Cutaneous adverse reaction during lithium treatment: a case report and updated systematic review with meta-analysis
Pinna et al. Int J Bipolar Disord
Cutaneous adverse reaction during lithium treatment: a case report and updated systematic review with meta-analysis
Martina Pinna 2
Mirko Manchia 0 1
Sergio Puddu 6
Giampaolo Minnai 2
Leonardo Tondo 3 4 5
Piergiorgio Salis 2
0 Section of Psychiatry, Department of Medical Science and Public Health, University of Cagliari , Via Liguria, 13, 09127 Cagliari, Sardinia , Italy
1 Department of Pharmacology, Dalhousie University , Halifax, NS , Canada
2 Psychiatry Unit, San Martino Hospital-Regional Health Agency , Oristano, Sardinia , Italy
3 Lucio Bini Mood Disorders Centers , Cagliari and Rome , Italy
4 The International Consortium for Mood & Psychotic Disorders Research, McLean Hospital , Belmont, MA , USA
5 Department of Psychiatry, Harvard Medical School , Boston, MA , USA
6 Regional Health Agency, National Health System , Oristano, Sardinia , Italy
Objectives: To present a new case of adverse cutaneous reaction during lithium treatment and to update the systematic review and meta-analysis of the incidence of this adverse reaction. Methods: We conducted a systematic search (performed in September 2016) for peer-reviewed articles in English indexed in Medline (2011-present). Meta-analytical estimates were obtained using the “Metafor” package. Case presentation: Ms. H., a 31-year-old Caucasian woman with BD1, was admitted to the inpatient unit for a full-blown psychotic episode and treated with carbamazepine 400 mg q.d., lithium carbonate 450 mg q.d., and risperidone 4 mg q.d. with clinical improvement. After 12 days from the start of psychopharmacological treatment, she manifested a cutaneous reaction that motivated the stop of carbamazepine treatment, as well as the increase in lithium carbonate dose (750 mg q.d.). Risperidone dose remained unvaried. Since the skin lesion persisted after 8 days from withdrawal of carbamazepine, the private practitioner stopped also lithium carbonate treatment (de-challenge), maintaining risperidone treatment. The cutaneous reaction resolved spontaneously after six days from withdrawal of lithium carbonate. Subsequently, the worsening of psychopathological conditions motivated a new admission during which lithium carbonate was reintroduced (16 days after its suspension) (re-challenge). On the following day, we observed an itching erythematous maculopapular rash involving the trunk, the four limbs, and the oral mucosa. Conclusions: Our case of an erythematous maculopapular rash during lithium treatment was the first to present a challenge-de-challenge-re-challenge sequence that suggests causality. Although meta-analysis does not point to an increased rate of adverse skin reaction during lithium treatment, clinicians should not neglect to monitor cutaneous symptoms during lithium treatment.
Skin disorders; Bipolar disorder; Long-term treatment
Lithium remains the mainstay for the treatment and
prevention of mood episodes in bipolar disorder (BD)
(Yatham et al. 2013)
. Its prophylactic effectiveness has
been demonstrated by naturalistic observational studies
which showed that approximately one-third of
lithiumtreated BD patients achieve full symptomatic remission
(Garnham et al. 2007; Baldessarini and Tondo 2000)
that this pattern of clinical response remains stable in the
(Berghofer et al. 2013)
However, the effectiveness of lithium should be
weighed against its side effect profile that might limit its
acceptability by patients
(McKnight et al. 2012)
it is well established that lithium treatment can impact
kidney, thyroid, and parathyroid function
et al. 2012)
. A degree of uncertainty remains, however,
on whether lithium, during short- and long-term
treatment, is associated with the manifestation of cutaneous
adverse reactions. Although quantitative meta-analytical
estimates did not show an increased rate of skin
disorders in lithium-treated patients compared to those given
(McKnight et al. 2012)
, there is substantial
anecdotic evidence supporting this association. Indeed, some
authors indicated that the rate of cutaneous adverse
reactions during lithium maintenance therapy might be as
high as 45%
. Here, firstly we presented
a new case of adverse cutaneous reaction during lithium
treatment, confirmed by a re-challenge of the drug after
its discontinuation. We then updated the study of
McKnight et al. (2012) which systematically reviewed and
performed data synthesis of pertinent literature published
(McKnight et al. 2012)
Ms. H., a 31-year-old Caucasian woman with BD1, was
voluntarily admitted to the psychiatric ward of the San
Martino Hospital of Oristano, Sardinia, Italy for a manic
episode with mood-congruent psychotic features
according to the Diagnostic and Statistical Manual of Mental
Disorders-5 (DSM-5) criteria.
