Concise report CED

Clinical and Experimental Dermatology

A feasibility study for a triple-blind randomized controlled trial

investigating the effects of oral isotretinoin on mood and quality of
life in patients with acne vulgaris
S. Rea,1 S. Tucker,2,3 V. Frittelli1,4,5 and R. Gunnarsson1,6,7
1
College of Medicine and Dentistry, James Cook University, Cairns, Australia; Departments of 2Dermatology and 3Cairns Skin Centre, Cairns, QLD,
Australia; 4Psychiatry, Cairns Hospital, Cairns, Australia; 5Royal Australian and New Zealand College of Psychiatrists, Melbourne, Australia; 6Department of
Public Health and Community Medicine/Primary Health Care, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg,
€
Sweden; and 7Research and Development Unit, Na€rha€lsan (Primary Health Care), Southern Alvsborg County, Bor as, Sweden

doi:10.1111/ced.13284

Summary Isotretinoin is used in the treatment of severe acne vulgaris (AV), but has controver-
sially been associated with depression and suicide. Large prospective studies have
failed to translate this clinically. We undertook a feasibility study to investigate the
parameters of a triple-blind, randomized controlled trial (RCT) assessing the effect of
oral isotretinoin on quality of life (QoL) and mood in patients with AV. Patients
meeting the inclusion criteria were randomized for 2 weeks to isotretinoin or doxy-
cycline. Participants completed verified depression and QoL screening questionnaires
at baseline and week 2. In total, 194 patients with AV were screened, with 48 meet-
ing the inclusion criteria and 13 of these being willing to participate. The follow-up
rate was 92% and questionnaire response rate was 96%. To our knowledge, this is
the first study to demonstrate a successful design for a triple-blind RCT investigating
the effects of isotretinoin on mood in patients with AV.

Oral isotretinoin has anecdotally been associated with
low mood in patients with AV. There remains a lack
of evidence-based research demonstrating a positive
correlation for isotretinoin-induced depression and sui-
cide. Past studies have often been punctuated with
design flaws, or have been retrospective in nature,
underpowered or single case reports. In addition, AV
itself and adolescence are separate risk factors for
mood disorders.1 These confounding factors make it
difficult for nonrandomized studies to clarify the rela-
tionship between oral isotretinoin and mood.
As isotretinoin is a vitamin A analogue, there is bio-
logical plausibility for its possible induction of mood
disturbance. Isotretinoin has the potential to cross the
blood–brain barrier and affect the hippocampus and
Correspondence: Dr Stephanie Rea, School of Medicine, James Cook
University, Cairns Hospital, Room A2.19, 165 Esplanade, Cairns North,
QLD, 4870, Australia
E-mail: drstephanierea@gmail.com
Conflict of interest: the authors declare that they have no conflicts of
interest.
Accepted for publication 5 February 2017
orbitofrontal cortex, areas of the brain that have been
implicated in the development of depression.2 Further-
more, a study by Schaffer et al. suggested that individu-
als with pre-existing mental health conditions may be
more susceptible to isotretinoin-induced depression.3 In
that study, the authors prospectively examined 10
patients with bipolar disorder who were treated with
oral isotretinoin, and found that 9 of the patients expe-
rienced worsening mood symptoms on isotretinoin
despite concurrently taking mood-stabilizing medica-
tion. In addition, 8 of the 10 patients had a resolution
of mood symptoms on cessation of isotretinoin.
Although theoretically, isotretinoin may negatively
affect mood, large prospective studies have failed
to translate these findings clinically. A prospective
study by Marron et al. found that treating AV with
isotretinoin improved mood in some patients.4
The literature on this topic recommends that well-
designed, blinded, randomized controlled trials (RCTs)
should be conducted to provide scientifically sound,
evidence-based data, but to date, this recommendation
has not been acted upon. Such trials are logistically

ª 2017 British Association of Dermatologists Clinical and Experimental Dermatology 1

