The TADS was the first study to compare efficacy and safety of FLX, CBT, their combination, and placebo in the treatment of pediatric depression. The study is also among a relatively small number of trials that used systematic assessment of AEs, as well as the general inquiry used in most clinical trials. Over 80% of the adolescents completed 12 weeks of treatment in their assigned treatment arm, indicating the TADS treatments were generally acceptable and tolerable.
Depressed adolescents had high rates of physical symptoms at baseline by systematic assessment, and as depression improved, physical symptoms also improved. Careful assessment of physical symptoms before initiating treatment is important to establish a baseline and identify change with treatment.
Systematic review of symptoms and spontaneous AE reporting produced quite different results, with systematic review eliciting substantially more positive symptoms. This is consistent with findings by Greenhill et al. (2004)
. Unlike many clinical trials, the definition of an AE in TADS included the requirement that the event be “clinically significant” (i.e., characterized by either interference in functioning or need to seek medical attention). It is unclear whether this change in definition affected the results between treatment conditions, but it is possible because there were fewer AE reports overall in this trial than in other clinical trials.
The difference in systematic versus spontaneous symptom reporting was most evident in the CBT group, where only nine spontaneous AEs were reported in the 111 patients randomized to that treatment group. Through systematic review, however, the CBT group had higher total adverse symptom scores at weeks 6 and 12 than the other three groups, suggesting under-reporting of AEs by CBT therapists. Hence, to compare AEs across treatment groups, future trials comparing different treatment modalities would profit from including a structured systematic assessment of AEs.
Few patients showed a worsening of psychiatric symptoms during the trial based on spontaneous report. Specifically, 22 showed a worsening of depression symptoms, with only three on FLX and two on COMB showing a worsening of depression. However, more patients on FLX reported psychiatric symptoms overall than those in COMB, PBO, or CBT. The numbers were too small, however, to detect statistical differences. Only one teen developed mania during the course of the study (in FLX), and the development of hypomania was also rare (one COMB, two FLX, one PBO). Interestingly, COMB did not have significantly more psychiatric AEs or more mania than PBO. It remains unclear how or why patients receiving FLX in combination with CBT had fewer psychiatric AEs than those receiving FLX alone. Is it CBT that provides protection or is it a dosing issue? The mean dose for the combination group was lower than in FLX alone, but it is unclear whether this led to a difference in physical or psychiatric event reporting.
Despite excluding patients in imminent danger of attempting suicide, rates of suicidal ideation were quite high at baseline (29.2%). Suicidal ideation improved over time, and only 9.6% had suicidal ideation at the end of 12 weeks. The COMB group had higher baseline severity scores, so the overall improvement in suicidal ideation was greater for COMB than the other three groups.
During the study, there were 24 reports of suicidal behavior (attempt, preparatory actions, self-injurious behavior with intent unknown, or suicidal ideation). Only five suicide attempts were reported during the acute trial in patients remaining in their assigned treatment arm (two COMB, two FLX, one CBT). Unlike the two previous placebo-controlled trials of FLX (Emslie et al., 1997
), there were significantly more suicide-related events reported in patients taking FLX than those on PBO. The majority of the suicide-related events in the trial consisted of suicidal ideation (n
= 18). Patients who had suicide-related events had a high number of risk factors, including moderate depression at the time of the event, psychosocial stressors before the event, high levels of suicidal ideation at baseline, and so forth. In spite of the common belief that suicide-related events occur shortly after initiating antidepressant treatment, in this study most events occurred over 1 month after initiating treatment, and this was consistent across all four groups.
