Psychiatry Research 225 (2015) 687–694

Contents lists available at ScienceDirect

Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Rational-emotive and cognitive-behavior therapy (REBT/CBT) versus

pharmacotherapy versus REBT/CBT plus pharmacotherapy in the
treatment of major depressive disorder in youth; A randomized
clinical trial
Felicia Iftene a, Elena Predescu b, Simona Stefan c, Daniel David c,n
a
Department of Psychiatry, Queens University, C/o Providence Care Mental Health Services, 752 King Street West, Kingston, Ontario, Canada K7L 4X3
b
Department of Neuroscience, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
c
Department of Clinical Psychology and Psychotherapy/International Institute for the Advanced Study of Psychotherapy and Applied Mental Health,
Babeş-Bolyai University, No 37 Republici Street, 400015 Cluj-Napoca, Romania

art ic l e i nf o a b s t r a c t

Article history: Major depressive disorder is a highly prevalent and debilitating condition in youth, so developing
Received 3 July 2014 efficient treatments is a priority for mental health professionals. Psychotherapy (i.e., cognitive behavioral
Received in revised form therapy/CBT), pharmacotherapy (i.e., SSRI medication), and their combination have been shown to be
27 October 2014
effective in treating youth depression; however, the results are still mixed and there are few studies
Accepted 12 November 2014
Available online 20 November 2014
engaging multi-level analyses (i.e., subjective, cognitive, and biological). Therefore, the aims of this
randomized control study (RCT) were both theoretical - integrating psychological and biological markers
Keywords: of depression in a multi-level outcome analysis - and practical – testing the generalizability of previous
Group rational-emotive and results on depressed Romanian youth population. Eighty-eight (N¼88) depressed Romanian youths
cognitive-behavior therapy
were randomly allocated to one of the three treatment arms: group Rational Emotive Behavior Therapy
Pharmacotherapy
(REBT)/CBT (i.e., a form of CBT), pharmacotherapy (i.e., sertraline), and group REBT/CBT plus pharma-
Clinical trial
Youth depression cotherapy. The results showed that all outcomes (i.e., subjective, cognitive, and biological) significantly
change from pre to post-treatment under all treatment conditions at a similar rate and there were no
significant differences among conditions at post-test. In case of categorical analysis of the clinical
response rate, we found a non-significant trend favoring group REBT/CBT therapy. Results of analyses
concerning outcome interrelations are discussed.
& 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction (Harrington et al., 1990). Although there are evidence-based treat-

1.1. The problem
Major depressive disorder in youth is one of the most prevalent
and debilitating psychiatric disorders for this age group (Costello et al.,
2003), with prevalence rates ranging from 2.8% in children under 13
and 5.6% in adolescents (Costello et al., 2006) and total incidence rate
ranging from 5% in children to 20% in adolescents, similar to the adult
incidence rate (Rohde et al., 2013). Depression in youth is associated
with an increased risk for other psychiatric disorders (e.g., Costello
et al., 2003) and/or difficulties in social functioning and school
performance (National Institute for Health and Clinical Excellence/
NICE, 2005), with a higher risk of reoccurrence in adulthood
n
Corresponding author. Tel.: þ 40 744266300; fax: þ 40 264 434141.
E-mail addresses: iftenef@providencecare.ca (F. Iftene),
predescu.elena@umfcluj.ro (E. Predescu), simonastefan@psychology.ro (S. Stefan),
daniel.david@ubbcluj.ro (D. David).
ments for depression in youth, both pharmacological and psychother-
apeutic, at least between one third and one half of depressed youth
still do not respond to treatment (Bridge et al., 2007; Weisz et al.,
2006), and almost half of treated youths experience recurrence within
4 years (Curry et al., 2011).
1.2. The treatment of depression in youth; a brief analysis
Following the principles of evidence-based practice, several
major randomized control trials (RCTs) have shown that both
psychosocial treatments, particularly cognitive behavioral therapy
(CBT), and pharmacological treatments (i.e., medication), particu-
larly selective serotonin reuptake inhibitors (SSRI), are effective,
both separately and in combination (e.g., Bridge et al., 2007;
Emslie et al., 1997; Vitiello, 2009) for treating youth depression.
For instance, one large-scale RCT, the TADS study (Treatment
for Adolescents With Depression Study Team, 2004), compared
CBT, pharmacotherapy, and their combination in treating major

