Adverse events reported by anxious school refusing adolescents receiving cognitive behavioral therapy with and without fluoxetine

Abstract

Background:

Investigating adverse events associated with antidepressant treatments in adolescents is important given the concerns about increased risk of suicidal ideation and behavior in this age group. The aim of this study is to investigate adverse and serious adverse events associated with the treatment of anxiety (cognitive behavioral therapy (CBT)-only, CBT-plus-placebo, and CBT-plus-fluoxetine) in anxious school-refusing adolescents.

Methods:

A side-effect symptom checklist was completed by participants prior to commencing treatment and during treatment (weekly/fortnightly).

Results:

CBT-plus-fluoxetine was well tolerated and not associated with higher levels of adverse events than the other treatments. Adverse events in all groups decreased over time, and the only adverse event distinct to fluoxetine was nausea. Baseline anxiety predicted higher levels of adverse events. There was one suicide attempt in the CBT-plus-placebo group but no statistically significant difference in suicide attempts between groups. Participants with a comorbid depressive disorder were more likely to report self-injury ideation but not suicidal ideation compared with those who did not have comorbid depressive disorder. Frequency of suicidal ideation and non-suicidal self-injury was significantly lower in the CBT-plus-fluoxetine group compared with the CBT-only group. Frequency of self-injury ideation was significantly lower in the CBT-plus-fluoxetine group compared with both other groups.

Conclusions:

Overall, the treatments were well tolerated and fluoxetine plus CBT appeared to be protective against suicidal ideation, non-suicidal self-injury, and self-injury ideation in this sample.

Keywords

School refusal antidepressants cognitive behavioral therapy anxiety disorder depression

Introduction

The increased risk of suicidal ideation and behavior in children/adolescents receiving antidepressant medications compared with placebo, in pooled data from clinical trials evaluating the efficacy of antidepressants (Hammad, Laughren, & Racoosin, 2006), has been particularly worrisome. However, the nature and extent of these suicidal adverse events is still not well understood with greater antidepressant prescription rates also being associated with declining suicide rates (Gordon & Melvin, 2014).

In one large child/adolescent anxiety, randomized controlled trial (RCT), comparing cognitive behavioral therapy (CBT), sertraline, placebo, and sertraline + CBT treatments (Walkup et al., 2008; N = 488), there was no significant difference in rates of suicidal and homicidal ideation between sertraline and placebo groups. No suicide attempts were recorded within the trial and only five participants withdrew from treatment due to adverse events, namely, suicidal ideation (placebo group), worsening of symptoms, tremor, and stomach pain (Walkup et al., 2008). A smaller RCT comparing fluoxetine and placebo for child/adolescent anxiety disorders also revealed no significant difference between groups in the frequency of suicidal adverse events (Birmaher et al., 2003, N = 74). However, a large RCT which used fluoxetine (alone or in combination with CBT) for the treatment of adolescent depression (Treatment for Adolescents with Depression Study Team (TADS), 2004; N = 439) indicated that suicide-related events were significantly higher in patients taking fluoxetine alone (9.7%) than placebo (2.7%). The finding of suicide-related events in this latter but not the former studies may reflect the fact that depression is a risk factor for suicidal ideation and behavior, as the other RCTs focused on the treatment of anxiety disorders.