It is often difficult to disentangle the factors that precipitate either suicidal ideation or suicide attempts. Is it a failure to treat the depression? Is it increased activation or agitation? Does the medication induce suicidal behavior? If it is simply a result of receiving medication, both FLX with and without CBT would be expected to have similar rates of suicide-related events; however, in this study, FLX monotherapy had more events than COMB, yet COMB had no more suicide-related events than CBT without medication. It is possible that CBT provides skills (e.g., coping skills, family conflict management) that can be used to reduce suicide-related events. It is also possible that the increased medication dose in the FLX-alone group influenced suicidal behavior. Finally, it may be that the reduced rate of suicide-related events in the combination group was related to the greater overall benefit and improvement of depression in that group. Other factors that may affect suicidal behavior are stressors and behavioral activation. TADS did not have adequate measures of these factors, so it is unclear what impact these factors may have had.
As noted in the Introduction to this special section by March et al., one important limitation to the TADS was that patients and clinicians in the COMB and CBT groups were not blind to treatment assignment, whereas the FLX and PBO arms were double blind. It is possible that spontaneous AE reporting was affected by this study design. Furthermore, subjects in COMB treatment had more frequent sessions, as these patients received full CBT sessions plus full psychotherapy sessions. Increased frequency of visits may have improved the safety outcomes for this treatment arm.
Another limitation is that CBT therapists have not historically assessed AEs per se, which was evident in this trial with so few reports of AEs in that group. It is likely that raters of different disciplines (e.g., medicine versus psychology), the amount of contact a rater has with subjects and the raters' awareness of treatment conditions may affect his or her assessment of safety. For example, discussion among CBT therapists revealed that general inquiry was at times either skipped or minimized in order to maximize the time available for topics and goals directly relevant to the CBT intervention. If CBT or other psychotherapy is evaluated as a comparator to medication in future research, it is essential that systematic assessment of these events be conducted. As seen with the self-report assessment on TADS, rates of physical symptoms were substantially more frequent than spontaneous AE reports, which is consistent with a recent study by Greenhill et al. (2004)
. Furthermore, systematic assessment should be done at each visit. In this study, one of the limitations was that the systematic assessment of physical symptoms was only done at weeks 6 and 12 of treatment. A subject who experienced one of these symptoms during the interim period may not have reported the event at the time the information was collected at the assessment visit.
Another limitation of the TADS trial was that other than mania, there was no systematic assessment of psychiatric symptoms, such as aggression, agitation, akathisia, and disinhibition, which are potentially associated with FLX. Because TADS provides only spontaneous reports of these events, which were rare and not associated with suicidality, a definitive answer to the question of whether an association between psychiatric symptoms and suicide-related events exists is not possible.
The TADS trial did provide a systematic measure of mania symptoms through weekly monitoring visits. However, the method used (ADS mania subscale) is not a standardized scale. Furthermore, it was noted by clinicians (both pharmacotherapists and CBT therapists) that scoring of the items was inconsistent, varying from clinician to clinician. Further complicating interpretations of data collected with this scale is that some of the endorsed items may have been the result of disorders other than mania/hypomania. For example, inattention, which was one of the most common positive items on the subscale, may have been caused by depression or ADHD, and it is not clear that clinicians discriminated in scoring based on cause of the symptom. Thus, if the symptom was problematic for the patient, it was likely to be coded as positive on the mania subscale, despite the fact that there may have been no other symptoms of mania or activation for that patient. This is likely to have resulted in selected items on this scale being evaluated as positive even in adolescents without mania or hypomania. As such, the results from the ADS mania subscale should be interpreted with caution. Still, TADS is the first depression trial to provide any systematic assessment of mania-related symptoms. Future studies will benefit from incorporating systematic measure of these symptoms both at baseline and throughout treatment.