http://dx.doi.org/10.1016/j.psychres.2014.11.021
0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
688 F. Iftene et al. / Psychiatry Research 225 (2015) 687–694
depressive disorder in adolescents and found that combining
fluoxetine with CBT appears superior to the other treatments
alone (i.e., on the Clinician's Global Index; CGI) at the end of the
acute treatment (TADS team, 2007) and it is more effective in
preventing suicidality in the long term (TADS team, 2007). Another
large-scale RCT, the TORDIA study (Emslie et al., 2010), compared
switching medication, and the combination of medication plus
CBT in treating SSRI-resistant adolescent depression (i.e, major
depressive disorder and dysthymia). The results confirmed that
the combination is more effective than medication alone in
reducing depressive symptoms.
However, other reviews have found only medium results for
CBT in treating youth depression (Weisz et al., 2006) and the
combination of CBT and medication has also yielded mixed results
(Dubicka et al., 2010), with some data showing that, at least for
moderate to severe major depression in adolescents, it is not clear
that combining CBT with medication adds significantly to treat-
ment efficacy (see the ADAPT study; Goodyer et al., 2008).
Therefore, conducting more RCTs investigating pharmacother-
apy, CBT, and their combination in treating youth depression is
extremely important, as many clinical aspects (e.g., multi-level
analyses of the outcomes) related to treatment response (e.g.,
efficacy/effectiveness) and its mechanisms of change still remain
to be clarified. In this sense, investigating new CBT approaches
would be a promising direction given the fact that current
treatments still elicit only a moderate success rate, with between
one third and one half of youths still not responding to treatment
(Bridge et al., 2007; Weisz et al., 2006). For instance, REBT, rational
emotive behavior therapy/REBT – a form of CBT – which assumes
that core irrational beliefs generate distorted automatic thoughts
that further generate dysfunctional consequences (e.g., dysfunc-
tional feelings, maladaptive behaviors) – has been found (see
David et al., 2008) effective in treating major depressive disorder
in adult population when compared to pharmacotherapy (being
included in the NICE Guidelines; see NICE, 2010), but no such
results have yet been reported for a youth population.
Another important issue is related to reported outcomes. First,
for instance, when a psychosocial intervention is used, investiga-
tors typically focus on psychological outcomes (e.g., subjective,
cognitive, behavioral) and often ignore biological outcomes. When
a pharmacotherapy intervention is used, typically the focus is on
the clinical symptoms and biological outcomes (e.g., platelet
serotonin reuptake, Axelson et al., 2005; dopamine, norepinephr-
ine, platelet serotonin, Goodnick et al., 1995), and key psycholo-
gical outcomes and mechanisms of change (e.g., cognitions) are
ignored.
Second, most of the studies investigating cognitive factors have
been conducted on adult population. Secondary analyses con-
ducted within the TADS study have shown that, for example,
clinical improvement is mediated by changes in perfectionism
(Jacobs et al., 2009), but there are still very few studies employing
measures of distorted thinking with adolescents receiving CBT.
Third, although research focusing on biological markers of
depression (i.e., biological factors) has found evidence for the role
of monoamines in the onset of depression, particularly serotonin
(5-HT) and norepinephrine (NE), few RCTs including a psychother-
apy arm have included biological parameters as outcomes or if
they did, they were mainly related to adult rather than to
adolescent depression. For instance, changes in serotonin uptake
have been correlated to improvements in depressive symptoms
following SSRI treatment (e.g., Axelson et al., 2005) and platelet
serotonin is related to symptom severity in adult patients treated
with citalopram (Fišar et al., 2008). Studies investigating SSRI
treatment response correlates of depressive symptoms have found
that platelet serotonin levels decrease after SSRI treatment (e.g.,
Goodnick et al., 1995; Maurer-Spurej et al., 2003), while the results
for plasmatic serotonin remain unclear, with some studies report-
ing a downward trend with fluoxetine treatment (e.g., Alvarez et
al., 1999), while other studies report increases in serotonin levels
following fluoxetine treatment (Blardi et al., 2002). With regard to
norepinephrine, studies found that administering sertraline to
healthy subjects leads to a decrease in plasma norepinephrine
compared to placebo (Shores et al., 2001) and the trend appears to
be downward for other antidepressants or electroconvulsive
therapy (Owens, 1996).
1.3. Overview of the present study
Given that youth depression is a complex disorder, measuring
multi-level outcomes in a RCT involving psychotherapy, pharma-
cotherapy, and their combination would bring relevant informa-
tion about treatment effects.
Therefore, the current RCT aimed to: (1) examine the efficacy of
group REBT/CBT, pharmacotherapy, and their combination for
depression in youth; this is necessary due to the mixed nature of
the previous results; (2) bring new innovations in the field by
engaging in the same design: (a) a multi-level analysis of the
outcomes (e.g., subjective, cognitive, and biological) and (b) a new
and potentially more efficacious CBT strategy (i.e., rational emotive
behavior therapy/REBT); this is fundamental because although the
standard CBT strategies seem to work, they still miss a large
segment of patients; and (3) investigate the generalizability and
stability of the current results on a new population (i.e., Roma-
nian); this is necessary as most of the previous studies were
conducted on English-speaking populations.
In order to provide a more cost-effective intervention, we used
a group format for this study, given the fact that group CBT has
been shown to be effective in treating youth depression (David-
Ferdon and Kaslow, 2008), yielding similar results to individual
psychotherapy (Weisz et al., 2006).
2. Method
2.1. Protocol and design
We used a three-arm randomized control trial in order to test the efficacy of
group REBT/CBT, pharmacotherapy, and their combination in treating youths with
major depressive disorder. Prior to conducting the study, ethical approval was
obtained from the involved institutions.
2.2. Participants
Adolescents (N ¼88) were recruited starting 2007, through specialized youth
mental health services, namely: (1) the Clinic of Child and Adolescent Psychiatry
and the Psychological Counseling Center in Cluj-Napoca; (2) the Institute for the
Advanced Studies of Psychotherapy and Applied Mental Health (Babes-Bolyai
University, Cluj-Napoca); (3) the Romanian Association for Cognitive-Behavioral
Therapies; (4) the private practice of team members; and (5) public service
announcements. Prior to recruitment, all participants and their parents signed an
informed consent, agreeing to participate in the trial. All participants were
diagnosed with major depressive disorder, following the DSM-IV, by using
Structured Clinical Interview for DSM-IV (KID-SCID, Hien et al., 1994). The
participants were aged 11–17 (m¼ 15.25, S.D.¼ 1.91), 49 were females and 39 were
males. Only adolescents with an IQ score of at least 80 were included in the current
sample. Our exclusion criteria were: bipolar disorder, severe conduct disorder,
substance use/abuse/dependence, pervasive developmental disorders, psychotic
disorders, being actively suicidal or having homicidal ideation, concurrent treat-
ment with psychotropic drug (stable stimulant for ADHD permitted) or psychother-
apy outside study, two previous failed SSRI trials or a failed trial of CBT for
depression, and intolerance to sertraline. A flow diagram of the progress through
the phases of the trial is presented in Fig. 1. There were no significant differences
among patients in the three groups concerning demographic and pretreatment
variables, including comorbidities (see Table 1).
 F. Iftene et al. / Psychiatry Research 225 (2015) 687–694 689

restructuring techniques to address the core irrational beliefs (e.g., demandingness

