Serious adverse events (SAEs) or adverse events that lead to discontinuation of treatment make up only a small percentage of the total number of adverse events in both placebo and active treatment groups in the clinical trials. It is important to keep in mind that reports of adverse events leading to discontinuation and SAEs may or may not overlap. In other words, a subject who has an SAE may or may not discontinue from the study. The alternative is also true: subjects who discontinue due to an adverse event may not be a SAE. Similarly, suicidal events may or may not be classified as SAEs or reasons for discontinuation. For example, a subject who has suicidal ideation may be maintained in the study, so that event would not count as a discontinuation, and if it is not life threatening or does not lead to hospitalization, it is not an SAE. On the other hand, a serious attempt that requires hospitalization and removal from the study would count as both an SAE and a reason for discontinuation. In all of these cases, the determination of how to categorize an event is made at the site level by the investigators. Thus, the following sections provide details of the studies related to those categories (adverse events, adverse events leading to discontinuation, serious adverse events, and suicidality), and subjects may be listed in one or more areas. Finally, with the recent FDA warning, details regarding behavioral activation, hostility and switch to mania are addressed in a separate section.
Adverse events. Adverse events are common in antidepressant trials with children and adolescents. Methods for eliciting adverse events, however, vary widely across trials, as there are currently no systematic methods to ascertain adverse events. In most studies, adverse events are collected from spontaneous reports from patients and families. Only the multi-site fluoxetine trial used an additional method to obtain adverse events (standardized Side Effects Checklist; Emslie et al., 2002a). Furthermore, the spontaneous events collected may or may not be related to the medication, and this determination is generally made by the investigator.
The most common adverse effects are generally physical rather than the more controversial and serious adverse events such as hostility, mania or suicide-related events. In addition, although adverse events are common in pediatric trials, adverse events are seen frequently in subjects on both active medication and placebo. Few side effects occur statistically more frequently in the active treatment groups. The most common physical adverse events seen with SSRIs and SNRIs in children and adolescents are similar to those reported in adults in the Physicians’ Desk Reference (2004), but may occur slightly less frequently than in adults.
In addition to physical adverse event, some patients may experience behavioral symptoms, such as aggression, hostility, mania, behavioral activation, motor restlessness, etc. Although not as common as physical symptoms, these adverse events are serious problems when they occur. Patients receiving antidepressant treatment should be monitored for such symptoms, and health care providers should adjust treatment interventions as needed. In the antidepressant trials reviewed, most did not list spontaneously reported adverse events (physical or behavioral) unless they met a certain level of difference (e.g., ≥5% and at greater incidence than placebo). However, if the events led to discontinuation or were considered a serious adverse event, they were specifically listed in most cases. These will be reviewed in the Discontinuation and SAE sections of this review.
Adverse events leading to discontinuation. One measure of general safety is the rate of discontinuation due to adverse events. In all of the placebo-controlled trials of SSRIs and in some of the SNRIs, rates of discontinuation due to adverse events were reported. Table 6 shows the rates of discontinuation due to adverse events in each of the placebo-controlled trials for both SSRIs and SNRIs. The rates of discontinuation are consistent across all studies ranging from 2 to 12%. In general, the rates of discontinuation were higher in the active medication groups versus the placebo groups with all medications, although the differences, where reported, were not statistically significant.