In addition to investigation of suicidal adverse events, non-suicidal adverse events have been assessed to determine patient safety and understand reasons for treatment cessation. While Birmaher et al. (2003, N = 74) found no significant difference between fluoxetine and placebo treatment for childhood anxiety in the total frequency of adverse events, significantly more participants in the fluoxetine group experienced gastrointestinal (abdominal pain and nausea) and neurological symptoms (drowsiness and headaches). In addition, behavioral disinhibition (13.5% of cases) was reported in the fluoxetine group requiring medication cessation. In Walkup et al.’s (2008, N = 488) child/adolescent anxiety trial, while there was no significant difference in rates of adverse events between sertraline and placebo groups, those in the CBT-only group reported lower frequency insomnia, fatigue, sedation, and restlessness than those in the sertraline group. The TADS adolescent depression study (TADS, 2004; N = 439) found that fluoxetine treatment (alone or in combination with CBT) was associated with greater spontaneously reported psychiatric adverse events than CBT or placebo, and those taking pills (combination, fluoxetine, or placebo) reported more physical adverse events compared with CBT alone (Emslie et al., 2006). The most common spontaneously reported physical adverse events were headache (7% combination; 12% fluoxetine), while abdominal pain, insomnia, vomiting, and sedation occurred in 2–4% of those receiving fluoxetine or combined treatment (Emslie et al., 2006). Overall, however, the rate of non-psychiatric adverse events in the TADS study was described as low.

It is difficult to discriminate between symptoms that are induced by treatment and those that are part of the underlying mental health condition. Including a placebo group is not entirely useful to make this discrimination because interestingly, many of the symptoms observed in the medication groups are also observed in the placebo groups (Birmaher et al., 2003; TADS, 2004). Patient expectancy effects, measured adverse events being symptoms of the underlying disorder rather than treatment emergent, and patient characteristics such as gender (female) and personality traits (neuroticism) have all been proposed as potential explanations for this finding (Cascade, Kalali, & Kennedy, 2009; Davis, Ralevski, Kennedy, & Neitzer, 1995; Haack, Seeringer, Thurmann, Becker, & Kirchheine, 2009; Rief et al., 2009). In combined CBT-plus-fluoxetine treatment studies, the CBT component also needs to be considered as a potential source of symptoms/adverse events, as CBT may also be associated with a temporary exacerbation of anxiety symptoms (Foa, Zoellner, Feeny, Hembree, & Alvarez-Conrad, 2002).

School refusal is often associated with anxiety and/or depressive disorders (McShane, Walter, & Rey, 2001). This association has justified the evaluation of antidepressant treatment for school refusal, given the promise of these medications in treating anxiety and depressive disorders in adolescence. However, few clinical trials have investigated antidepressant treatment for school refusal (Melvin & Gordon, 2018). Four RCTs of antidepressant medication for school refusal have investigated tricyclic antidepressants (Berney et al., 1981; Bernstein et al., 2000; Bernstein, Garfinkel, & Borchardt, 1990; Gittelman-Klein and Klein, 1971), a class of medication not often used with adolescents due to safety and efficacy concerns (Hazell, O’Connell, Heathcote, & Henry, 2002). Wu et al. (2013) compared CBT with and without fluoxetine for school refusal and reported 10 of 39 (25.6%) experienced adverse events. Dry mouth (20.8%), dizziness (16.7%), attention problems (12.5%), and sleep disorders (12.5%) were the most commonly reported adverse events. The only suicidal adverse event in these five studies occurred in the Bernstein et al. (1990) study. A participant who was prescribed imipramine experienced increasing depression symptoms including the emergence of suicidal ideation.

The aim of this study was to investigate both suicidal and non-suicidal adverse events experienced by school-refusing adolescents with anxiety disorders participating in a RCT involving fluoxetine (Melvin et al., 2017). It is noteworthy that this school-refusing population is typically excluded from other child/adolescent anxiety studies (e.g. Walkup et al., 2008) and many also meet diagnostic criteria for depressive disorders. In evaluating the tolerability of fluoxetine, the adverse events of all treatment groups (CBT-plus-fluoxetine, CBT-plus-placebo, and CBT-only) and the relationship between adverse events and anxiety symptoms were investigated. Based on the findings from previous research, it was hypothesized that the most common adverse events in all three groups would be abdominal pain, nausea, insomnia, headaches, and drowsiness; total adverse events would not differ significantly between the three groups; and that female gender and baseline anxiety severity would predict higher levels of adverse events. As the current sample included primarily anxious adolescents, over half with comorbid depression (58%), no directional hypotheses could be made in regard to which treatment group would experience greater suicidal and non-suicidal self-injury-related thoughts/behaviors. The impact of comorbid depression on the number of suicidal and self-injury adverse events was also investigated.

