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International Journal of Risk & Safety in Medicine 27 (2015) 85–91 DOI 10.3233/JRS-150645IOS Press Suicidal risk from TADS study was higherthan it first appeared G¨oran H¨ogberga,b,∗, David O. Antonuccioc and David Healyda Department of Women's and Children's Health, Child and Adolescent Psychiatric Unit,Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, SwedenbStockholm Child and Adolescent Psychiatry, BUP Huddinge, Stockholm, SwedencDepartment of Psychiatry and Behavioral Sciences, University of Nevada School of Medicine,Reno, NV, USAdBangor University, Wales, UK Received 11 November 2014Accepted 6 April 2015 Abstract. Completed suicides are a major cause of death in adolescents in Sweden. Forensic analysis of completed suicides in
children and adolescents shows there is one completed suicide per 1000 children taking a selective serotonin re-uptake inhibitor
(SSRI). In order to elucidate these events we undertook a study of the results and reporting of suicidal events in the Treatment
of Adolescents with Depression Study (TADS). We conclude that a major, albeit underreported, finding in the TADS was the
significant increase of suicidal events in the adolescents on antidepressant medication in comparison to the group on placebo
medication. The proportions of suicidal events were 11% and 2.7% respectively. This increased risk of suicidal events might be
related to the high incidence of medication with an SSRI in the group of completed suicides among Swedish adolescents.
Keywords: SSRIs, suicide, adolescent depression, TADS, CBT There have been multiple meta-analyses focusing on the risk of increased suicidality in SSRI-treated adolescents. Dubicka et al. analysed 15 studies with SSRIs and young people diagnosed with depression[1]. They found that suicide attempts and self-harm occurred more frequently in the SSRI-treated groupcompared with the placebo group (fixed effects odds ratio 1.70, 95% CI, 1.13–2.54, P = 0.01). Hammadet al. included 16 pediatric SSRI studies with the diagnostic category of depression [2]. The increased riskfor those treated with SSRIs compared with those treated with placebo was 1.66 (95% CI, 1.02–2.68).
The conclusion was that "Use of antidepressant drugs in pediatric patients is associated with a modestlyincreased risk of suicidality". Bridge et al. in a meta-analysis of 27 pediatric studies with SSRIs indifferent clinical conditions found an increased risk difference of suicidal ideation/suicide attempt in all ∗Address for correspondence: G¨oran H¨ogberg, BUP Huddinge, Paradistorg 4, 117 66 Huddinge, Sweden. Tel.: +46 8 514 529 00; Fax: +46 8 514 529 05; E-mail: 0924-6479/15/$35.00 2015 – IOS Press and the authors. All rights reserved G. H¨ogberg et al. / Inconsistent reporting of TADS suicidality results trials (0.7%; 95% CI, 0.1% to 1.3%), the number needed to harm was 143, thus there were 0.7% suicidalevents with an antidepressant [3]. Finally, in a matched case-control study, Olfson et al. found a significantincreased risk with antidepressant drugs in children and adolescents regarding suicide attempts (OR, 1.52;95% CI, 1.12–2.07), and completed suicides (OR, 15.62; 95% CI, 1.65-infinity) [4].
Individual studies vary in how they measure suicidality. Suicidality is usually not reported as an outcome measure but rather as a spontaneously reported adverse event. Suicides are usually not classified basedon a systematic assessment. Studies also evaluate different types of SSRIs. All of these factors make itdifficult to compare across studies.
In this short report we aim to better understand the relationship between a prescription of an SSRI and completed suicide in children and adolescents in Sweden. In the USA and in Europe the only SSRIapproved for administration to depressed children and adolescents is fluoxetine. We chose to analyse thefindings and reporting on suicidality related to fluoxetine. Because the Treatment of Adolescents withDepression Study (TADS) systematically analysed adverse reactions for suicidal events during the trial,we chose to examine the results and the presentations of the suicidal events data from TADS.
2. Methods
We selected and closely scrutinized the publications from TADS presenting the clinical results, includ- ing aspects of safety. We studied those articles and compared the presentation of their findings regardingsuicidal events in the abstracts of the articles with the actual results.
3. Results
Although TADS did not have a separate reporting of suicidal events, these data were included among the adverse events reported by patients and parents. These events were reviewed and coded by the ColumbiaClassification Algorithm of Suicidal Assessment (C-CASA). The C-CASA is a retrospective Columbiasuicide severity rating scale (C-SSRS). The coding was done independently by the Columbia UniversitySuicidality Classification group [5]. The concept "suicidal event" consisted of ".discrete episodes ofsuicidal ideation, suicidal attempts, or preparatory acts toward an imminent attempt" [6]. Self-injury without suicidal intent was not registered as a suicidal event.