The family history of Ms. H. was positive for mood
disorders: her father was diagnosed with BD1 and her
paternal grandmother with mood disorder not otherwise
specified (NOS). Her premorbid personality had been
characterized by cyclothymic temperament and rejection
sensitivity. Her first illness episode presented at 21 years
in concomitance with the end of a romantic
relationship. Specifically, she developed depressed mood, social
withdrawal, and persecutory delusion for which she was
treated with unspecified psychopharmacological
treatment. At the age of 24, during a euthymic phase, and in
the absence of pharmacological treatment, she started
presenting somatic symptoms (abdominal pain, change
in bowel habits, and bloating) after a surgical operation
for ovarian cyst removal. Around the same time, she
experienced marked anxiety, ruminations, and social
discomfort with subsequent social withdrawal. Treatment
with selective serotonin reuptake inhibitors (SSRI) was
started with clinical remission.
Although in the following years the patient had a good
social and work functioning, several residual
psychopathological symptoms remained, including mood
fluctuations, hypochondriac thoughts and behaviors, marked
anxiety, and dietary restraint with weight loss aimed at
facilitating control of bowel function. The absence of a
complete clinical remission was partially due to the lack
of compliance to clinical monitoring and
psychopharmacological treatment. The progressive increase in the
severity of these psychopathological symptoms led to
manifestation of a full-blown psychotic episode in early
2016. This clinical picture motivated a 1-week admission
at the end of March 2016 at the acute inpatient
psychiatric unit in Pisa, Italy, where she was started on
carbamazepine 400 mg q.d., lithium carbonate 450 mg q.d.,
and risperidone 4 mg q.d., which led to substantial
clinical improvement. Laboratory workup, including thyroid
function parameters, was normal. After discharge from
hospital, she moved to Sardinia and was seen by a
private practitioner for follow-up visits. After 12 days from
the start of psychopharmacological treatment, she
manifested a cutaneous reaction that motivated the stop of
carbamazepine treatment, as well as the increase in
lithium carbonate dose (750 mg q.d.) (challenge phase).
Risperidone dose remained unvaried. Since the skin lesion
persisted after 8 days from withdrawal of carbamazepine,
the private practitioner stopped also lithium
carbonate treatment (de-challenge), maintaining risperidone
treatment. The cutaneous reaction resolved
spontaneously after 6 days from withdrawal of lithium carbonate.
On May 2016 after the manifestation of marked
anxiety, flight of ideas, pressured speech, decreased ability
to concentrate, insomnia, and persecutory delusions,
she came to our attention and was admitted at our unit
where lithium carbonate was reintroduced (16 days after
its suspension) (re-challenge). On the following day, we
observed an itching erythematous maculopapular rash
involving the trunk, the four limbs, and the oral mucosa.
The dermatologist consultation indicated the presence
of: “a drug-induced toxic reaction, characterized
morphologically by eruption of a large number of
erythematous macules of varying size, mostly with papules, which
became confluent and itching. It is observable also a
palmoplantar eruption of pale erythematous macular lesions
with scarlatiniform characteristics”. Lithium
carbonate was immediately stopped with resolution of the skin
lesion on the subsequent day. This severe adverse
reaction was described and sent to the Sardinian Regional
Centre of Pharmacovigilance. Their assessment with the
(Naranjo et al. 1981)
relationship between the cutaneous adverse reaction and
the use of lithium as “probable.”
Systematic review and meta‑analysis
To update the study of McKnight et al. (2012), we
conducted a systematic search (performed in September
2016) for peer-reviewed articles in English indexed in
Medline (2011-present). The terms used for the
electronic database search were: lithium AND (skin OR
dermatology OR cutaneous side effects OR psoriasis
OR rash OR Stevens-Johnson syndrome). Studies were
included if they reported on adverse cutaneous reaction
during lithium treatment. Data on cutaneous adverse
reactions in published or unpublished randomized
clinical trials (RCTs) since 2011, comparing lithium (as
monotherapy or add-on) with placebo or other
pharmacological treatments, were extracted from ClinicalTrials.
gov, which is a database of publicly and privately
supported clinical studies of human participants conducted
around the world (www.ClinicalTrials.gov).
Meta-analytical estimates were obtained using the “Metafor” package
. Since adverse cutaneous reactions in
the included clinical trials comparing lithium with
placebo were very rare, we used the Peto odds ratio (OR)
Our systematic search found 93 studies indexed in
Medline. We also found 28 clinical trials including one
previous study examined in the meta-analysis of
McKnight et al. (2012). The review process is summarized
in Fig. 1 according to the preferred reporting items
for systematic reviews and meta-analyses (PRISMA)
(Moher et al. 2009)
. Five of the studies indexed in
Medline met inclusion criteria for the qualitative synthesis:
four were case reports and one was an observational
case/control study (Table 1). The four case reports
presented a varying spectrum of skin disorders
associated with lithium treatment. Specifically,
et al. (2012
) reported on a 55-year-old male affected
by psychosis who developed psoriasis verrucosa, a rare
and atypical form of psoriasis. Although the patient
improved after treatment with adalimumab, a tumor
necrosis factor-alpha (TNF-α) inhibitor, it was not
specified whether an attempt was made to discontinue
lithium in order to observe a decrease in the severity of
The case described by
Wang and Yang (2013)
concerned a 37-year-old BD1 woman who presented a
nonitching, erythematous, maculopapular rash after the
start of therapy with lithium 900 mg q.d. which resolved
spontaneously after its discontinuation. Further,
and Arunachalam (2013)
reported on the manifestation
of facial acne in a 40-year-old woman after 4 months of
treatment. Again, the skin lesion completely resolved
after treatment discontinuation. Finally, Bugueno et al.