Table 6. Rates of discontinuation due to adverse events and rates of SAEs
| ||Discontinuation due to AE||SAEs|
|Drug (n)||Placebo (n)||p-value||Drug (n)||Placebo (n)||Source|
| Fluoxetine 1997||10.4% (5)||4.2% (2)||NR||2%(1)||2% (1)||Emslie et al., 1997|
| Fluoxetine 2002||4.6% (5)||8.2% (9)||.408||1% (1)||4% (4)||Emslie et al., 2002a|
| Fluoxetine 2004||UNK||UNK||UNK||UNK||UNK||March et al., 2004|
| Paroxetine 2001||9.7% (9)||6.9% (6)||NR||12% (11)||2% (2)||Keller et al., 2001|
| Sertraline 2003||9% (17)||2% (4)||NR||4% (7)||3% (6)||Wagner et al., 2003|
| Citalopram 2004||5.9% (5)||5.6% (5)||NS||0% (0)||NR||Wagner et al., 2004|
| Paroxetine (Study#701)||8.9% (9)||2% (2)||NR||5.9% (6)||1% (1)||Emslie et al., 2004b|
| Paroxetine (Study#377)||11.8% (22)||7% (7)||NR||11.8% (22)||6.5% (6)||GSK website|
| Nefazodone||3% (3)||3% (3)||NR||None||NR||Emslie et al., 2002b|
| Venlafaxine (combined)||10% (18)||3% (5)||NR||8% (14)||3% (5)||Emslie et al., 2004a|
| Citalopram||10.7% (13)||8% (9)||UNK||UNK||UNK||MHRA Report (Dec. 2003)|
| Nefazodone||UNK||UNK||UNK||UNK||UNK||Emslie et al., 2002b|
| Mirtazapine||5.3% (9?)||3.4% (3?)||UNK||1.2% (2)||1.1%(1)||Organon data on File|
In the single site fluoxetine trial (Emslie et al., 1997), 2 subjects (4%) on placebo and 5 on fluoxetine (10%) discontinued the study due to adverse events. One subject on placebo developed mania and one had a suicide-related event. Three of the fluoxetine subjects developed manic symptoms, one developed a rash, and one had a suicide-related event. In the multi-site fluoxetine trial (Emslie et al., 2002a), rates of discontinuation were not statistically different between the active treatment group (4.6%) and the placebo group (8.2%), but were slightly higher in the placebo group. In the fluoxetine group, 1 each discontinued for rash, agitation, constipation, hyperkinesias and manic reaction (n = 5). In the placebo group, 1 each discontinued for rash, abdominal pain, alopecia, anxiety, dizziness, headache, kidney infection, aggressive behavior, and self-mutilatory behavior (n = 9). Three of the placebo subjects who discontinued treatment were also considered SAEs because the event required hospitalization (kidney infection, aggressive behavior, and self-mutilatory behavior). Data are unavailable for the rates of discontinuation due to adverse events for the TADS study.
In the published paroxetine study, discontinuation due to adverse events occurred in 9.7% (n = 9) for paroxetine and 6.9% (6) for placebo (Keller et al., 2001).
The GSK website (http://www.gsk.com/media/paroxetine.htm) also provides details about adverse events for the 2 unpublished trials. In the international adolescent only trial (#377), discontinuation due to adverse events occurred in 11.8% (22/187) of subjects in the paroxetine group and 7% (7/99) of subjects on placebo. These rates are not statistically significant.
In the child and adolescent trial (#701), 9 subjects (8.9%) in the paroxetine group and 2 subjects (2%) in the placebo group discontinued due to adverse events. Four paroxetine subjects had worsened depression and 1 had a suicide attempt (‘emotional lability’). In addition, 1 discontinued due to agitation and irritability (‘nervousness’), 1 for hostility, and 2 for medical problems. In contrast, 2 subjects on placebo were discontinued: 1 for suicidality (‘emotional lability’) and 1 for mood swings (‘emotional lability’), insomnia, and restlessness (‘nervousness’). No statistically significant differences in discontinuation due to adverse events were found between the two groups.
Nine percent (17/189) of subjects in the sertraline group discontinued from the study due to adverse effects; 2% (4/187) of those on placebo discontinued due to adverse events (MHRA website). The majority (13/17) of subjects who discontinued from the sertraline arm due to adverse effects were children (Wagner et al., 2003). The commonest reason for discontinuation was psychiatric adverse events. These were suicidal thoughts (3 sertraline), suicide attempt (2 sertraline, 2 placebo), aggressive behavior (1 sertraline), agitation (3 sertraline), and hyperkinesias (2 sertraline) (Wagner et al., 2003; MHRA website).