Randomized (n = 88) and self-depreciation, but also catastrophizing/awfulizing and frustration intoler-
ance, if they appear) and restructure them into rational beliefs (e.g., preference/
flexibility rather than demandingness; self-acceptance rather than self-deprecia-
tion). Thus, the group REBT/CBT protocol was focused on: (a) emphasizing
Allocation unconditional self-acceptance; (b) secondary problems like depression about
depression (meta-emotions); and (c) restructuring demandingness in particular,
which is considered a core belief in major depressive disorder (e.g., Ellis, 1987;
Solomon et al., 2003). Automatic thoughts were not specifically targeted first in
psychotherapy (as in other CBT strategies), but they were identified, analyzed, and
used to access and then change core beliefs (i.e., irrational beliefs, often in the form
of demandingness and/or self-depreciation).
Treatment combining group REBT/CBT and medication included all the com-
Allocated to medication Allocated to group Allocated to group ponents from the two conditions alone.
alone (n =33) REBT/CBT alone (n = REBT/CBT and
28) medication combined (n
Received allocated = 27) 2.4. Outcomes
intervention (n = 33) Received allocated
intervention (n = 26) Received allocated 2.4.1. Categorical/diagnosis measures
Did not receive intervention (n = 26) Diagnosis and comorbidities were assessed using the Structured Clinical Inter-
view for DSM-IV (KID-SCID, Hien et al., 1994) which was administered at
pretreatment by certified clinicians.

Analyses
2.4.2. Continuous measures
2.4.2.1. Subjective outcomes. Depression symptoms were evaluated with the Child
Depression Inventory (CDI; Kovacs, 1992), a commonly-used 27-item instrument
sensitive to changes in depressive symptomatology in children and adolescents.
Analyzed Analyzed Analyzed According to the literature (Kazdin, 1989), we used a cut-off point of 19 to delineate
between clinical and non-clinical symptom scores. Item nine from the CDI was also
Intent-to-treat (n =33) Intent-to-treat (n=26) Intent-to-treat (n = 26) distinctively used to assess suicidality. The CDI has been adapted for Romanian
population, and more recent analyses showed that it has good psychometric pro-
Post-treatment (n = 28) Post-treatment (n =23) Post-treatment (n = 23) perties (Sirbu and Iliescu, 2012). On our sample, the alpha Cronbach coefficient was
0.85 at post-treatment. In addition to depression scores, we also included sub-
Fig. 1. Flow diagram of the progress through the phases of the trial. jective measures of general distress by using the Profile of Mood States, short ve-
rsion, (POMS; Dilorenzo et al., 1999), a 47-item, widely-used instrument which
assesses general distress. The POMS was previously adapted and used with Rom-
anian population, achieving a high internal consistency index (David et al., 2013). In
Table 1 the current sample, the POMS (i.e., distress score) achieved an alpha Cronbach of
Demographics and pretreatment variables (Total N¼ 88). 0.95 at post-treatment.

Variables Group Medication Medication þGroup

2.4.2.2. Cognitive outcomes. Regarding the cognitive factors, we used the Automatic
REBT/CBT (N ¼33) REBT/CBT (N ¼ 27)
Thoughts Questionnaire (ATQ; Hollon and Kendall, 1980), a 15-item instrument
(N ¼28)
designed to assess automatic thoughts particularly related to depression, having
been administered to children in previous research (Kazdin, 1990). The ATQ has
Gender
been previously adapted for Romanian population with good psychometric proper-
Male 16 13 12
ties (Moldovan, 2007), and has been previously used in research (e.g., Cristea et al.,
Female 12 20 15
2013). For our sample, we obtained an alpha Cronbach coefficient of 0.95 at post-
Age, mean þ S.D. 15.14 15.27 15.30 (1.83)
treatment.
(in years) (1.84) (2.05)
Mean (S.D.) no. of previous 0.14 0.27 0.11 (0.320)
episodes (0.448) (0.517)
2.4.2.3. Biological outcomes. Biological markers (i.e., serotonin and norepinephrine)
Axis I baseline comorbidities were measured by blood samples, following established practice protocols. Serum
Any psychiatric condition 13 16 15 serotonin and norepinephrine levels were measured using Cromsystems kits. The
Anxiety 5 7 7 analyses were obtained by high-performance liquid chromatography (HPLC Agilent
Tics and Tourette's disorder 2 4 4 1100), with an electrochemical detection (500 mV, 251; 20 μl).
Disruptive behavior 6 2 3

