Psychiatry Research Review TM Making Education Easy Issue 39 – 2015 Welcome to issue 39 of Psychiatry Research Review. In this issue: An association exists between selective serotonin reuptake inhibitors (SSRIs) and violent crime, report researchers from the University of Oxford. In particular, subgroup analysis highlighted that this association was evident in people aged Reanalysis of Study 329: 15–24 years, but not significant for those aged ≥25 years. As the study authors note, the data do not prove causation, paroxetine efficacy disputed since possible confounding by one or more unidentified factors linked to both SSRI use and violent crime may explain the results. Nevertheless, the data have good credibility: this was a large study from Sweden, involving about 850,000 An association between individuals (10.8% of the Swedish population) who were prescribed SSRIs over the 3-year study period; 1% of these SSRIs and violent crime individuals were convicted of a violent crime. In another study, a research group from Wellington, New Zealand, linked national breast and colorectal cancer registrations (2006–2010) in order to explore cancer survival in the context of mental illness. Their data attest to poorer CBT improves insomnia survival after diagnosis with breast or colorectal cancer among men and women with a history of recent psychiatric associated with comorbid service use compared with those without such a history. The researchers call for further investigation of the cancer mental illness treatment journey amongst those with experience of mental illness, to help explain this survival difference. We hope you find this issue useful for your daily practice and we welcome any comments or feedback. Are childhood and adult Kind regards, ADHD the same disorder? Associate Professor Wayne Miles Associate Professor David Menkes [email protected] [email protected] Worse cancer survival in NZ psychiatric service users Restoring Study 329: efficacy and harms of paroxetine and Smoking and risk of imipramine in treatment of major depression in adolescence schizophrenia Authors: Le Noury J et al. Summary: This reanalysis of data from SmithKline Beecham’s Study 329 (Keller MB et al. J Am Acad Child Adolesc Use of the Maze Psychiatry. 2001;40(7):762-72) reviewed original trial documents from this trial that was conducted between 20 April Navigation Test in older 1994 and 15 February 1998 involving 275 adolescents (aged 12–18 years) with unipolar major depression who New Zealanders were randomised to 8 weeks of double-blind twice-daily treatment with paroxetine (20–40mg; n=93), imipramine (200–300 mg; n=95), or placebo (n=87). The reanalysis was performed according to the restoring invisible and abandoned trials (RIAT) initiative (see Doshi P et al. BMJ. 2013;346:f2865). The prespecified primary efficacy variables Positive Emotions Program were change from baseline to the end of the 8-week acute treatment phase in total Hamilton depression scale for Schizophrenia (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at 8 weeks. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical How can detection of global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapsed during the maintenance phase. Neither paroxetine nor imipramine first-episode psychosis was statistically or clinically significantly different from placebo for any of the prespecified efficacy outcomes. HAM-D be improved? scores decreased by 10.7, 9.0 and 9.1 points (least squares mean), respectively, for the paroxetine, imipramine and placebo groups (p=0.20). Both drugs were associated with clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the Anticholinergics imipramine group. compromise QoL in dementia Comment (DM): This reanalysis and republication of Study 329 marks a milestone in efforts to disentangle psychiatric research from distortion by vested interests. For years, the original 2001 publication had been challenged repeatedly by psychiatrists and others concerned with the famous study’s shortcomings, in particular the disconnect between the numerical results and the conclusions. As documented in a website dedicated to the Abbreviations used in this issue issue (http://study329.org/), these concerted efforts were essentially ignored by the study’s authors, their home ADHD = attention-deficit/hyperactivity disorder institutions, the sponsor, and the high-impact journal in which the original study appeared. Remarkably, even with CBT = cognitive behavioural therapy the damning reanalysis and republication in the BMJ, the original study has not been retracted or corrected, and FEP = first-episode psychotic illness continues to be cited as evidence that paroxetine is “safe and effective” in adolescent depression. There are several HAM-D = Hamilton depression scale ‘take-home’ lessons from this remarkable saga. One is that journal editors and reviewers, and indeed readers, HRQoL = health-related quality of life