Methods

Participants

Participants comprised 59 of the 62 that participated in Melvin et al. (2017) study (n = 2 CBT-only and n = 1 CBT-plus-placebo participants discontinued prior to adverse events data collection). Participants and their parents provided written informed consent, in accordance with the hospital and university Human Research Ethics Committees. Participants were aged between 10 and 16.5 years (M = 13.59, standard deviation (SD) = 1.08), 32 (54%) were male, and they were randomized to treatment: n = 18 CBT-only, n = 20 CBT-plus-placebo, and n = 21 CBT-plus-fluoxetine. School attendance rates were less than 50% in the preceding 4 weeks, and participants were home with parental knowledge. They met Diagnostic and Statistical Manual of Mental Disorders - IV- Text Revision (DSM-IV-TR) (American Psychiatric Association, 2000) diagnostic criteria for at least one of: social phobia, specific phobia, generalized anxiety disorder, separation anxiety disorder, panic disorder with or without agoraphobia, or anxiety disorder not otherwise specified (NOS); this anxiety disorder needed to be the primary clinical problem.

Exclusion criteria included physical illness precluding school attendance, psychotropic medication use, pregnancy, intellectual disability, insufficient English language, current inpatient admission, primary behavior disorder (e.g. conduct disorder), bipolar disorder, psychosis, obsessive compulsive disorder (OCD), post-traumatic stress disorder, or substance abuse disorder.

Measures

Measures were administered at baseline, post-acute-treatment (12 CBT sessions), and post-maintenance treatment (6 months) and 12 months follow-up. The Revised Children’s Manifest Anxiety Scale (RCMAS; Reynolds & Richmond, 1985) was used as self-report measure of anxiety severity. The Anxiety Disorders Interview Schedule for DSM-IV-Child and Parent Version (ADIS: C/P) (Albano & Silverman, 1996) was used to establish diagnoses of primary and comorbid disorders among participants. It is a structured interview designed to assess for differential diagnosis of anxiety, mood, somatoform, and substance use disorders in children/adolescents.

A modified version of the New York State Psychiatric Institute Side-effects Form for Children and Adolescents (SEFCA) (Klein et al., 1994) was used to regularly monitor symptoms during treatment. Four items about suicidal and self-harm thoughts/behaviors were added due to their clinical relevance. The frequency and severity of each symptom was rated on a scale of 1–3 (1 = mild, 2 = moderate, and 3 = severe).

Procedure

Detailed information about the administered treatments and about the demographic and clinical characteristics of the sample is provided in Melvin et al. (2017). The double-blind RCT took place in a hospital-based University clinic and a community-based child, and an adolescent mental health service in outer suburban Melbourne. Participants in each group received 12 x 50-minute CBT sessions which included psychoeducation, relaxation training, social skills training, problem solving, cognitive therapy and systematic desensitization for a graded return to school, and 3 monthly maintenance sessions. Concurrent parent therapy sessions were also offered. Fluoxetine (10–30 mg, with a mean dose of 22.5 mg) or placebo was administered concurrently with CBT, with dosage and adverse events monitored weekly or fortnightly during acute treatment and monthly in the 12-week maintenance phase. While the intervention period was nominally 12 weeks, in practice it averaged 16 weeks, due to rescheduling missed appointments.

Data analyses

To ascertain the most common adverse events in each treatment group, frequency scores for each symptom on the SEFCA were converted to a binary variable, to indicate the presence or absence of each adverse event for each participant at each time point (i.e. a frequency equal to or greater than 1 was recorded to 1). The mean frequency of each adverse event was then calculated for each group, and the symptoms were ranked by mean score.