Although this is the first study to report substantial detail regarding suicide-related events occurring within the treatment trial, several unanswered questions remain. First, although adolescents completed a self-report about suicidal ideation at baseline, specific details about past suicidal behavior were not collected. For future studies, detailed prospective assessment of suicidal behavior is needed to better evaluate treatment-emergent suicidality. In this study, there were no significant differences between the four treatment groups on emergence or worsening of suicidal ideation or behaviors based on self- and clinician-report. However, these systematic assessments were only conducted at weeks 6 and 12, and only provide a snapshot of the suicidality at the time of those assessments. Another limitation related to suicidality assessment involved the recording of the actual suicide events. Suicidal behaviors were identified and recorded based on site discretion, which has been reported as one of the limitations of the safety outcomes in most clinical trials. To address this problem, all potentially suicide-related events were reevaluated by a national expert panel; thus, events were not simply interpreted by the site. However, the description of events provided to national expert panel were those submitted regarding the event in question, and the level of available information on these events varied greatly. Therefore, in some instances, limited information was available to the group to determine the classification. Future studies may want to conduct more intensive and standardized assessment of suicide-related AEs in order to complete a more comprehensive assessment.
Finally, suicidal events are a very low base-rate phenomena, which require extremely large samples for study. The number of suicide-related events in the present study was small, although they were more frequent than in two prior trials of FLX trials. Several possible explanations for the increase in this study exist. First, it is possible that the increased incidence was by chance. Second, it is possible that it is related to dosing (the prior two FLX trials were 20-mg fixed-dose studies). Third, this study included only adolescents, whereas the prior two trials included children as well. Adolescents have a higher base rate of suicidal behavior than children, which could also account for the increase.
Finally, the increased rate of suicidal behavior in this trial may be a result of the longer trial length (12 weeks versus 8–9 weeks). As mentioned, more systematic assessment of the possibly related behavioral activation symptoms mentioned by the FDA in the black box warning will help disentangle these unknowns. This study was simply too small too answer these questions.
Although research in the treatment of pediatric depression has expanded significantly over the past decade, TADS is the first study to directly compare pharmacological and psychosocial treatment modalities. As more trials are being published on this population, the tendency may be for clinicians to focus primarily (or exclusively) on the efficacy results; yet the safety results are equally important, if not more so.
Clinicians treating depressed youths should note that these patients report relatively high incidences of physical symptoms, as has been described in several reports (Lewinsohn et al., 1996
; Rhee, 2003
; Williams et al., 2002
; Yates et al., 2004
). It is possible that depressed adolescents visiting their pediatrician or primary care physician may present with physical complaints rather than specific mood symptoms. It is also important to note that physical symptoms decreased as depression improved.
Given the recent FDA warning, it is important to routinely assess psychiatric symptoms, such as hostility, agitation, and mania. Based on the present study, psychiatric AEs causing moderate to severe impairment are rare, but do occur. It is possible that psychiatric AEs are dose related or that concurrent psychotherapy offers some protection against such changes, but this area needs further study.
Finally, despite the fact that all of the treatment arms were effective in reducing suicidal ideation, individual teens in clinical trials such as TADS will express suicidal ideation and make suicide attempts in the context of preexisting suicidal ideation, worsening of depression, stressful life events, and perhaps also in the context of improving depressive symptoms. Clearly, suicidal thinking and behavior need to be assessed carefully, both before and prospectively during treatment. Clear understanding and identification of any event are also necessary. That is, clinicians need to collect adequate information about the event to determine whether it was suicidal ideation, self-injurious behavior without intent to die, or an actual suicide attempt (suicidal ideation with intent to die). Based on guidelines from the FDA, patients beginning medication treatment should be observed closely for clinical worsening, suicidality, or unusual changes in behavior (face-to-face with the clinician weekly for 4 weeks of treatment, then every other week for 1 month, and again at 12 weeks). In addition, parents and teens should be given adequate information about risks associated with antidepressants and the importance of parental monitoring of the youths. Furthermore, in this study, suicide-related events often occurred more than 1 month after treatment began, so continued monitoring of suicidal ideation and behavior throughout the course of treatment is important. In summary, this article, combined with the TADS primary efficacy paper (TADS, 2004
), provides important information for clinicians to better help their patients and families make informed assessment of the risk-benefit ratio when treating adolescent depression.