In TADS, 439 depressed youths were randomly assigned to four treatment arms. These were placebo (PBO, n = 112), fluoxetine only (FLX, n = 109), cognitive behaviour therapy only (CBT, n = 111), or acombination of cognitive behaviour therapy and fluoxetine (COMB, n = 107). These four groups under-went a randomized controlled trial (RCT) over 12 weeks, with an open continuation follow-up untilweek 36 of the study. During the follow-up, several former PBO subjects switched to active treat-ment with FLX or COMB [7]. The suicidal events during the study were depicted as in Fig. 1 fromVitiello et al. [6].
In Fig. 1, based on the original figure from Vitiello et al., the total number of suicidal events in FLX and COMB are shown as black symbols [6] while empty symbols are suicidal events without fluoxetinein the PBO and CBT groups. There were 44 subjects with at least one suicidal event during the 36study weeks, and of these, 55% were hospitalized. Based on the data depicted in Vitiello et al., theseresearchers concluded that the percentage of suicidal events was 14.7% (n = 16) with fluoxetine only and10.7% (n = 12) with placebo, a non-significant difference. However, it is of note that of those 12 placebocases, 9 subjects were in fact taking fluoxetine medication, i.e., there were only three subjects taking G. H¨ogberg et al. / Inconsistent reporting of TADS suicidality results Fig. 1. Circles represent suicidal ideation and squares represent suicide attempts. Black filled symbols are subjects on fluoxetineand open symbols are subjects on placebo or cognitive behavioural therapy.
The 12 week comparison among PBO, FLX, CBT and COMB concerning suicidal events Significance Fisher's exact test 2-tailed placebo who had a suicidal event. In a table footnote, the authors reported a significantly higher levelof suicidal events on FLX when compared with the CBT only and PBO patients who were not actuallytaking medication. They also found that there was a significant relationship between high pre-treatmentscores on the self-administered depression questionnaire (the Reynolds Adolescent Depression Scale)and the emergence of suicidal events. Another important finding was that the suicidal events were notnecessarily preceded by clinical deterioration or behavioural activation. Regarding homicidal ideation,two subjects treated with fluoxetine had an episode of increased homicidality [8].
However, alerted by this table footnote [6], we changed the classification of the two subjects on SSRI in the placebo group as they could not be reasonably classified as placebo at the time of the suicidal event(Fig. 2). The numbers and percentages of suicidal events associated with each treatment during the 12weeks are shown in Table 1. The significance of the differences in proportion of youths with suicidalevents between the placebo group and the other groups was calculated with Fisher's exact test, two-tailed,and the significance threshold was set at 0.05.
G. H¨ogberg et al. / Inconsistent reporting of TADS suicidality results Reporting of suicidality in the TADS abstracts Reporting on suicidality in the abstracts for the different treatment arms "Clinically significant suicidal thinking, which This does not report the significantly therapy, and their combination was present in 29% of the sample at baseline, higher rate of suicidal events in for adolescents with improved significantly in all 4 treatments the fluoxetine group compared depression, 2004 [9] Treatment for adolescent with " Statistically, only FLX had more suicide-related This was a correct reporting depression study (TADS): events than PBO". "In this study, psychiatric although it did not mention that safety results, 2006 [8] AEs and suicide-related events are more the difference regarding suicidal common in FLX-treated patients" events was statistically significant The treatment for adolescents "Despite the fact that suicidality improved There was an omission of the fact with depression study (TADS): markedly across all of the treatment conditions, that there was a significantly methods and message at 12 suicidal events were twice as common in higher rate of suicidal events in patients treated with FLX alone than with the fluoxetine group compared to COMB or CBT alone, perhaps indicating that the placebo group CBT protects against suicidal events" The treatment for adolescents "Suicidal events were more common in patients There was an omission of the with depression study (TADS) receiving fluoxetine therapy (14.7%) than placebo group and the long-term effectiveness and combination therapy (8.4%) or CBT (6.3%)" significantly higher rate of suicidal safety outcomes, 2007 [11] events in the fluoxetine group Assessment of safety and "There were no differences between groups in This statement was not in long-term outcomes of initial rates of suicidal events, study retention, or accordance with the results treatments with placebo in symptom worsening" showing 17 suicidal events in the group taking fluoxetine between12 and 36 weeks and none in theCBT or placebo group Suicidal events in the treatment "Forty-four patients (10.0%) had at least one There was no comment on the for adolescents with depression suicidal event (no suicide occurred)" difference between treatment study, 2009 (TADS) [6] AUTHOR COPY arms.Thefollowingnoteabout suicidal events with fluoxetine intable 1 was not mentioned in theabstract: "Higher than in CBT(p = 0.04) or PBO (p = 0.02), whenconsidering only the CBT andPBO patients who were not onmedication at time of the event" Relative cost-effectiveness of " . . the cost of services received outside The authors did not mention that this treatments for adolescent Treatment of Adolesents with Depression Study increased cost was from depression: 36-week results in fluoxetine-treated patients (mean $ 5,382, psychiatric hospital use related to from the TADS randomized median $ 2,341) were significantly higher than those participants treated withcognitive-behavioral therapy(mean $3,102,median $1,373) . . " G. H¨ogberg et al. / Inconsistent reporting of TADS suicidality results Fig. 2. Circles represent suicidal ideation and squares represent suicide attempts. Black filled symbols are subjects on fluoxetineand open symbols are subjects on placebo.