Adverse events were then quantified to enable comparison between groups by totaling the number of symptoms endorsed by participants on each modified SEFCA. To compare adverse events between groups, and to examine potential predictors of adverse events, a piecewise linear (or “broken stick”) random effects (repeated measures) regression model was used to express the number of adverse events as a function of the number of weeks since the start of treatment (time), controlling for treatment group (CBT-only, CBT + placebo, CBT + fluoxetine), gender, age, and RCMAS total anxiety score. Interactions between time (in two sections; up to 16 weeks (acute treatment) and after 16 weeks (maintenance treatment) and treatment group were fitted to assess whether the average trajectory over time depended on treatment group, allowing for a change in the average response after 16 weeks. The analysis was separated into these two time sections given the different rate of adverse events monitoring during acute treatment (weekly fortnightly) and maintenance treatment (monthly). Ancillary analyses were performed to investigate whether the frequency of suicidal and non-suicidal self-injury adverse events after baseline varied by treatment group and by comorbid depressive disorder status. The binary variable for adverse event, indicating the presence or absence of the symptom, was used in this analysis. A p value > 0.05 was used to indicate statistical significance on all analyses.

Results

Adverse events leading to study withdrawal

All treatments in the study were well tolerated with two participants withdrawing due to adverse events. One participant (CBT-plus-placebo group) made a suicide attempt (placebo pill overdose) after 7 weeks of treatment and was discontinued from the study and referred to a psychiatrist for treatment. She had reported passive suicidal ideation at pre-treatment assessment and had made two prior suicide attempts. Another participant (CBT-plus-fluoxetine group) chose to discontinue after self-reporting weight-gain, sore veins, difficulties speaking, and a distrust of the study doctors and tablets.

Common adverse events

There were a total of 680 SEFCA forms completed by the 59 participants, 174 in the CBT-only group, 237 in the CBT-plus-placebo group, and 269 in the CBT-plus-fluoxetine group. The 10 most commonly endorsed symptoms across all groups at baseline and in each group at baseline and during treatment are displayed in Table 1. Results indicate that there is considerable overlap in items at baseline and during treatment across the treatment groups.

Table 1.

Ten most commonly endorsed side-effect checklist items across all groups at baseline and within each group at baseline and after baseline.

Rank	All groups		CBT only				CBT placebo				CBT fluoxetine
	Baseline		Baseline		After baseline		Baseline		After baseline		Baseline		After baseline
	N = 59	M (SD)	n = 14	M (SD)	n = 160	M (SD)	n = 20	M (SD)	n = 217	M (SD)	n = 20	M (SD)	n = 249	M (SD)
1	Difficulty falling asleep	.63 (.49)	Difficulty falling asleep	.79 (.43)	Difficulty falling asleep	.49 (.50)	Lethargy, apathy	.70 (.47)	Headache	.39 (.49)	Difficulty falling asleep	.60 (.50)	Headache	.33 (.47)
2	Lethargy, apathy	.56 (.50)	Difficulty arousing in morning	.71 (.47)	Difficulty arousing in morning	.41 (.49)	Headache	.60 (.50)	Irritability	.32 (.47)	Depression	.50 (.51)	Difficulty arousing in morning	.30 (.46)
3	Irritability	.56 (.50)	Irritability	.64 (.50)	Irritability	.41 (.49)	Difficulty falling asleep	.55 (.51)	Outbursts of anger	.30 (.46)	Lethargy, apathy	.50 (.51)	Difficulty falling asleep	.29 (.45)
4	Headache	.52 (.50)	Headache	.57 (.51)	Drowsiness	.32 (.47)	Irritability	.55 (.51)	Difficulty arousing in morning	.29 (.45)	Irritability	.50 (.51)	Lethargy, apathy	.21 (.41)
5	Difficulty arousing in morning	.52 (.50)	Drowsiness	.57 (.51)	Outbursts of anger	.31 (.46)	Difficulty arousing in morning	.50 (.51)	Difficulty falling asleep	.26 (.44)	Difficulty concentrating	.50 (.51)	Outbursts of anger	.20 (.40)
6	Depression	.44 (.50)	Depression	.57 (.51)	Lethargy, apathy	.30 (.46)	Outbursts of anger	.50 (.51)	Sadness	.20 (.40)	Headache	.40 (.50)	Difficulty concentrating	.19 (.40)
7	Outbursts of anger	.43 (.50)	Abdominal pain	.50 (.52)	Headache	.29 (.46)	Joint aches	.40 (.50)	Nasal congestion	.18 (.39)	Difficulty arousing in morning	.40 (.50)	Irritability	.19 (.40)
8	Difficulty concentrating	.41 (.50)	Nausea	.50 (.52)	Difficulty concentrating	.27 (.44)	Nasal congestion	.35 (.49)	Depression	.18 (.38)	Drowsiness	.40 (.50)	Drowsiness	.18 (.39)
9	Drowsiness	.37 (.49)	Outbursts of anger	.50 (.52)	Sadness	.24 (.43)	Dizziness	.30 (.47)	Lethargy, apathy	.16 (.37)	Sadness	.40 (.50)	Nausea	.18 (.38)
10	Sadness	.35 (.48)	Lethargy, apathy	.43 (.51)	Depression	.23 (.42)	Abdominal pain	.30 (.47)	Abdominal pain	.15 (.36)	Outbursts of anger	.30 (.47)	Nasal congestion	.18 (.38)
						Depression	.30 (.47)			Pallor	.30 (.47)
						Difficulty concentrating	.30 (.47)

