse rates in the longer term. The objective of this publication, under the Restoring Invisible and Abandoned Trials (RIAT) initiative, was to see whether access to and analysis of the previously unpublished dataset from the continuation phase of this randomized controlled trial would have clinically relevant implications for evidence-based medicine. METHODS: The study was an eight-week double-blind randomized placebo-controlled trial with a six month continuation phase. The setting was 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. 275 adolescents with major depression were originally enrolled in Study 329, with 190 completing the eight-week acute phase. Of these, 119 patients (43%) entered the six-month continuation phase (paroxetine n = 49; imipramine n = 39; placebo n = 31), in which participants were continued on their current treatment, blinded. As per the protocol, we have looked at rates of relapse (based on Hamilton Depression Scale scores) across both acute and continuation phases, and generated a safety profile for paroxetine and imipramine compared with placebo for up to six months. ANOVA testing (generalized linear model) using a model including effects of site, treatment and site x treatment interaction was applied. Otherwise we used only descriptive statistics. RESULTS: Of patients entering the continuation phase, 15 of 49 for paroxetine (31%), 12 of 39 for imipramine (31%) and 12 of 31 for placebo (39%) completed as responders. Across the study, 25 patients on paroxetine relapsed (41% of those showing an initial response), 15 on imipramine (26%), and 10 on placebo (21%). In the continuation and taper phases combined there were 211 adverse events in the paroxetine group, 147 on imipramine and 100 on placebo. The taper phase had a higher proportion of severe adverse events per week of exposure than the acute phase, with the continuation phase having the fewest events. CONCLUSIONS: The continuation phase did not offer support for longer-term efficacy of either paroxetine or imipramine. Relapse and adverse events on both active drugs open up the risks of a prescribing cascade. The previously largely unrecognised hazards of the taper phase have implications for prescribing practice and need further exploration.

Bipolar disorder and its outcomes: two cohorts, 1875–1924 and 1994–2007, compared

We compared admission rates and outcomes for bipolar disorder patients using the medical records of patients with a first hospital admission in 1875–1924 retrospectively diagnosed based on International Classification of Diseases (ICD)-10 criteria, and patients with a first admission in 1994–2007. The incidences of first admissions in the historical and contemporary periods are comparable: 1.2 and 1.3 per hundred thousand per year, respectively. Manic episodes constituted a greater proportion of admissions historically, while depressive episodes made up more in the contemporary sample. There is no evidence for a reduction in the mean inter-admission intervals with duration of illness. This study suggests that modern treatments may have decreased lengths of stay in hospital, but at a cost of contributing to more admissions. It also points to a shift in the threshold for admissions.

Sudden cardiac death & the Reverse Dodo Verdict.

Adverse effects of treatment on cardiac QT intervals were first reported 50 years ago. A clear link to sudden death was established, but the problem remained relatively unknown. The issue of treatment related effects on the heart, and the contribution this might make to sudden cardiac deaths in general, came more clearly into focus 20 years ago, linked to regulatory actions. In an era of polypharmacy, and mixing of prescribed and non-prescribed pharmacologically active agents it is now becoming increasingly clear that unanticipated cardiac effects may be common and a significant cause of mortality. There is likely underreporting and also underdiagnosis, as recognition requires a timely ECG. This paper proposes two methods to handle the problem.

Mental health admissions in paediatric populations in North Wales: two cohorts compared 1875-1924 and 1994-2008.

Objectives To investigate frequency of under-18s admitted to mental health services (MHS) in North West Wales (NWW) between 1875 and 2008. There are claims that 1 in 10 children have a mental illness, but there are little data on their inpatient MHS utilisation. Setting Looking at admissions at the secondary care level, three data samples were included; the first comprises historical asylum admissions, the second comprises contemporary admissions to acute psychiatric beds, and the third comprises admissions to district general hospital (DGH) beds that resulted in a mental health coding. Participants All were under 18. There were 65 historical patients, 41 contemporary mental illness admissions and 943 DGH admissions. Primary and secondary outcome measures The primary outcome measures were diagnoses based on case notes of the historical cohort between 1875 and 1924, as well as details of paediatric admissions to MHS from 1994 to 2008 and paediatric admissions with a mental health component to the DGH in NWW. Results The incidence of admission to a mental health bed was 1.55 per year in the historical cohort compared with 2.9 in the contemporary. The overall incidence of admission to any bed in the contemporary cohort was 129 patients per year. There has been a twofold increase in the incidence of admissions for schizophrenia and related psychosis, but this most likely stems from an earlier age of admission rather than a true increase. Conclusions There is a greater frequency of hospital admissions for youth under the age of 18 in NWW for mental health today than previously. The rates reported in the DGH sample are consistent with data from community surveys of patients meeting criteria for mental disorders and complement such data when it comes to planning for paediatric MHS. However, they also raise questions about the boundaries between disease and distress.