Journal of Affective Disorders 122 (2010) 306308

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Journal of Affective Disorders

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d

Preliminary communication

Psychiatric reactions to isotretinoin in patients with bipolar disorder

Linda C. Schaffer a,, Charles B. Schaffer b, Susan Hunter c, Amber Miller b
a
b
c

Sutter Community Hospitals, United States

University of California, Davis, Medical Center, Department of Psychiatry, United States
University of Nevada, Reno, School of Medicine, United States

a r t i c l e

i n f o

Article history:
Received 24 July 2009
Received in revised form 1 September 2009
Accepted 9 September 2009
Available online 27 September 2009
Keywords:
Isotretinoin
Bipolar disorder
Dermatology

a b s t r a c t
Background: Isotretinoin (Accutane) has been available for the treatment of severe cystic
acne for about twenty-ve years. There have been several reports of adverse psychiatric
reactions to isotretinoin, including depressive symptoms and suicide. However, there have
been only three case reports of patients with bipolar disorder (BD) who experienced an
untoward psychiatric side effect while receiving isotretinoin treatment. In this study, the
psychiatric side effects from isotretinoin were assessed in a larger group of BD patients than has
previously been reported.
Methods: A retrospective chart review of 300 BD outpatients identied ten patients treated
with isotretinoin.
Results: Nine of these ten patients experienced a signicant worsening of mood symptoms, and
three developed suicidal ideation. Eight experienced a reversal of the relapsed mood symptoms
when the isotretinoin was discontinued, whether prematurely or after a full course.
Limitations: The limitations of this study include small sample size, retrospective data
collection, absence of double-blind controlled design, and inability to control for spontaneous
mood episodes in patients with BD.
Conclusions: These results indicate that BD patients treated with isotretinoin for acne are at risk
for clinically signicant exacerbation of mood symptoms, including suicidal ideation, even with
concurrent use of psychiatric medicines for BD. The clinical implications of this study are
especially relevant to the treatment of patients with BD because acne usually occurs during
adolescence, which is often the age of onset of BD and because a common side effect of lithium
(a standard treatment for BD) is acne.
2009 Elsevier B.V. All rights reserved.

1. Introduction
Isotretinoin (Accutane) was approved for the treatment of
refractory severe nodular and cystic acne in 1982, and it is now
widely accepted as an efcacious medication for this condition.
Reports of serious psychiatric side effects appeared in the post
marketing literature soon after isotretinoin was introduced for
public use. These reactions included depressive symptoms,
suicidal ideation, suicidal attempts and completed suicide.
These reports resulted in a warning issued to physicians by
the FDA in 1998 regarding a possible association between
Corresponding author. 1455 34th Street, Sacramento, CA 95816, United
States. Tel.: +1 916 452 1504; fax: +1 916 452 8107.
E-mail address: schafferpsych@sbcglobal.net (L.C. Schaffer).
0165-0327/$ see front matter 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jad.2009.09.005

isotretinoin and depression, psychosis, suicidal ideation and

suicide (Lamberg, 1998). Critics of these studies state that they
are inconclusive because of deciencies in design and methodology, especially the lack of double-blind controlled investigations (although these would be considered unethical in this
patient population). Several useful review articles on this
subject have been published; the reader is referred to them
for a more detailed discussion of the multiple publications on
this topic (Enders and Enders, 2003; Hull and Demkiw-Bartel,
2000; Jacobs et al., 2001; Magin et al., 2005; Ng and Schweitzer,
2003; O'Donnell, 2003; Strahan and Raimer, 2006). These same
review articles also mention other studies that have failed to
incriminate isotretinoin as the cause of adverse psychiatric
reactions, as well as a few studies which claim that successful
treatment with isotretinoin may contribute to the improvement

L.C. Schaffer et al. / Journal of Affective Disorders 122 (2010) 306308

of preexisting psychiatric symptoms such as depression and

anxiety. However, most experts in this area believe that there is
enough evidence, especially from reports of patients who are
dechallenged and rechallenged with isotretinoin, to justify
inclusion of the possible risk of mood symptoms as part of the
informed consent process for patients who are considering
isotretinoin treatment.
There have been only three case reports of psychiatric reactions to isotretinoin in patients with known bipolar disorder
(BD). In 1988, Bigby described a BD patient taking lithium who
became suicidal after six and a half weeks of treatment with
isotretinoin (Bigby and Stern, 1988). In 2000, Cott provided a
detailed report of a patient with BD who experienced a
psychiatric reaction to isotretinoin. This patient developed
psychotic manic symptoms after four weeks of treatment with
isotretinoin, resulting in the addition of an antipsychotic to her
medication regime (Cott and Wisner, 1999). Van Broekhoven, in
2003, reported a case of a 22 year old male with known BD taking
isotretinoin who experienced depression and suicidal ideation.
He was admitted to a psychiatric hospital, where he committed
suicide (van Broekhoven et al., 2003). An additional study of 500
soldiers treated with isotretinoin for acne reported that ve of
these patients developed manic psychosis. Although none of
these ve patients had a previous history of BD, three of them had
a family history of BD in a rst degree relative (Barak et al., 2005).
The ndings from this study indicate that isotretinoin might
provoke bipolar symptoms in individuals who are predisposed to
BD. In this study, we will report the psychiatric reaction of a larger
sample of patients with BD during treatment with isotretinoin.
2. Methods
This study passed review by the Sutter Central Area
Institutional Review Committee. A retrospective review of charts
was conducted for 300 consecutive patients who have been
DSM-IV-TR diagnosed with any type of BD (APA, 2000). The
patients have been treated in a private outpatient practice
at some time during the past eleven years by two of the authors
(L.C.S. and C.B.S.), both board certied psychiatrists who have
specialized in the treatment of BD for over 25 years. The following
variables were assessed from the investigators' psychiatric
treatment records of patients who were treated either concurrently or at any time in the past by a dermatologist with isotretinoin for acne: age, gender, baseline mood symptoms,
psychiatric response to isotretinoin treatment, duration of isotretinoin use, concurrent psychiatric medication use, and intervention for psychiatric adverse effects.
The change in the patient's mood status associated with
taking isotretinoin was rated on the Clinical Global Impression
ScaleBipolar Version (CGI-BP) (Spearing et al., 1997). A
clinically signicant mood response to isotretinoin was dened
as a much worse or very much worse rating on the Change
Item (IIa) of the CGI-BP. Patient reports of increased suicidal
ideation in association with isotretinoin treatment were noted if
the patient reported thoughts of attempting suicide which were
not present before starting isotretinoin therapy.
3. Results
The results are summarized in Table 1. Ten BD patients
treated with isotretinoin were identied. Seven were adoles-