(2013) described the onset of an oral lichenoid mucosal
lesion in concomitance with the initiation of the
treatment in a 25-year-old BD female patient. Complete
resolution of the skin lesion was observed after
discontinuation of lithium. The large observational case-control
Spoendlin et al. (2014
) interestingly found that
lithium treatment was associated with a decreased risk of
Data on cutaneous adverse reactions were extracted for
meta-analysis from three clinical trials:
Goodwin et al.
Geller et al. (2012
), and NTC01189812 (Table 2).
The first study was also included in the meta-analysis
of McKnight et al. (2012). Meta-analysis did not show
a significant difference in the rate of cutaneous adverse
reaction between lithium- and placebo-treated patients
(Peto OR 1.14, 95% [Confidence Interval (CI) 0.44–2.94],
P = 0.78; heterogeneity Q = 0.92, P = 0.34), as well as
between those treated with lithium or with other
treatments (OR 0.61, [95% CI 0.34–1.11], P = 0.11;
heterogeneity Q = 0.91, P = 0.63).
Discussion and conclusion
We presented a case of a diffuse erythematous
maculopapular rash during lithium treatment in a 31-year-old
woman with BD1. This observation adds to the limited
anecdotal literature on adverse cutaneous reaction
during lithium treatment. The manifestation of the lesion
appeared similar to that described in previous reports
(Swartz and Holkesvick 1981; Wang and Yang 2013)
However, differently from most of previously published
reports, our clinical case strongly suggests causality
between the use of lithium and the onset of the skin
reaction, particularly in light of the reoccurrence of the
maculopapular rash following drug re-challenge.
BD bipolar disorder, BD1 bipolar disorder type 1, NA: not available, C–D–R challenge–de-challenge–re-challenge, C–D challenge–de-challenge
NA not available, BD bipolar disorder, BD1 bipolar disorder type 1, MDD major depressive disorder, DNOS depression not otherwise specified, BPD borderline
One could argue that the use of carbamazepine could
be related to the manifestation of the skin reaction.
However, the maculopapular rash persisted 8 days after
discontinuation of carbamazepine and it is unlikely
that the drug might have remained in the bloodstream
for such a time given that its half-life should have been
around 10–20 h after 8 weeks of treatment
. Further, cross-reactivity, which is common for
adverse skin reactions with carbamazepine and
chemically related drugs, should be excluded since lithium does
not have any similarity with the aromatic structure of
One final comment is needed on the findings of our
meta-analysis. We confirmed that the evidence so far
available does not point to an association between
lithium treatment and cutaneous adverse reaction. These
findings should be reconciled, however, with the
recurrent manifestation of these events in lithium-treated
patients. One possible explanation is that the incidence
rate of these events is quite heterogeneous, with
estimates ranging from 3.4 to 45%
Therefore, the probability of observing an adverse cutaneous
reaction during lithium treatment depends on the design
of the clinical trial (duration of follow-up, inclusion
criteria, method of assessment of adverse reactions) as well
as on the characteristics of the patients included (type of
diagnosis, presence and duration of lithium treatment
before the start of the clinical trial, pre-existing allergic
diathesis, history of psoriasis). It is conceivable that large
registry study might be more suitable to the task of
quantifying the incidence of this adverse reaction of lithium.
In conclusion, we presented a case of an erythematous
maculopapular rash during lithium treatment. Although
this type of skin reaction has been reported previously
in the literature, our case is the first to present a
challenge–de-challenge–re-challenge sequence that suggests
causality. Although meta-analysis does not point to an
increased rate of adverse skin reaction during lithium
treatment, clinicians should not neglect to monitor
cutaneous symptoms, particularly in BD patients at high risk,
such as those with an allergic diathesis.
BD: bipolar disorder; BD1: bipolar disorder type 1; DSM-5: diagnostic and
statistical manual of mental disorders-5; SSRI: selective serotonin reuptake
inhibitors; OR: odds ratio; CI: confidence interval; RCTs: randomized clinical trials.
MP wrote the first draft of the manuscript; MM critically revised the
manuscript and performed the systematic search and meta-analysis; LT oversaw the
meta-analysis and critically revised the paper; SP performed the
dermatological consultation and critically revised the manuscript; PS and GM contributed
to interpretation of data and critically revised the manuscript. All authors read
and approved the final manuscript.
Part of this work was presented at the 30th International Group for The Study
of Lithium Treated Patients held in Cagliari, Italy from September 29th to
October 2nd 2016.
The authors declare that they have no competing interests.
Consent for publication
The patient provided written and verbal consent to current case study
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