In the published trial of citalopram, the rate of discontinuation due to adverse events was similar for citalopram and placebo (5.6% vs. 5.9%). Discontinuation due to agitation was reported in 2 subjects and discontinuation due to worsening depression was reported in 2 subjects. All 4 of these subjects were on citalopram (Wagner et al., 2004). In the unpublished trial reported in the MHRA report, there were 13/121 (10.7%) discontinuations in the treatment group and 9/112 (8.0%) in the placebo group. Five of the discontinuations in the treatment group were due to suicide-related events compared to 2 in the placebo group. As mentioned previously, this study included both inpatients and outpatients, so it is possible that the baseline severity of this population was greater. Until more data are available on the study design and other outcomes, it is difficult to interpret these results.
In the combined trials of venlafaxine, 18 (10%) on venlafaxine and 5 (3%) on placebo discontinued due to adverse events. Reasons for discontinuation from venlafaxine were physical symptoms (n = 8), psychiatric symptoms (n = 5: 2 hostility/aggression, 2 mania, 1 hallucination), and suicidal behavior (n = 5: 4 suicidal ideation, 1 attempt). Reasons for discontinuation from placebo were medical (n = 2) and psychiatric symptoms (n = 3: 2 nervousness/hostility, 1 mania). In addition, there were 5 subjects who discontinued during the placebo run-in period for adverse events: 1 with depression, 1 hostility, 1 suicidal ideation, 1 accidental injury, and 1 unexpected pregnancy) (Emslie, personal communication).
The discontinuation rate due to adverse events in the nefazodone study was 3% (n = 3) for both active medication and placebo. Specific details about the reasons for discontinuation are not reported in the abstract (Emslie et al., 2002b).
In the two placebo-controlled trials of mirtazapine, adverse events were reported as one combined sample size. The rate of discontinuation due to adverse events was similar for mirtazapine and placebo (5.3% vs. 3.4%, respectively).
Serious adverse events. The reporting of SAEs has been consistent in clinical trials with SSRIs and SNRIs. Adverse events are considered to be SAEs if any of the following occurs:
Life threatening: The subject was at substantial risk of dying at the time of the adverse event.
Hospitalization (initial or prolonged): Admission to the hospital or prolongation of a hospital stay results because of the adverse event.
Disability: The adverse event resulted in a significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life.
Congenital anomaly/birth defect: There are suspicions that exposure to a medical product prior to conception or during pregnancy resulted in an adverse outcome in the child.
Event requires intervention to prevent permanent impairment or damage: A condition that requires medical or surgical intervention to preclude permanent impairment or damage to a subject.
Other important medical events: Events that may not result in death, be life threatening, or require hospitalization may be considered a serious adverse drug experience if they may jeopardize the subject or may require medical or surgical intervention (e.g., failed suicide attempts).
Determining whether an event is an SAE is made at the site level by the investigator. Furthermore, the relationship of the event to the medication is determined by the investigator. Psychiatric adverse events, such as worsening of mood or suicidal behavior, are often difficult to categorize, as it is unclear if the event is related to the medication or to the illness. Suicide-related events are reported as SAEs if they cause any of the 7 SAE definition requirements; however, some suicidal behaviors would not qualify as an SAE. For example, in some cases of suicidal gestures (e.g., cutting) or suicidal ideation, the event may not be documented as an SAE. As mentioned, classification is further made problematic because many of the psychiatric adverse events or SAEs may be a result of the illness, rather than the medication. Placebo-controlled trials are needed to evaluate whether there is increased incidence in such events in active medication over placebo. Table 6 shows the rates of SAEs in the included trials.
In the single-site fluoxetine trial, no SAEs were reported in the manuscript. However, 1 subject on fluoxetine and 1 subject on placebo were hospitalized due to suicide related events, which would qualify as SAEs (Emslie, personal communication). In the multi-site trial, 5 SAEs were reported: 1 fluoxetine and 4 placebo subjects. The fluoxetine subject was hospitalized for swollen tonsils; the four placebo subjects were hospitalized for each of the following: kidney infection, aggressive behavior, abdominal pain/appendicitis, and self-mutilation. Data on the SAEs occurring in the TADS study are not yet available.