The analysis of the data showed that there was a statistically significant difference in proportion of youths with suicidal events between the PBO condition (2.7%) and the FLX treatment (11%) during the12 weeks of treatment. After 12 weeks of the randomized controlled trial, several PBO participants startedtreatment with FLX or COMB for the last 24 weeks of the study. Over these 24 weeks there were 17suicidal events, all of them in subjects taking SSRI (Fig. 1). What we also did note was that the suicidalevents in the study were evenly distributed over the entire time period; thus highlighting that the risk forsuicidal events in SSRI-treated adolescents appears to be increased up to eight months after the start ofmedication.
None of the seven abstracts from TADS publications mentioned the fact that there were four times more suicidal events with fluox etine than with placebo during the randomized controlled trial, and that this difference was statistically significant (Table 2).
The findings of SSRI-related increased suicidality in TADS underlines the need for specific monitoring of suicidality in studies on depressed adolescents. The Columbia Suicide Severity Rating Scale, whichmeasures both suicidal ideation and suicide attempts, is a promising tool for such standardised observation[5]. Antidepressant induced violent behaviour is serious enough to also warrant standardised assessment.
We suggest that a similar scale should be developed for homicidality, measuring both homicidal ideationand homicidal acts.
A hypothetical mechanism for the increased suicidality in adolescents taking SSRIs could be a disrup- tion of affect regulation with ensuing lack of constraints on suicidal impulses. Negative affective statesin adolescents treated with an SSRI have for instance been described as "amotivational syndrome" byGarland and Baerg and as "selective serotonin reuptake inhibitor-induced apathy" by Reinblatt and Riddle[13, 14]. A similar effect of anhedonia with SSRI-treatment has been described by Price, Victoria, and G. H¨ogberg et al. / Inconsistent reporting of TADS suicidality results Goodwin [15]. Another study on 1829 adult subjects receiving SSRI-treatment found that 60% reportedemotional numbness as a side-effect [16 ]. This "care less syndrome" might diminish the empathy withothers that functions as a hindrance to acting on suicidal impulses. It might also create a state of emptinessand lifelessness that can become unbearable to the young person. Finally a potential mechanism for anSSRI induced suicidal event could be the reported risk of pathological intoxication, amnesia and loss ofimpulse-control, with moderate doses of alcohol combined with an SSRI [17].
TADS neglected to report in the abstracts the finding of a significantly higher rate of suicidal events with fluoxetine compared with placebo. The omission of an important negative clinical outcome from anystudy is not in the interest of patients or clinicians who are trying to practice evidence based medicine.
We suggest for future publications that reviewers and publishers examine more closely the congruencebetween findings and abstracts.
The findings of completed suicides on SSRI-medication in Swedish adolescents may be relevant to the reported increased risk with SSRI in adolescents. In the reported forensic examination of completedsuicides (2006–2010) by adolescents in Sweden a selective serotonin reuptake inhibitor (SSRI) was foundin the blood of adolescent patients from 42 suicides, 14% of completed suicides [18]. During the sameperiod 40,437 children age 10–19 were prescribed a SSRI [19]. From these figures one can calculate arate of 0.1 per cent (1/1000) completed suicides in children and adolescents prescribed a SSRI as notedby the Swedish National Board of Health and Welfare. The suicide rate in Sweden in this age group isabout 4/100,000 persons. The relative risk of completed suicide in a clinical sample with an SSRI in thisage group is thus about 25.
In summary, the data from Sweden showed that there was a high proportion of SSRI medication in completed suicides among patients in treatment. TADS showed there was a significant increase in suicidalevents with fluoxetine, that the risk remained high during the entire treatment period, that the increasedsuicidality was associated with higher intake scores in self-evaluated depression, and that there wereno identified clinical signs indicating the risk for a suicidal event. This increased risk of suicidal eventswith SSRI in TADS may help us understand the observed completed SSRI-related suicides in Swedishadolescents. These data from TADS are important for regulatory agencies on drug safety. It is imperativethat the vigilance system for adverse drug effects considers and registers suicidal events with SSRIs aspossible adverse side effects. Also it is crucially important that depressed youth taking SSRIs be closelymonitored throughout the duration AUTHOR COPY of treatment.
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Aerobic kinetoplastid flagellate Phytomonas does not require heme for viabilityLud ˇek Ko ˇrenýa,b, Roman Sobotkab,c, Julie Ková ˇrováa,b, Anna Gnipováa,d, Pavel Flegontova,b, Anton Horváthd,Miroslav Oborníka,b,c, Francisco J. Ayalae,1, and Julius Luke ˇsa,b,1 aBiology Centre, Institute of Parasitology, Czech Academy of Sciences and bFaculty of Science, University of South Bohemia, 370 05 Ceské Budejovice, CzechRepublic; cInstitute of Microbiology, Czech Academy of Sciences, 379 81 Trebo