GRAND ROUND
Oral Aripiprazole-Induced Severe Hypoglycemia
Somnath Mondal, MPharm,* Indranil Saha, MD, Saibal Das, MBBS, Abhrajit Ganguly, MBBS,
Abhinaba Ghosh, MBBS, and Akhila Kumar Das, MPharm
Abstract: This case report highlights a very rare adverse drug
reaction caused by oral aripiprazole resulting in severe hypoglyce-
mia. A 72-year-old-male patient suffering from Parkinson disease on
prolonged carbidopa plus levodopa combination therapy (carbidopa
25 mg plus levodopa 100 mg, thrice daily) for 1.3 years was recently
diagnosed with psychosis and was initiated 10 mg/day oral aripipra-
zole. After 10 days of aripiprazole therapy, the patient experienced
symptoms of hypoglycemia and on the 21st day, he was hospitalized
for severe hypoglycemia. Other long-term concomitant medications
taken by this patient were oral losartan (25 mg/day) and rosuvastatin
(40 mg/day). Dechallenge and rechallenge with aripiprazole revealed
that there is a denite (according to Naranjo adverse drug reaction
probability scale) relationship between administration of aripiprazole
and onset of hypoglycemic events.
Key Words: psychosis, aripiprazole, hypoglycemia, atypical anti-
psychotic agent
(Ther Drug Monit 2012;34:245248)
CLINICIAN
A 72-year-male patient suffering from Parkinson dis-
ease was on carbidopa plus levodopa combination therapy
(carbidopa 25 mg plus levodopa 100 mg, thrice daily) for 1.3
years. Recently he was also found to suffer also from psy-
chosis, for which he was prescribed 10 mg/day of oral aripi-
prazole. Before initiation of aripiprazole therapy, his blood
glucose levels were as follows:
1. Fasting blood glucose: 106 mg/dL (5.89 mmol/L) [nor-
mal range: 75110 mg/dL (4.26.1 mmol/L)]
2. Two hours postprandial blood glucose: 116 mg/dL
(6.44 mmol/L) [normal range: 70120 mg/dL (3.9
6.7 mmol/L)]
Other biochemical parameters including liver function
tests, lipid prole, and thyroid function tests were well within
normal limits.
Received for publication January 16, 2012; accepted March 13, 2012.
From the *Department of Clinical and Experimental Pharmacology, Calcutta
School of Tropical Medicine, Kolkata, India; Department of Psychiatry,
Medical College Kolkata, Kolkata, India; General Emergency, NRS Medical
College and Hospital, Kolkata, India; NRS Medical College and Hospital,
Kolkata, India; and Department of Pharmacology, RG Kar Medical College
and Hospital, Kolkata, India.
This is an honest original work. Ethical guidelines have been followed. There
are neither nancial interests nor any conict of interests from the part of
the contributing authors. No funding was received for this work.
Correspondence: Dr. Saibal Das, MBBS, 14 Kabi Sukanta Lane, P.O.
Santoshpur, Kolkata 700 075, India (e-mail: saibaldas123@gmail.com).
Copyright 2012 by Lippincott Williams & Wilkins
Ther Drug Monit  Volume 34, Number 3, June 2012
After 10 days of aripiprazole therapy, the patient
experienced some nonspecic behavioral changes along
with generalized weakness, fatigue, anxiety, and palpitation.
These symptoms gradually progressed, and on the 21st day
the patient suddenly developed severe confusion, palpita-
tion, sweating, hunger, paresthesia, and sudden loss of
consciousness with no chest pain. The patient was immedi-
ately hospitalized.
Physical examination of the patient revealed pallor, a
pulse rate of 120/minute and a blood pressure of 146/90 mm
of Hg. Further investigation revealed the following:
A. Blood:
1. Hemoglobin 11.8 g/dL
2. Random blood glucose: 46 mg/dL (2.56 mmol/L)
3. Serum urea: 15.2 mg/dL
4. Serum creatinine: 0.76 ng/mL
5. Serum sodium: 139 meq/L
6. Serum potassium: 4.6 meq/L
7. Serum calcium: 9.2 mg/dL
B. Twelve-lead electrocardiography: Tachycardia and non-
specic T-wave attening in leads V3 and V5. No
evidence of ischemia was found.