CBT: cognitive behavioral therapy; SD: standard deviation.

Adverse event comparison between groups and predictors of adverse events

Figure 1 shows the number of adverse events displayed in a non-linear time trajectory in locally weighted scatterplot smoothing (lowess) curves for each of the three treatment groups. The lowess mean graphed is calculated in a moving window containing the nearest 80% of the plotted points, giving a relatively smooth curve.

Figure 1.

Number of adverse events over time for the CBT + Fluoxetine (top), CBT-only (middle) and CBT + placebo (bottom) groups.

Results of the random effects piecewise linear regression indicated that the treatment groups did not differ significantly in the number of adverse events reported (Table 2).

Table 2.

Random effects piecewise linear regressions of number of adverse events accounting for treatment group (CBT-only, CBT + placebo, CBT + fluoxetine) (Model 1), and collapsed across treatment group (Model 2).

	Model 1 estimate	p-value	Model 2 estimate	p-value
Treatment group (ref: CBT + fluox)
CBT only	2.18	.058
CBT + placebo	−0.39	.712
Time 1: first 16 weeks	–0.20	<.001	–0.24	<.001
Treatment by Time 1 interaction
CBT only	−0.12	.101
CBT + placebo	−0.02	.716
Time 2: after 16 weeks	0.14	.179	0.20	.014
Treatment by time 2 interaction
CBT only	0.20	.275
CBT + placebo	−0.05	.818
After 16 weeks	2.04	.002	2.05	.001
Male	−0.50	.543	−0.52	.527
Age at start of treatment	0.03	.947	0.24	.541
RCMAS total score	0.32	<.001	0.31	<.001
Intercept	1.96	.727	−0.23	.968
Observations	680		680
Participants	59		59

RCMAS: Revised Children’s Manifest Anxiety Scale; CBT: cognitive behavioral therapy.

Significant differences (p<0.05) are boldfaced.

Due to the lack of significant difference between the groups, Figure 2 plots the number of adverse events over time, collapsed across treatment group. The two non-drug treatment groups did not differ in time trajectory from the CBT-plus-fluoxetine treatment, during acute or maintenance treatment phases. Adverse events declined gradually during acute treatment, but appeared stable during maintenance treatment. Adverse events were higher during maintenance treatment than during acute treatment. After accounting for treatment groups, time periods and their possible interactions, Model 1 estimates an average increase of about 2 (2.04, p < .001) adverse events after the 16-week acute intervention period (see Table 2). There was no evidence of association of the outcome with gender, nor age, but a positive association with total RCMAS score (.32 extra side-effects for a positive difference between participants of one RCMAS total score point, p < .001).