2.5. Safety assessments

2.3. Interventions
Treatment reflected current standard practice for SSRI treatment, group REBT/
CBT, and their combined use, and it lasted for 16 weeks for all three groups. All
psychotherapy sessions took place at the same site (the Institute for the Advanced
Studies of Psychotherapy and Applied Mental Health), and all the medication
sessions took place in the same location (the Clinic of Child and Adolescent
Psychiatry and the Psychological Counseling Center in Cluj-Napoca). The study was
approved by the National Agency for Medication (No. 7290/24.07.2007).
Drug treatment – the SSRI used in this RCT was sertraline, which was
administered following the standard protocol. Patients received 25–50 mg sertra-
line daily for 16 weeks and had to participate in eight evaluation sessions which
included treatment response monitoring, physical examinations, and safety assess-
ments. The drug treatment was delivered in an individual format.
Psychotherapy – group REBT/CBT followed the principles of Rational Emotive
Behavior Therapy (Ellis, 1987; Dryden and Neenan, 2002) and was delivered in 16
weekly group sessions. There were 6 to 8 members in a therapy group. The protocol
was adapted after the one previously used with adults in Romania (David et al.,
2008). The protocol included the combined use of behavior activation and cognitive
Adverse events were constantly monitored, and included medical conditions
and side-effects, stressful life events, harm-related, and suicidal adverse events.
Adverse events were defined similarly to previous research (e.g., the TADS team,
2007), as including factors that significantly interfered with functioning, required
medical attention, or were associated with marked impairment in functioning,
requiring the use of concomitant medication.
2.6. Statistical analyses
Analyses were conducting using the intent to treat (ITT) principle, including
those outcome measures that participants completed last (i.e., provided they
attended at least one intervention session). Using this analysis could highlight a
more realistic effect of the interventions, since only treated participants were
included in the analyses. We used repeated measures ANOVA procedures to test for
time-treatment interactions on outcome measures. Data collected were analyzed at
pretreatment, midtreatment (week 8), and post-treatment (week 16) for subjec-
tive/symptom and cognitive measures and at pretreatment and post-treatment for
biological measures. The post-treatment scores we reported refer to ITT scores.
690 F. Iftene et al. / Psychiatry Research 225 (2015) 687–694
3. Results
3.1. Participants
Over 200 participants were initially assessed for eligibility, and
88 were randomized under the three treatment conditions.
Participants who were initially assessed and were not further
recruited in the study were excluded because they did not meet
the inclusion and/or exclusion criteria (60%), or refused to parti-
cipate (40%) for various reasons (e.g., unable to attend all the visits
for assessment and/or intervention due to distance etc.). In the
medication group, 33 out of 33 participants received intervention,
in the group REBT/CBT alone group 26 of 28 received intervention,
and 26 out of 27 participants received intervention in the
combined treatment group (see Fig. 1).
3.2. Pharmacotherapy
In addition to sertraline, some of the participants received
other psychotropic medication, namely alprazolam, risperidone,
olanzapine, or zolpidem. The additional medication was necessary
in some cases in order to address comorbidities (e.g., tics and
Tourette syndrome, disruptive behavior).
3.3. Attendance
Participants in the three groups attended treatment sessions at
an approximately equal rate. In the pharmacotherapy group, five
participants did not complete treatment (15.15%), in the group
REBT/CBT group five participants did not complete treatment
(17.85%), while in the group REBT/CBT plus pharmacotherapy
group four participants did not complete treatment (14.81%).
3.4. Adherence to group REBT/CBT protocol
Group REBT/CBT was delivered by an experienced psychothera-
pist (BM) and co-psychotherapist (RM), certified (at supervisory
level) by the Albert Ellis Institute/AEI (the original site of REBT).
Apart from their professional expertise and qualifications, the
therapists were specifically and intensively trained to apply the
protocols developed for the study, the training lasting for 14 days.
Treatment adherence was assessed using a monitoring and cali-
brating system. Meetings involving all therapists (including those
administering pharmacotherapy) were held every 2 weeks and
therapists were provided feedback and guidance. A sample of
sessions were analyzed by the second author (DD, a supervisor
certified by the AEI), using the REBT competency scale (David,
2007), an instrument adapted after Therapy Adherence and
Competency Scale (Young et al., 2006), passing satisfactorily the
quality criteria.
3.5. Outcome analyses
The means and standard deviations for the pretreatment,
midtreatment, and post-treatment main outcomes under the three
treatment conditions are displayed in Table 2. As previously
mentioned, we considered subjective/symptom-related outcomes
(CDI; POMS), cognitive (ATQ), and biological outcomes (serum
serotonin and norepinephrine). The results are presented for the
entire sample, by providing intent-to-treat scores as post-
treatment results.
3.6. Between group analyses
3.6.1. Pretreatment
We assessed pretreatment group differences by using one-way
analyses of variance (ANOVAs), and we found no significant
differences among conditions in terms of CDI total scores, F(2,
85)¼ 0.472, p 40.05; POMS distress scores, F(2, 85) ¼ 1.23,
p4 0.05; ATQ scores, F(2, 85) ¼0.476, p 40.05; and serotonin,
F(2, 85)¼ 0.884, p 40.05 and norepinephrine levels, F(2, 85) ¼
1.317, p4 0.05.
3.6.2. Outcome at 8 weeks (mid-treatment)
Mid-treatment outcome (8 weeks) differences were computed
using one-way analyses of variance (ANOVAs), and we found no
significant differences among the three conditions on the CDI total
scores, F(2, 74) ¼0.317, p 40.05; POMS distress scores, F(2, 75) ¼
2.226, p 40.05; and ATQ scores, F(2, 75) ¼2.904, p 40.05.
3.6.3. Outcome at post-treatment
3.6.3.1. Continuous analyses. Post-treatment outcome differences
were computed using one-way analyses of variance (ANOVAs), and
we found no significant differences among the three conditions on
the CDI total scores, F(2, 84) ¼0.220, p4 0.05; POMS distress
scores, F(2, 84) ¼ 0.177, p 40.05; ATQ scores, F(2, 84) ¼ 0.460,
p4 0.05; and serotonin, F(2, 74) ¼2.222, p4 0.05; and
norepinephrine levels, F(2, 74) ¼0.268, p 40.05.
3.6.3.2. Categorical analyses. Clinical response rate at post-
treatment was defined as scores lower than 19 on the CDI (see
also Kazdin, 1989), meaning that the patients do not meet the
criteria for clinical depression anymore (i.e., the inclusion criteria).
There was a 67.85% response rate in the group REBT/CBT alone
group, a 60.60% response rate under the medication condition, and
a 53.84% response rate in the medication plus group REBT/CBT
condition. Even though there was a positive trend favoring group
REBT/CBT, the differences were not significant (all ps40.05).
3.7. Time-treatment interaction and within group analyses
We used repeated measures ANOVAs in order to test for time-
treatment interaction effects for all outcomes. While there are no
differences among treatment groups related to improvement,
there are significant differences from pre to mid and post-
treatment for all outcomes. Table 2 displays the summary statistics
for subjective, cognitive, and biological outcomes, including time-
treatment interaction F values, time effect F values, effect sizes
(Cohen's d), and the percentage of pretreatment participants who
would score above the average post-treatment participant (i.e.,
higher scores indicating more symptoms). This last indicator,
signifying a transformation of Cohen's d to percentages, was
proposed by Coe (2002) and allows for a more clinically-oriented
data presentation, beyond significance values and effect sizes.
Mean outcomes by treatment groups for the most important
outcomes (i.e., CDI, ATQ, and sertraline, and norepinephrine levels)
are presented in Fig. 2.
3.8. Additional analyses
Results also showed that changes (delta change pre-post
scores) in symptoms (CDI) are significantly related to changes
(pre-post) in ATQ scores, r ¼0.421, p o0.001. Also, pre-mid
changes in ATQ were prospectively associated to the pre-post
changes in CDI total scores (r ¼ 0.220, p ¼0.026). These results are
consistent to REBT/CBT theory.
 F. Iftene et al. / Psychiatry Research 225 (2015) 687–694 691