Feasibility study for a RCT investigating the effect of isotretinoin on mood  S. Rea et al.
difficult to randomize, and previous studies have theo-
rized that patients would be unlikely to consent to
randomization, possibly resulting in them receiving
another drug, as they would not wish to delay optimal
treatment with isotretinoin. Others have questioned
the ethics of randomizing patients in such a study,
given the superior efficacy of oral isotretinoin in the
treatment of AV.5 However, with close supervision,
any potential iatrogenic cause of mood symptoms
should be reasonably investigated.
Report
The human research ethics committee at James Cook
University approved the study on 1 September 2014
(reference: H5801). All patients with acne visiting
three private dermatology practices sharing a single
consultant in Cairns, Australia, were screened for
inclusion. Eligible patients were assessed to find if they
met the clinical criteria to be treated with either isotre-
tinoin or doxycycline. Patients currently being treated
with or who had been treated within the past
18 months with isotretinoin were ineligible. Patients
who had known hypersensitivity to retinoids or tetra-
cyclines, had known/diagnosed history of mental
health conditions (specifically depression, suicidal idea-
tion and past suicide attempts), had severe hepatic
impairment, hypercholesterolaemia or pre-existing
hypervitaminosis A, or who were pregnant or lactat-
ing were also excluded. Women of child-bearing age
were advised of the category X classification of isotreti-
noin and the risk of birth defects, and were provided
with a pregnancy screening blood test and contracep-
tive counselling prior to inclusion in the trial. Given
the superior efficacy of isotretinoin, patients were
excluded if they had severe scarring or if they had suf-
ficiently severe that delaying isotretinoin therapy by
2 weeks could have a detrimental effect.
The screening dermatologist, primary investigator
administering the questionnaires, patient, dispensing
pharmacist and statistician were all blinded to the
groups. Patients who met inclusion criteria were ran-
domized for 2 weeks to either doxycycline 50 mg
twice daily or isotretinoin 20 mg twice daily. Ques-
tionnaires screening for depression [(K10; Center for
Epidemiologic Studies Depression Scale (CES-D)] and
quality of life [World Health Organization Quality of
Life Scale Brief Version (WHOQOL-BREF); Dermatology
Life Quality Index (DLQI)] were taken at baseline and
week 2. Following the trial, all patients were offered
standard care. Therefore, if patients were determined
by the screening dermatologist as likely to benefit from
2 Clinical and Experimental Dermatology
isotretinoin, they were provided with a prescription
and follow-up care at the conclusion of the trial.
In total, 194 patients with AV were screened, but
only 48 patients (25%) met the strict inclusion criteria
as the majority were already on isotretinoin or had
been in the past. Of those patients who met the inclu-
sion criteria, 27% (n = 13) agreed to participate in the
trial. The main reasons for nonparticipation were tra-
vel distance to the clinic, as many patients lived in
rural areas (29%; n = 14), and not wishing to delay
treatment with oral isotretinoin (35%; n = 17). The
follow-up rate for the study was 92%, and the ques-
tionnaire response rate was 96%. The average time to
complete all four included questionnaires was 9 min.
As funding limited the trial duration, participants were
asked whether they would agree to partake in a theo-
retical 4-month trial, and 77% agreed. No participants
reported any serious adverse effects (AEs) from the
medications other than dry skin, lips and mucous
membranes in the isotretinoin group.
This study demonstrates that patients are willing to
accept randomization with isotretinoin despite its
known superior efficacy in the treatment of AV.
Although there are ethical concerns regarding ran-
domizing with oral isotretinoin, this study design
attempted to minimize them. No participants received
placebo; all received systemic treatment for their AV.
Patients included in the trial had not previously
received isotretinoin. Although isotretinoin is often
prescribed ‘off-label’ as first-line therapy, Pharmaceuti-
cal Benefits Scheme (PBS) indications for isotretinoin
are for severe nodulocystic acne or acne that has
failed a trial of systemic antibiotic therapy. The results
confirmed that many new patients would accept ran-
domization to doxycycline, which may be due to its
better AE profile compared with isotretinoin.
The AE profile of isotretinoin is distinct, making it
difficult to blind. In an attempt to overcome this issue,
patients were provided with verbal and written infor-
mation regarding the AEs of doxycycline and isotretin-
oin concurrently; the researchers hoped this would
make the expectant clinical patterns for each drug less
clear to participants.
Approximately one-third of eligible patients screened
declined to participate, not wishing to delay optimal
treatment with oral isotretinoin. This may have intro-
duced an element of selection bias, as patients with
perceived or actual worse acne and possibly suffering
worse mental health AEs from the condition may have
been excluded.
This study is limited by its size and duration due to
financial constraints and the regional geographical
ª 2017 British Association of Dermatologists
 Feasibility study for a RCT investigating the effect of isotretinoin on mood  S. Rea et al.
location of Cairns, Australia. Furthermore, the number
of patients required to generate sufficient power may
limit a larger trial. However, this feasibility study suc-
cessfully sets an ethical precedent and demonstrates
that patients will accept randomization for a larger
RCT.
Learning points
• To date, there remains a lack of evidence-based
research demonstrating a positive correlation for
isotretinoin induced depression and suicide, and
there have been no triple-blinded RCTs on this
topic.
• As isotretinoin is a vitamin A analogue, there
is biological plausibility for its association with
depression.
• Patients with pre-existing mental health condi-
tions may be more susceptible to isotretinoin-
induced depression.
• AV and adolescence are both independent risk
factors for depression and suicide.
• Given its known AE profile, isotretinoin may be
difficult to blind.
ª 2017 British Association of Dermatologists
• With close supervision, any potential iatrogenic
cause of mood symptoms should be reasonably
investigated.
• Patients will accept randomization with oral
isotretinoin for research purposes.
References
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Dermatol 2013; 168: 474–85.
2 Bremner JD, McCaffery P. The neurobiology of retinoic
acid in affective disorders. Prog Neuropsychopharmacol Biol
Psychiatry 2008; 32: 315–31.
3 Schaffer LC, Schaffer CB, Hunter S, Miller A. Psychiatric
reactions to isotretinoin in patients with bipolar disorder. J
Affect Dis 2010; 122: 306–8.
4 Marron SE et al. Anxiety, depression, quality of life and
patient satisfaction in acne patients treated with oral
isotretinoin. Acta Derm Venereol 2013; 93: 701–6.
5 EJ McGrath CL, Gillson F, Darvay A, Hickey JR,
Skevington SM. A prospective trial of the effects of
isotretinoin on quality of life and depressive symptoms. Br
J Dermatol 2010; 163: 1323–9.
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