307

Table 1
Patient data and psychiatric reactions to isotretinoin.
Age Gender Psych Duration
meds a of use

Response

Suicidal Post
ideation isotretinoin
symptom
reversal

15
16
17
17

M
M
M
F

No
Yes
No
Yes

Mixed
Hypomanic
Mixed
Dep.

Yes
No
Yes
No

Yes
Yes
Yes
Yes

17

Yes

None

No

N/A

17

Yes

Mixed

No

Yes

19
26

F
F

Yes
Yes

Mixed
Mixed

Yes
No

No
Yes

37

Yes

Dep.

No

Yes

39

Yes

Mixed

No

Yes

a
b

4 weeks
10 weeks
4 weeks
Complete
course b
Complete
course
Complete
course
4 weeks
Complete
course
Complete
course
8 weeks

Concurrent psychiatric medications.

The duration of a complete course of isotretinoin is 1520 weeks.

cents at the time of the isotretinoin treatment, and the gender

ratio was equal. The age range was 15 to 39. Nine of the
patients experienced an exacerbation of mood symptoms
while taking isotretinoin compared to baseline. Of these nine,
six had mixed symptoms, two had depressive symptoms and
one had hypomanic symptoms. Three experienced suicidal
ideation, but none of the patients attempted suicide. None
reported or demonstrated psychotic symptoms. Four of the
nine symptomatic patients completed the full course (15 to
20 weeks) of isotretinoin treatment, and ve had to discontinue prematurely because of the psychiatric adverse effects.
All four of the patients who completed an isotretinoin course
had rapid clinical improvement following discontinuation of
isotretinoin. Four of the ve who discontinued isotretinoin
early experienced a prompt reversal of the aggravated mood
symptoms upon discontinuation of isotretinoin. Seven of the
nine isotretinoin-treated patients who experienced exacerbation of their mood symptoms were taking maintenance
psychiatric medications for BD at the time of the apparent
reaction.
4. Discussion
The results of this study indicate that treatment for acne
with isotretinoin can be associated with worsening of mood
symptoms, including suicidal ideation, in some patients with
BD. Mood response in this situation can include predominantly
mixed symptoms, depressive symptoms or hypomanic symptoms. In most cases the exacerbation of mood symptoms
associated with isotretinoin was reversed when the isotretinoin
was discontinued. Concurrent use of psychiatric medicines for
BD was not always protective against these adverse effects of
isotretinoin.
The clinical implications of this study are especially relevant
to the treatment of patients with BD for two additional reasons
which are unique to this patient population. First, the symptoms
of BD usually become apparent during teenage years or early
adulthood, and acne often appears during the same

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L.C. Schaffer et al. / Journal of Affective Disorders 122 (2010) 306308

developmental era. Secondly, lithium is considered the medication of rst choice for many patients with BD, especially for a
hypomanic or manic episode, and acne is not an uncommon
side effect of lithium (33%) (Chan et al, 2000).
This study has some limitations. The sample size, although
larger than the three previous case reports for BD patients treated
with isotretinoin, is small. The subjects were being treated in a
private outpatient psychiatric practice, and a similar study using a
different population of BD patients might produce different
results. The collection of data was done retrospectively and not
prospectively. Specic symptom rating scales were not utilized.
The validity of our ndings cannot be denitively conrmed in
the absence of a double-blind placebo controlled design. Patients
with BD can experience spontaneous relapses of mood symptoms, and this phenomenon could have been mistaken for
isotretinoin induced relapse in this study. It should be noted,
however, that eight of the nine symptomatic patients experienced a prompt reversal of the relapsed mood symptoms when
the isotretinoin was discontinued prematurely or after a full
course.
The mechanism of action to explain the induction of new
mood symptoms or worsening of preexisting mood symptoms
in patients with mood disorders such as BD has yet to be
determined. Isotretinoin is a retinoid, which is a derivative of
Vitamin A, and there have been case reports of untoward
psychiatric reactions, including manic type symptoms, in
patients who have taken high doses of Vitamin A (Restak,
1972). A recent study using positron emission tomography in
nonpsychiatric patients taking isotretinoin for acne reported
that isotretinoin, but not antibiotic treatment, was associated
with decreased brain metabolism in the orbitofrontal cortex,
which is a brain area known to mediate symptoms of depression
(Bremner et al., 2005). Similar studies using neuroimaging
techniques to study BD patients during isotretinoin treatment
may provide useful information to advance our understanding
of the biological basis for psychiatric reactions to isotretinoin.
Role of funding source
No grants, individual or industry support was provided to any of the
authors related to this study.
Conict of interest
All authors declare that they have no actual or potential conicts of
interest.

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