Table 2
Means (and Standard Deviations) of outcome variables (N ¼ 88) at pretreatment, mid-treatment (8 weeks), and post-treatment (Intent-to-treat), time-treatment interaction,
time effect, pre-post effect sizes, and percentage of participants scoring higher at pretreatment than the average participant at post-treatment.

Pre-treatment 8 weeks Post-treatment Time-treatment Time effect Pre-post effect % Pre-treatment

interaction, P (pre-post), size (Cohen's d) participants higher
value P value than the average
Post-treatment
participant

CDI total score

REBT/CBT 23.60 (5.82) 21.12 (6.67) 15.92 (6.49) F (2, 82) ¼ 0.543; F (1, 82)¼ 71.059; 1.201 88
Medication 24.78 (6.33) 20.10 (8.55) 15.39 (8.76) p ¼ 0.583 o 0.001 1.179 88
Combined 23.48 (5.14) 21.75 (7.29) 16.80 (8.78) 0.845 79

POMS (distress)
REBT/CBT 75.91 (31.07) 61.97 (25.97) 37.44 (25.06) F (2, 82) ¼ 1.402; F (1, 82)¼ 55.622; 1.311 90
Medication 70.45 (36.10) 44.93 (25.86) 42.00 (33.77) p ¼ 0.252 o 0.001 0.791 79
Combined 61.85 (33.98) 51.84 (35.48) 38.30 (34.51) 0.664 76

ATQ
REBT/CBT 46.21 (11.52) 41.14 (11.78) 27.78 (9.52) F (2, 82) ¼ 1.078; F (1, 82)¼ 104.751; 1.670 76
Medication 45.51 (11.89) 32.89 (10.52) 31.09 (15.72) p ¼ 0.345 o 0.001 0.991 82
Combined 43.14 (13.32) 36.80 (14.79) 29.46 (12.64) 1.017 84

Serotonin
REBT/CBT 248.42 (113.70) – 174.17 (125.63) F (2, 72) ¼0.693; F (1, 72) ¼ 16.856; 0.599 73
Medication 210.92 (113.18) – 115.42 (117.29) p ¼ 0.503 o 0.001 0.805 79
Combined 274.00 (288.07) – 113.09 (91.37) 0.441 66

Norepinephrine
REBT/CBT 358.16 (178.15) – 292.35 (188.43) F (2, 72) ¼0.797; F (1, 72) ¼ 8.928; 0.347 62
Medication 406.49 (199.25) – 320.52 (140.37) p ¼ 0.454 0.004 0.480 69
Combined 450.29 (251.55) – 295.10 (131.58) 0.685 76

Note. Standard deviations are given in parentheses. REBT/CBT ¼ Rational Emotive Behavior Therapy/Cognitive Behavior Therapy; CDI ¼Child Depression Inventory; POMS
(distress)¼ Profile of Mood States, Distress score; ATQ¼ Automatic Thoughts Questionnaire.