need to redouble their vigilance regarding potential conflicts of interest in submitted manuscripts, as these can SSRI = selective serotonin reuptake inhibitor quite clearly affect analysis and interpretation of results. Another conclusion is that public access to primary data from clinical trials should be mandatory, irrespective of whether or not the given study is published. I encourage Research Review readers to support efforts, spearheaded by the Cochrane Collaboration, to ensure this becomes RESEARCH REVIEW NZ standard practice (see, for example, www.alltrials.net); NZ psychiatrists should be gratified that the RANZCP has, IS ON TWITTER somewhat belatedly, joined the list of supporters. FOLLOW US @ResearchRev_NZ Reference: BMJ. 2015;351:h4320 OR https://twitter.com/ResearchRev_NZ Abstract www.researchreview.co.nz a RESEARCH REVIEW publication ™ 1 Psychiatry Research Review Selective serotonin reuptake inhibitors and violent crime: Cognitive behavioral therapy a cohort study for insomnia comorbid with Authors: Molero Y et al. psychiatric and medical Summary: These researchers compared the rate of violent crime while individuals were prescribed conditions: a meta-analysis serotonin reuptake inhibitors (SSRIs) with the rate of violent crime in the same individuals while not Authors: Wu JQ et al. receiving medication, using matched data from the Swedish Prescribed Drug Register and the Swedish national crime register. A total of 856,493 individuals aged ≥15 years residing in Sweden who were Summary: This meta-analysis included 37 prescribed SSRIs in 2006 were followed-up to 31 December 2009. An overall association was found randomised controlled trials that had at least one between SSRIs and violent crime convictions (hazard ratio [HR] 1.19; 95% CI, 1.08 to 1.32; p<0.001; cognitive behavioural therapy (CBT) arm for insomnia absolute risk = 1.0%). Age-stratified analysis revealed a significant association between SSRIs and violent and enrolled an adult population meeting diagnostic crime convictions for individuals aged 15–24 years (HR 1.43; 95% CI, 1.19 to 1.73; p<0.001, absolute criteria for insomnia as well as a concomitant condition risk = 3.0%), but not for those aged 25–34 years (HR 1.20; 95% CI, 0.95 to 1.52; p=0.125, absolute risk (n=2,189). At post-treatment evaluation, a significantly = 1.6%), 35–44 years (HR 1.06; 95% CI, 0.83 to 1.35; p=0.666, absolute risk = 1.2%), or ≥45 years larger proportion of patients who received CBT for (HR 1.07; 95% CI, 0.84 to 1.35; p=0.594, absolute risk = 0.3%). Increased risks were also found in those insomnia were in remission compared with those in the aged 15–24 years for violent crime arrests with preliminary investigations, non-violent crime convictions, control or comparison conditions (36.0% vs 16.9%; non-violent crime arrests, non-fatal accidental injuries, and emergency inpatient or outpatient treatment pooled odds ratio [OR] 3.28; 95% CI, 2.30 to 4.68; for alcohol intoxication or misuse. p<0.001). Pretreatment and post-treatment controlled effect sizes were medium to large for most sleep Comment (DM): For many years there has been concern that antidepressants may be associated parameters (self-reported sleep efficiency: Hedges with disinhibited and sometimes violent behaviour. For example, our study a decade ago in the same g = 0.91, 95% CI, 0.74 to 1.08; sleep onset latency: journal (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564177/) highlighted this possibility based on Hedges g = 0.80, 95% CI, 0.60 to 1.00; wake after a case series, together with suggestive data regarding “hostility” in paroxetine drug trials. The current sleep onset: Hedges g = 0.68; subjective sleep quality: study is far more powerful, based on its use of Swedish national registers of prescriptions, forensic and Hedges g = 0.84; all p<0.001), except total sleep hospital outcomes. The results are striking and indicate significant risk, particularly in younger patients. time. Comorbid outcomes yielded a small effect size Of particular interest is the association with alcohol intoxication and misuse in the same demographic. (Hedges g = 0.39, 95% CI, 0.60 to 0.98; p<0.001); These results are consistent with our recent report (http://www.ncbi.nlm.nih.gov/pubmed/25214162) improvements were greater in psychiatric than in of a significant interaction between antidepressants, particularly SSRIs, and alcohol. Implications for medical populations (Hedges g = 0.20, 95% CI, 0.09 to clinical practice are substantial; even though the absolute risk appears modest, of the order of 1–3%, 0.30; χ2 test for interaction = 12.30; p<0.001). the prevalence of antidepressant prescription in New Zealand (similar to many Western countries, including Sweden), coupled with uncommon but serious and sometimes catastrophic outcomes, means Comment (DM): Most psychiatrists and other that these risks need to be considered by both prescribers, patients, and their families.