Figure 2.

Number of adverse events over time, collapsed across treatment group.

Given that the treatment groups were shown not to be relevant to either the number or the time trajectory of number of adverse events, a simpler model was estimated, combining estimates across the treatment groups (see model 2, Table 2). Model 2 results are in substantial agreement with the results outlined for model 1.

Serious adverse events suicidal- and non-suicidal self-injury-related adverse events

The differences in mean scores for suicide attempt were not significantly different between the three groups when calculated either in terms of all side-effect forms completed (Table 3), or by whether or not each participant attempted suicide during the study, F(2, 56) = .97, p = .384. For each of the other three adverse events, mean scores were highest for the CBT-only group, followed by the CBT-plus-placebo group, and then the CBT-plus-fluoxetine group. Games-Howell post hoc tests confirmed that mean scores for both suicidal ideation and non-suicidal self-injury were significantly lower in the CBT-plus-fluoxetine group compared with the CBT-only group, and mean scores for self-injury ideation were significantly lower in the CBT-plus-fluoxetine group compared with both other groups. We analyzed the effect of depressive disorder (yes/no) on suicide attempt/ideation with negative binomial regression models using generalized estimating equations (GEE) to control for the clustering of repeated reports within each individual person, while adjusting for age and gender. The results showed that adolescents with comorbid depressive disorder reported significantly more incidents of self-harm ideation compared with those without comorbid depressive disorder (p = .008). There was no evidence showing that suicidal ideation was associated with comorbid depressive disorder, and there were too few suicide attempts and non-suicidal self-injury to analyze.

Table 3.

Frequencies, means, standard deviations, test statistics and significance levels for suicide- and self-injury-related adverse events for the three treatment groups and by comorbid depressive disorder status after baseline.

	CBT		CBT + placebo		CBT + fluoxetine		F(2, 623)	p	Depressive disorder		No depressive disorder		p
	n = 160		n = 217		n = 249				n = 348		n = 273
	n	M (SD)	n	M (SD)	n	M (SD)			n	M (SD)	n	M (SD)
Suicide attempt	0	.00 (.00)	1	.00 (.07)	0	.00 (.00)	.942	.390	1	.00 (.05)	0	.00 (.00)	–
Suicidal ideation	20	.13 (.34)	23	.11 (.31)	14	.06 (.23)	3.64	.027	47	.14 (.34)	10	.04 (.19)	.146
Non-suicidal self-injury	6	.04 (.19)	2	.01 (.10)	0	.00 (.00)	5.67	.004	5	.01 (.12)	3	.01 (.10)	–
Self-injury ideation	15	.09 (.29)	16	.07 (.26)	6	.02 (.15)	4.94	.007	33	.09 (.29)	4	.01 (.12)	.008

CBT: cognitive behavioral therapy; SD: standard deviation.

Significant differences (p<0.05) are boldfaced.

No valid results could be estimated due to the small number of reported incidents for “Suicide attempt” and “Non-suicidal self-injury.”

Discussion

Fluoxetine was well tolerated in this sample of anxious school-refusing adolescents, many of whom also suffered from comorbid depression (58%) consistent with prior research (Birmaher et al., 2003; TADS, 2004). CBT-plus-fluoxetine was not associated with a higher level of adverse events than CBT-plus-placebo or CBT treatment. Two participants withdrew from treatment due to adverse events, one making a suicide attempt (CBT-plus-placebo) and one reporting weight-gain, sore veins, difficulties speaking and a distrust of study doctors and tablets (CBT-plus-fluoxetine). There was no statistically significant difference in suicide attempts between the three groups, and overall the frequencies of suicidal ideation, non-suicidal self-injury, and self-injury ideation in the study were low. There were significant differences between groups in suicidal ideation, non-suicidal self-injury, and self-injury ideation. Mean scores for suicidal ideation and non-suicidal self-injury were significantly lower in the CBT-plus-fluoxetine group compared with the CBT-only group, and self-injury ideation was significantly lower in the CBT-plus-fluoxetine group compared with both other groups. While requiring replication in a larger sample, this suggests that fluoxetine treatment in combination with CBT may indeed be protective against suicidal ideation, non-suicidal self-injury, and self -injury ideation in anxious school refusing adolescents. Only self-harm ideation was more likely to be reported by participants with a comorbid depressive disorder than those without comorbid depressive disorder. The small number of suicide attempts and episodes of non-suicidal self-injury precluded analysis of these groups. This may suggest that those with both anxiety and depressive disorder are more vulnerable to self-harm ideation, but it may also reflect greater overall comorbidity experienced by this group.