However, changes (pre-post) in symptom scores (CDI) and ATQ
are not related to changes (pre-post) in serotonin, r ¼ 0.047 and
norepinephrine levels, r ¼0.185, ps40.05, and, respectively,
r ¼0.056, and r ¼−0.004. Also, changes (pre-post) in serotonin
and norepinephrine levels are not inter-related, r ¼  0.004,
p 40.05.
3.9. Suicidality
Suicidal ideation was assessed using item nine from the CDI.
None of the participants actually attempted suicide during the
trial. Reports of suicidal ideation significantly decreased from pre
to post-treatment, F(4, 72) ¼25.37, p o0.001, but there were no
differences across groups, F(2, 72) ¼0.042, p 40.05.
3.10. Adverse events
None of the participants reported major side-effects. Some
participants reported mild side-effects, displayed in Table 3.
4. Discussion
Generally, the results of the current study show that group
REBT/CBT, pharmacotherapy (i.e., sertraline), and their combina-
tion were equally effective in treating youth depression. There
seems to be a non-significant trend favoring group REBT/CBT
(when compared to the combined condition), when we used the
categorical analysis for response rates in depressive symptoms
(group REBT/CBT - 67.85% versus Pharmacotherapy - 60.60% versus
Combination - 53.84%). These results are consistent to the pre-
viously reported research data (Dubicka et al., 2010; Goodyer et al.,
2008; Vitiello, 2009) showing that medication, psychotherapy, and
their combination are similarly effective in treating youth
depression. In addition, the positive impact on depressive symp-
toms was extended to general distress (measured by POMS), thus
potentially impacting the quality of life and social functioning.
Also, automatic thoughts, a central cognitive feature of depres-
sion (e.g., Beck, 1976) and biological markers (i.e., serum serotonin
and norepinephrine) significantly dropped from pre to post-
treatment, with no differences among treatment arms. While for
norepinephrine this appears to be a consistent result in the
literature (e.g., Owens, 1996; Shores et al., 2001), the findings
regarding serotonin are mixed. Indeed, some studies (e.g., Alvarez
et al., 1999) report a downward trend with treatment, while other
studies report increases in plasma serotonin (e.g., Blardi et al.,
2002).
Additional analyses showed that cognitive changes correlate
with depressive symptom (i.e., subjective outcome) changes, both
simultaneously and prospectively, thus pointing to the link
between cognitive factors and subjective outcomes. However,
none of the subjective (CDI) and cognitive (ATQ) outcomes was
associated with changes in biological markers (i.e., serum seroto-
nin and norepinephrine levels). Similar results have been fre-
quently reported in previous studies (e.g., Kelly et al., 1989; Tyrer
et al., 1990; Alvarez et al., 1999), highlighting the complex and still
incompletely understood pathogenesis and pathophysiology of
depression (e.g., Hindmarch, 2001; Krishnan and Nestler, 2008).
Apart from these general conclusions, the current findings
warrant more nuanced discussions. First of all, on some measures,
the TADS study (the TADS team, 2007) found that combining CBT
and fluoxetine significantly adds to treatment efficacy for youth
depression at post-intervention (on one of the outcome measures)
and reduces suicidality compared to fluoxetine alone. Our results
did not confirm this finding, as we found no significant differences
among treatment arms on any of the outcomes, consistent with
other findings (see Dubicka et al., 2010). However, some metho-
dological differences might explain these results. First, we used
692 F. Iftene et al. / Psychiatry Research 225 (2015) 687–694

Fig. 2. Mean outcomes for CDI total score, and ATQ at pretreatment, week 8, and post-treatment, and mean outcomes for serum serotonin at pretreatment and post-
treatment.