In the published report of paroxetine, 11 (12%) patients on paroxetine and 2 (2%) patients on placebo were reported to have SAEs (Keller et al., 2001). SAEs in the study were defined as serious if they resulted in hospitalization, were associated with suicidal gestures, or were determined by the treating physician to be serious. Of the 11 SAEs with paroxetine, 1 was a severe headache and the other 10 subjects had various psychiatric events including worsening of depression (2), ‘emotional lability’ (e.g., suicidal ideation/gestures; 5), hostility or conduct problems (2), and euphoria (1). Seven of these patients were hospitalized. Only the subject with headache was considered to have a drug-related SAE. In the placebo group, 1 subject developed ‘emotional lability’ and 1 had a worsening of depression.
In the international adolescent trial (#377), 11.8% (22) of paroxetine and 6.8% (6) of placebo subjects had SAEs. Three of the paroxetine subjects had agitation and 6 had ‘emotional lability’. In contrast, none of the placebo subjects had agitation, 3 had ‘emotional lability’, and 1 had nervousness.
In the child and adolescent trial (#701), SAEs occurred in 6/101 (5.9%) subjects in the paroxetine group and 1/102 (1%) patient in the placebo group. In the paroxetine group, 3 subjects had worsening of depression, 1 subject had suicidal ideation (termed ‘emotional lability’), and 2 had a suicide attempt (termed ‘emotional lability’) with subsequent medical conditions (1 hypertension, 1 arm laceration). Four of these subjects were discontinued following the SAEs. In the placebo group, 1 subject had suicidality (termed ‘emotional lability’), and was discontinued from the study.
Seven subjects (4%) in the sertraline group had SAEs: 2 with a suicide attempt, 3 with suicidal ideation, 1 with aggressive behavior, and 1 requiring hospital admission for medical problems. In contrast, 6 (3%) of subjects in the placebo group had SAEs: 2 with suicide attempt and 4 with hospitalization due to medical conditions.
In the published trial of citalopram, no SAEs occurred in patients treated with citalopram (Wagner et al., 2004). The report does not mention if there were any SAEs in the placebo group. In the unpublished trial of citalopram, specific information about SAEs was not provided in the MHRA report (MHRA website). However, 15 (12.4%) subjects in the treatment group versus 9 (8%) in the placebo group were hospitalized during the study for psychiatric disorders.
In the combined trials (Emslie et al., 2004), 14 (8%) on venlafaxine and 5 (3%) on placebo had SAEs. Medical SAEs occurred in 4 subjects on venlafaxine. Other SAEs in the venlafaxine group were due to psychiatric symptoms (1 agitation/hostility, 1 mania, 2 worsening of depression, 1 hallucinations) and suicidal behaviors (4 suicidal ideation and 1 suicide attempt). Types of SAEs in the placebo group were similar: 1 medical, 3 psychiatric (2 hostility, 1 mania), and 1 suicidal behavior (self-injurious behavior).
No SAEs occurred in the nefazodone study for patients receiving nefazodone. The report did not include information about SAEs in the placebo group.
Only 3 SAEs were reported following randomization (2 on mirtazapine and 1 on placebo). Only 1 of these involved worsening of depression and suicidal ideation (mirtazapine), and in the opinion of the investigator, this event was unlikely due to the study drug. The other 2 SAEs involved medical events: 1 overdose on Depakote after being ‘dared’ (mirtazapine), which required emergency room treatment and was considered by the investigator to be unlikely related to study drug, and 1 increased temperature with possible viral infection (placebo), which required hospitalization and was considered to be unrelated to study drug in the opinion of the investigator.