The hypothesis that the most common adverse events in all groups would be abdominal pain, nausea, insomnia, headaches, and drowsiness was partially supported. The most common adverse events (after baseline) were difficulty falling asleep, difficulty arousing in the morning, outbursts of anger (all treatments), headache (CBT-plus-fluoxetine, CBT-plus-placebo), irritability (CBT-only, CBT-plus-placebo), drowsiness (CBT-only), lethargy, and apathy (CBT-plus-fluoxetine). Abdominal pain appeared in the top 10 only in the CBT-plus-placebo group, and nausea was in the top 10 only in the CBT-plus-fluoxetine group. The only adverse event that appeared to be related only to fluoxetine was nausea, which did not appear in the CBT-plus-fluoxetine top 10 list at baseline but did during treatment and was not among the most common adverse events during treatment in the other two groups. The finding of similar adverse events in the CBT-only group suggests that something other than purely drug/placebo side effects are being measured in this study. The most common adverse event of difficulty falling asleep (and rousing in the morning), is an occurrence often reported in this sample, that is usually attributed to worries about attending school.

In all groups, adverse events gradually decreased over time during acute treatment, but remained fairly stable during maintenance treatment. As not everyone in this study was taking fluoxetine, there must have been another mechanism involved in the reduction of adverse events over time. Perhaps the CBT clinician-contact contributed to a decrease in anxiety over time, reflected as a reduction in adverse events. Regardless of the mechanism involved, this finding suggests that clinicians treating clients with either CBT alone or CBT augmented with fluoxetine have reason to expect that the treatment will be associated with increasing levels of comfort. Interestingly, adverse events during maintenance treatment were higher than those reported during acute treatment. This may reflect reporting on adverse events occurring over the last month versus the last week/fortnight, and/or anxiety associated with a reduction in clinician contact.

No evidence of age or female gender predicting adverse events was found. Baseline anxiety did, however, predict higher levels of adverse events, of which many were anxiety and depression symptoms. This suggests that the “adverse events” measured may actually reflect symptoms of the underlying anxiety disorder rather than being treatment emergent.

Limitations and suggestions for future research

The lack of a fluoxetine-only group limits conclusions that can be made about treatment components. It is possible that the CBT in the fluoxetine-plus-CBT group mitigates actual or awareness of adverse events. Thus, conclusions about side effects of fluoxetine can only be made in the context of combined (fluoxetine-plus-CBT) treatment. Furthermore, fluoxetine dose varied between 10 and 30 mg and given its pharmacokinetics, exposure could have varied more than threefold which may have influenced experience of adverse events.

As systematic assessment of adverse events generally reveals higher adverse event rates than spontaneous reporting (Rief et al., 2009), it is possible that the extensive side-effect checklist detected adverse events or symptoms which would not ordinarily have been reported, thus masking “true” adverse events. In particular, the ranked list of most to least common adverse events may have been different had adverse events been measured by spontaneous report rather than by systematic checklist. Future studies could investigate whether the pattern of results changes if anxiety symptoms are excluded from the total adverse event analyses, although it is acknowledged that distinguishing between adverse events and anxiety symptoms would be difficult. Finally, the sample size was relatively small, but overall a very large number of side-effect forms were completed, forming the basis of most analyses.