Table 3 Moreover, the efficacy of medication has been already extensively

Adverse events by treatment group (Total N ¼ 88). documented (e.g., Wagner et al., 2003; Weersing and Brent, 2006),
so it seems unlikely that changes in symptom scores were due to
Adverse Group REBT/CBT Medication Medication þ Group
events (N ¼ 28) (N¼ 33) REBT/CBT (N ¼27)
placebo effects or the mere passage of time. Indeed, the response
rate in our study for pharmacotherapy is similar to other studies
Headaches 1 2 3 (see Hetrick et al., 2012). Second, the sample size was not large
Insomnia 1 1 0 enough to small capture differences between the three groups;
Sleepiness 0 1 1
however, the sample was large enough to capture differences in
Low appetite 0 2 1
Weight gain 0 1 0 the high-medium range or large. Third, we measured serum and
Fatigue 0 1 0 not platelet serotonin. While not itself a limitation, data seem to
Dizziness 0 0 1 indicate a more stable trend for platelet serotonin in response to
Sweats 0 0 1 SSRI treatment (e.g., Goodnick et al., 1995; Maurer-Spurej et al.,
2003). Forth, the psychological measures were
self-report. However, the self-report measures have good psycho-
metric properties, having been used largely in previous interna-
sertraline instead of fluoxetine as it constitutes the standard tional studies on Romanian population also (e.g., Cristea et al.,
practice in treating youth depression in Romania and has been 2013; David et al., 2013). The lack of parent-based measures could
proved effective in previous studies (e.g., Wagner et al., 2003). also be seen as a limit, but the mean age of the sample is high
Third, we used a group-delivered CBT intervention and not an enough to argue that the self-report and the objective/biological
individual one, and although previous studies showed it is measures are valid indicators of the outcomes. Last but not least, at
equivalently effective with individual psychotherapy in treating this moment, no follow up data were available, so we cannot draw
youth depression (Weisz et al., 2006), the differences in protocol conclusions about the long term participants' evolution.
could explain these results. Finally, our sample size was signifi- In summary, to our knowledge, this is the first RCT comparing
cantly smaller and it is possible not to have detected small psychotherapy (i.e., group REBT/CBT), pharmacotherapy, and their
between-group differences in outcomes. combination conducted on depressed youth, assessing multi-level
The present study is not without limits. First, we did not outcomes. At a theoretical level, the results of our RCT indicate
estimate treatment efficacy with reference to a control group that administering group REBT/CBT, sertraline, or a combined
(waitlist or placebo). However, this comparison was not intended intervention for depressed youth leads to similar results, in terms
in the first place, since our goal was to delineate the influence of of subjective, cognitive, and biological markers of depression,
reference treatment approaches on multi-level outcomes. these results opening interesting questions about clinical
 F. Iftene et al. / Psychiatry Research 225 (2015) 687–694
strategies and mechanisms of change. At a practical level, group
REBT/CBT protocols are now available to mental health profes-
sionals dealing with depression in youth, this study being the first
RCT for depressed youth conducted on Romanian population.
Acknowledgment
This research was supported by the Grant number CEEX nr.
156/2006, awarded by the National Council for Research in Higher
Education (CNCSIS).
The authors wish to thank Bianca Macavei and Ramona
Moldovan for their important contribution to the process of
protocol implementation.
References
Alvarez, J.-C., Gluck, N., Fallet, A., Gregoire, A., Chevalier, J.-F., Advenier, C., Spreux-
Varoquaux, O., 1999. Plasma serotonin level after 1 day of fluoxetine treatment:
a biological predictor for antidepressant response? Psychopharmacology 143,
97–101.
Axelson, D.A., Perel, J.M., Birmaher, B., Rudolph, G., Nuss, S., Yurasits, L., Brent, D.A.,
2005. Platelet serotonin reuptake inhibition and response to SSRIs in depressed
adolescents. The American Journal of Psychiatry 162, 802–804.
Beck, A.T., 1976. Cognitive Therapy for Emotional Disorders. International Univer-
sity Press, New York.
Blardi, P., De Lalla, A., Leo, A., Auteri, A., Iapichino, S., Di Muro, A., Castrogiovanni, P.,
2002. Serotonin and fluoxetine levels in plasma and platelets after fluoxetine
treatment in depressive patients. Journal of Clinical Psychopharmacology 22,
131–136.
Bridge, J.A., Iyengar, S., Salary, C.B., Barbe, R.P., Birmaher, B., Pincus, H.A., Brent, D.A.,
2007. Clinical response and risk for reported suicidal ideation and suicide
attempts in pediatric antidepressant treatment: a meta-analysis of randomized
controlled trials. The Journal of the American Medical Association 297,
1683–1696.
Coe, R., 2002. It's the effect size, stupid: what effect size is and why it is important.
In: Proceedings of the Paper Presented at the British Educational Research
Association Annual Conference, Exeter, England.
Costello, E.J., Erkanli, A., Angold, A., 2006. Is there an epidemic of child or
adolescent depression? Journal of Child Psychology and Psychiatry 47,
1263–1271.
Costello, E.J., Mustillo, S., Erkanli, A., Keeler, G., Angold, A., 2003. Prevalence and
development of psychiatric disorders in childhood and adolescence. Archives of
General Psychiatry 60, 837–844.
Cristea, I., Montgomery, G.H., Szamoskozi, S., David, D., 2013. Key constructs in
“classical” and “new wave” cognitive behavioral psychotherapies: relationships
among each other and with emotional distress. Journal of Clinical Psychology
69, 584–599.
Curry, J., Silva, S., Rohde, P., Ginsburg, G., Kratochvil, C., Simons, A., March, J., 2011.
Recovery and recurrence following treatment for adolescent major depression.
Archives of General Psychiatry 68, 263–270.
David, D., 2007. REBT competency scale. Unpublished manuscript.
David, D., Coteț, C.D., Szentagotai, A., Mcmahon, J., Digiuseppe, R., 2013. Philoso-
phical versus psychological unconditional acceptance: implications for con-
structing the unconditional acceptance questionnaire. Journal of Cognitive &
Behavioral Psychotherapies 13, 445–464.
David, D., Szentagotai, A., Lupu, V., Cosman, D., 2008. Rational emotive behavior
therapy, cognitive therapy, and medication in the treatment of major depres-
sive disorder: a randomized clinical trial, post-treatment outcomes, and six-
month follow-up. Journal of Clinical Psychology 64, 728–746.
David-Ferdon, C., Kaslow, N.J., 2008. Evidence-based psychosocial treatments for
child and adolescent depression. Journal of Clinical Child and Adolescent
Psychology 37, 62–104.
Dilorenzo, T.A., Bovbjerg, D.H., Montgomery, G.H., Valdimarsdottir, H., Jacobsen, P.B.,
1999. The application of a shortened version of the profile of mood states in a