From published and unpublished trials of SSRIs and SNRIs in children and adolescents, there are reports of increased suicide-related events in patients treated with medication versus placebo (Table 7). One difficulty in interpreting suicidal behaviors in depression studies is that suicide and suicidal ideation are a symptom of depression. Suicide is the 3rd leading cause of death in adolescents. Approximately 19% of teenagers (age 15–19) in the general population think about suicide and nearly 9% of teenagers make an actual suicide attempt (MMWR, 2002). These rates are even higher in patients receiving some type of care for depression. Studies find that 35–50% of these youth have made, or will make, a suicide attempt. Thus, when an individual patient makes a suicide attempt during the course of treatment, it is simply not possible to know if the event was related to the medication or if it was a part of the illness itself. In many cases, patients have suicidal ideation prior to treatment, as part of the illness. Continuation or worsening of such symptoms could be related to medication, but could also simply be lack of improvement. Only when there are sufficient numbers of patients in placebo-controlled trials will we be able to determine if medication treatment is associated with increased suicidal behavior.
Table 7. Overall relative risk for suicide-related events in clinical trials of youth by drug
|Drug||Relative risk (95% CI)|
|MDD trials||All trials|
|Celexa||1.37 (.53, 3.50)||1.37 (.53, 3.50)|
|Luvox||No MDD trials||5.52 (.27, 112.55)|
|Paxil||2.15 (.71, 6.52)||2.65 (1.00, 7.02)|
|Prozac||1.53 (.74, 3.16)||1.52 (.75, 3.09)|
|Zoloft||2.16 (.48, 9.62)||1.48 (.42, 5.24)|
|Effexor XR||8.84 (1.12, 69.51)||4.97 (1.09, 22.72)|
|Remeron||1.58 (.06, 38.37)||1.58 (.06, 38.37)|
|Serzone||No events||No events|
|Wellbutrin||No MDD trials||No events|
|Total||1.66 (1.02, 2.68)||1.95 (1.28, 2.98)|
The other major difficulty in interpreting data on suicidal behavior in these studies is terminology. Suicidal behavior is not the same as suicidal ideation. Different studies use varying terminology. For example, in the paroxetine trial, ‘emotional lability’ included suicidal ideation and suicidal gestures. Furthermore, investigators within a single study may use different terminology. An event such as cutting may be labeled several different things: suicidal gesture, self-mutilatory behavior, suicide attempt, etc. Clearly, hospitalization due to an actual attempt is not equal to hospitalization due to increased ideation. Thus, analyzing the events is somewhat difficult. Furthermore, within events that are actual suicidal behaviors (i.e. actually doing something that could lead to death), there are wide degrees of difference. Self-harm with no ideation or intent is not the same as a suicidal gesture, which is not the same as an attempt. Therefore, the FDA recently completed a project to re-evaluate each of these types of events across the pediatric antidepressant RCTs, and re-categorize them consistently across all studies.
Table 7 presents the results of the FDA re-analyses of suicide-related events in youth from antidepressant trials for MDD and for all indications. The overall relative rate of suicide related events was 1.95 (95% CI = 1.28–2.98) events (including suicidal ideation, self-harm, or attempts) for the trials (all disorders). As seen in Table 7, with the exception of venlafaxine, subjects on individual antidepressants were not statistically more likely to experience suicide-related adverse events compared to placebo, possibly because of the low rate of such occurrences. However, the overall rate for suicide-related events was statistically significant.
One interesting trend emerged from the FDA re-analyses. There was a large numeric difference between the increased risks for suicide ideation compared with actual suicide attempts for subjects on venlafaxine. Most of the risk-ratio for venlafaxine was driven by suicidal ideation events, rather than by actual suicidal behavior events (all suicide-related events 8.84, 95% CI = 1.12–69.51; suicidal ideation 7.89, 95% CI = .99–62.59; suicidal behaviors 2.77, 95% CI = .11–67.10). This was also true for sertraline. However, in subjects treated with paroxetine, citalopram or fluoxetine, the risk was higher for suicidal behaviors compared to suicidal ideation, although none of these differences were significant between medication and placebo, either by event or for the total.
The overall risk difference between the drug and placebo groups was 2–3%. However, even after extensive sub-analyses, no predictive factors were identified which distinguished between subjects with treatment emergent suicide-related adverse events and those with suicide-related events related to their depressive disorder.