The lack of attention usually given to potential negative effects of psychological treatments in the literature has recently come to attention (e.g. Rozental, Kottorp, Boettcher, Andersson, & Carlbring, 2016). Our finding of increased adverse events in the CBT-only group suggests that this is an interesting area of future research, perhaps utilizing specially developed questionnaires such as Rozental et al.’s (2016) Negative Effects Questionnaire to further investigate their occurrence and symptoms.

Key points

Overall, fluoxetine combined with CBT was well tolerated. Only nausea was specific to CBT treatment with fluoxetine.

Adverse events were similar across groups, did not differ in overall levels between groups, reduced over the acute treatment period in all groups, and were predicted by baseline anxiety symptoms.

There was no evidence that fluoxetine was associated with greater suicidal thoughts or behaviors, which is an important finding given concerns with this age-group. While requiring replication in a larger sample, results suggested that fluoxetine may indeed be protective against suicidal ideation, non-suicidal self-injury, and self-injury ideation in this school-refusing population.

Participants with a comorbid depressive disorder were more likely to report self-injury ideation but not non-suicidal self-injury or suicidal ideation or behavior compared with those who did not have comorbid depressive disorder.

Footnotes

Authors’ Note

Amanda L Dudley is now affiliated with School of Psychology, Faculty of Health, Deakin University, Australia.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by the National Health and Medical Research Council (545968), beyondblue: the National Depression Initiative and the Financial Markets Foundation for Children. No funding or support was received from the pharmaceutical industry. We thank Professor Neville King (retired) who made a substantial contribution to the establishment of this study, the team of clinicians, Slade Pharmacy for preparation of the fluoxetine/placebo, Dr Nan Hu PhD for statistical advice, and all the participating adolescents and their families.

Trial Registry

Australian New Zealand Clinical Trials Registry (, trial # ACTRN12606000103561). Trial name: Treatment of school refusal.

Author biographies

Glenn A Melvin is an Associate Professor. He is a Clinical Psychologist from the Centre for Developmental Psychology and Psychiatry at Monash University and has an Honorary Associate Professor position at the Centre for Educational Development, Appraisal and Research, University of Warwick. Glenn was a Director and clinician in the School Refusal Program at Monash Medical Centre. He has been recently involved in the establishment of the International Network for School Attendance (INSA).

Linda Finnin completed her Honours thesis within the School Refusal Program at the Monash University Centre for Developmental Psychiatry & Psychology. Linda is a psychologist who works in private practice providing cognitive and academic assessments.

John Taffe is a biostatistician who holds an adjunct senior lecturer position at the Centre for Developmental Psychiatry & Psychology, Monash University.

Amanda L Dudley is a Psychologist and Lecturer in the School of Psychology, Deakin University. Amanda was formerly the clinic co-ordinator at the School Refusal Program at Monash Medical Centre.

Ester I Klimkeit is a Clinical Psychologist who has experience in teaching, research and clinical practice. She is an honorary Senior Lecturer at Monash University and her research interests are in the area of developmental disorders, anxiety and depression and health psychology.

Michael S Gordon is an Associate Professor. He is a Child and Adolescent Psychiatrist and is a Unit Head at the Monash Health Early in Life Mental Health Service. Michael is also an Adjunct Clinical Associate Professor at the Centre for Developmental Psychiatry & Psychology at Monash University. Michael’s research interest include school refusal, adolescent depression and suicide prevention.

Bruce Tonge is an Emeritus Professor. Tonge has a distinguished record of teaching and research in child psychiatry. He established and directed the internationally recognised Monash University Centre for Developmental Psychiatry and Psychology. He has research and teaching interests in the area of developmental psychiatry with a particular focus in the areas of Autism Spectrum Disorders and behavioural and emotional disturbance in children and adolescents with intellectual disability and treatment outcome studies in childhood anxiety, school refusal and depressive disorders.

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