sample of breast cancer chemotherapy patients. British Journal of Health Psychol-
ogy 4, 315–325.
Dryden, W., Neenan, M., 2002. Rational Emotive Behavioral Group Therapy. Whurr
Publishers, London.
Dubicka, B., Elvins, R., Roberts, C., Chick, G., Wilkinson, P., Goodyer, I.M., 2010.
Combined treatment with cognitive-behavioural therapy in adolescent depres-
sion: meta-analysis. The British Journal of Psychiatry 197, 433–440.
Ellis, A., 1987. A sadly neglected cognitive element in depression. Cognitive Therapy
and Research 11, 121–145.
Emslie, G.J., Mayes, T., Porta, G., Vitiello, B., Clarke, G., Wagner, K.D., Brent, D., 2010.
Treatment of Resistant Depression in Adolescents (TORDIA): week 24 out-
comes. American Journal of Psychiatry 167, 782–791.
Emslie, G.J., Rush, A.J., Weinberg, W.A., Kowatch, R.A., Hughes, C.W., Carmody, T.,
Rintelmann, J., 1997. A double-blind, randomized, placebo-controlled trial of
693
fluoxetine in children and adolescents with depression. Archives of General
Psychiatry 54, 1031–1037.
Fišar, Z., Kališová, L., Paclt, I., Anders, M., Vevera, J., 2008. Platelet serotonin uptake
in drug-naïve depressive patients before and after treatment with citalopram.
Psychiatry Research 161, 185–194.
Goodnick, P.J., Henry, J., Kumar, A., 1995. Neurochemistry and paroxetine response
in major depression. Biological Psychiatry 37, 417–419.
Goodyer, I.M, Dubicka, B., Wilkinson, P., Kelvin, R., Roberts, C., Byford, S., et al., 2008.
A randomised controlled trial of cognitive behaviour therapy in adolescents
with major depression treated by selective serotonin reuptake inhibitors. The
ADAPT trial. Health Technology Assessment 12.
Harrington, R., Fudge, H., Rutter, M., Pickles, A., Hill, J., 1990. Adult outcomes of
childhood and adolescent depression. I. Psychiatric status. Archives of General
Psychiatry 47, 465–473.
Hetrick, S.E., McKenzie, J.E., Cox, G.R., Simmons, M.B., Merry, S.N., 2012. Newer
generation antidepressants for depressive disorders in children and adoles-
cents. Cochrane Database of Systematic Reviews 11 (Art. No.: CD004851), John
Wiley & Sons.
Hien, D., Matzner, F.J., First, M.B., Spitzer, R.L., Williams, J., Gibbon, M., 1994.
Structured Clinical Interview for DSM-IV Childhood Diagnoses (KID-SCID).
Presented at the Biometrics Research presentation, New York.
Hindmarch, I., 2001. Expanding the horizons of depression: beyond the mono-
amine hypothesis. Human Psychopharmacology 16, 203–218.
Hollon, S.D., Kendall, P.C., 1980. Cognitive self-statements in depression: develop-
ment of an automatic thoughts questionnaire. Cognitive Therapy and Research
4, 383–395.
Jacobs, R.H., Silva, S.G., Reinecke, M.A., Curry, J.F., Ginsburg, G.S., Kratochvil, C.J.,
March, J.S., 2009. Dysfunctional attitudes scale perfectionism: a predictor and
partial mediator of acute treatment outcome among clinically depressed
adolescents. Journal of Clinical Child & Adolescent Psychology 38, 803–813.
Kazdin, A.E., 1989. Identifying depression in children: a comparison of alternative
selection criteria. Journal of Abnormal Child Psychology 17, 437–454.
Kazdin, A.E., 1990. Evaluation of the automatic thoughts questionnaire: negative
cognitive processes and depression among children. Psychological Assessment
2, 73–79.
Kelly, M.W., Perry, P.J., Holstad, S.G., Garvey, M.J., 1989. Serum fluoxetine and
norfluoxetine concentrations and antidepressant response. Therapeutic Drug
Monitoring 11, 165–170.
Kovacs, M., 1992. Children's Depression Inventory. Multi-Health System, North
Tonawanda, N.Y.
Krishnan, V., Nestler, E.J., 2008. The molecular neurobiology of depression. Nature
455, 894–902.
Maurer-Spurej, E., Pittendreigh, C., Solomons, K., 2003. The influence of selective
serotonin reuptake inhibitors on serotonin metabolism in human platelets.
Thrombosis and Haemostasis 91, 119–128.
Moldovan, R., 2007. Chestionarul gandurilor automate [Automatic thoughts ques-
tionnaire]. In: David, D. (Ed.), Sistem de evaluare clinica [Clinical Evaluation
System]. RTS Publishing, Cluj-Napoca, RO.
NICE, 2005. CG28 Depression in children and young people: NICE guideline.
Guidance/Clinical Guidelines. Retrieved December 11, 2012, from 〈http://pub
lications.nice.org.uk/depression-in-children-and-young-people-cg28〉.
NICE, 2010. The treatment and management of depression in adults (updated
edition). Retrieved from 〈http://www.nice.org.uk/nicemedia/live/12329/45896/
45896.pdf〉.
Owens, M.J., 1996. Molecular and cellular mechanisms of antidepressant drugs.
Depression and Anxiety 4, 153–159.
Sirbu, C., Iliescu, D., 2012. Inventarul de depresie pentru copii, Manual tehnic
[Children's Depression Inventory - manual]. Sinapsis Publishing Projects,
Bucharest.
Rohde, P., Lewinsohn, P.M., Klein, D.N., Seeley, J.R., Gau, J.M., 2013. Key character-
istics of major depressive disorder occurring in childhood, adolescence, emer-
ging adulthood, and adulthood. Clinical Psychological Science 1, 41–53.
Shores, M.M., Pasqualy, M., Lewis, N.L., Flatness, D., Veith, R.C., 2001. Short-term
sertraline treatment suppresses sympathetic nervous system activity in healthy
human subjects. Psychoneuroendocrinology 26, 433–439.
Solomon, A., Arnow, B.A., Gotlib, I.H., Wind, B., 2003. Individualized measurement
of irrational beliefs in remitted depressives. Journal of Clinical Psychology 59,
439–455.
TADS team, 2007. The Treatment for Adolescents With Depression Study (TADS)
long-term effectiveness and safety outcomes. Archives of General Psychiatry
64, 1132.
Treatment for Adolescents With Depression Study Team, 2004. Fluoxetine,
cognitive-behavioral therapy, and their combination for adolescents with
depression: Treatment for Adolescents With Depression Study (TADS) rando-
mized controlled trial. The Journal of the American Medical Association 292,
807–820.
Tyrer, S.P., Marshall, E.F., Griffiths, H.W., 1990. The relationship between response to
fluoxetine, plasma drug levels, imipramine binding to platelet membranes and
whole-blood 5-HT. Progress in Neuro-Psychopharmacology & Biological Psy-
chiatry 14, 797–805.
Vitiello, B., 2009. Combined cognitive-behavioural therapy and pharmacotherapy
for adolescent depression: does it improve outcomes compared with mono-
therapy? CNS Drugs 23, 271–280.
694 F. Iftene et al. / Psychiatry Research 225 (2015) 687–694

Wagner, K.D., Ambrosini, P., Rynn, M., Wohlberg, C., Yang, R., Greenbaum, M.S.,
Deas, D., 2003. Efficacy of sertraline in the treatment of children and
adolescents with major depressive disorder: two randomized controlled trials.
The Journal of the American Medical Association 290, 1033–1041.
Weersing, V.R., Brent, D.A., 2006. Cognitive behavioral therapy for depression in
youth. Child and Adolescent Psychiatric Clinics of North America 15, 939–957.
Weisz, J.R., McCarty, C.A., Valeri, S.M., 2006. Effects of psychotherapy for depression
in children and adolescents: a meta-analysis. Psychological Bulletin 132,
132–149.
Young, J., Arntz, A., Giesen-Bloo, J., 2006. Therapy Adherence and Competency
Scale.