C. Noncontrast computed tomographic (CT) brain scan: mild
cortical atrophy. No other abnormalities.
The patient was diagnosed with severe hypoglycemia
and was infused with 25 g intravenous glucose followed by 2
bottles (each containing 500 mL) of 25% dextrose infusion.
His condition improved immediately after he was given
oral uids containing glucose and fruit juices. His blood
glucose level after the resuscitation effort was 130 mg/dL
(7.22 mmol/L). His condition was further stabilized and was
discharged after 2 days with the following:
1. Fasting blood glucose 111 mg/dL (6.17 mmol/L)
2. Two hours postprandial blood glucose: 120 mg/dL
(6.67 mmol/L)
TDM CONSULTANT
Aripiprazole is an atypical antipsychotic agent widely
used in psychosis.1 It seems from the neuroglycopenic
(adrenergic and cholinergic) symptoms2 and blood investi-
gation reports that after taking aripiprazole, the patient had
progressive hypoglycemia terminating in a hypoglycemic
attack, which might have been drug induced. The electro-
cardiogram changes were also compatible with a hypoglyce-
mic episode.3 Mild cortical atrophy in the CT scan was most
likely due to senile atrophy and existing Parkinson disease.4
What may be the cause of this sudden onset of hypoglyce-
mia in this patient?
245
Mondal et al
CLINICIAN
The patient was a nonsmoker, nonalcoholic, non-
diabetic, and there was no family history of diabetes either,
and there was no indication that he was taking any
antidiabetic medications. The patient was on a regular diet
with no known episodes of fasting and was not subjected
to any unaccustomed physical activities. His renal function
tests were normal. There were no known episodes
of reactive (postprandial) hypoglycemia in this patient
since childhood. He had no other illnesses, such as renal,
hepatic or cardiac failure, or sepsis. There was no evidence
of b cell or nonb cell tumor found in the CT scan of the
abdomen.
Hormonal assays revealed the following results:
1. Glucagon: 53 pg/mL (normal range: 20200 pg/mL)
2. Growth hormone: 2.3 ng/mL (normal range: 0.5
17.0 ng/mL)
3. Fasting cortisol (at 8 AM): 17 mg/dL (normal range:
525 mg/dL)
Since there do not seem to be any organic causes, the
hypoglycemia was likely drug induced.
TDM CONSULTANT
What other concomitant medications was the patient
taking?
CLINICIAN
The patient was previously diagnosed with hyper-
tension and has been on low dose oral losartan (25 mg/day)
for the last 2 years. His blood pressure has been well
controlled ever since. The patient was also diagnosed with
hyperlipidemia 2 years ago and has been taking oral
rosuvastatin (40 mg/day) since then. Now he has a normal
lipid prole.
TDM CONSULTANT
So the patient was on 4 oral medications:
1. Oral losartan (25 mg/day) for last 2 years
2. Oral rosuvastatin (40 mg/day) for last 2 years
3. Oral carbidopa plus levodopa combination (carbi-
dopa 25 mg plus levodopa 100 mg, thrice daily) for
last 1.3 years
4. Oral aripiprazole (10 mg/day) for 21 days
There may be a risk of drug interactions when
different drugs are used concomitantly. However, there have
been no known interactions with any of these drugs taken by
the patient. Aripiprazole at very low doses is effective in
treating dyskinesia induced by prolonged treatment with
levodopa in patients with Parkinson disease.5 There is no
conclusive adverse report of rosuvastatin causing hypogly-
cemia. Losartan can attenuate symptomatic and hormonal
responses to hypoglycemia in humans.6 There are no known
interactions between rosuvastatin and losartan,7 rather a syn-
ergistic protective effect of losartan and rosuvastatin were
found in vascular injury, mediated by cuff-induced neointi-
mal hyperplasia.8
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Ther Drug Monit  Volume 34, Number 3, June 2012
How was aripiprazole determined to be the cause of
severe hypoglycemia?
CLINICIAN
The patient was treated with rosuvastatin, losartan, and
carbidopa plus levodopa combination for a considerable
period of time and his glycemic status was well within
normal limits, as demonstrated by the regular monitoring of
his blood glucose levels for the last 2 years, so we suspected
aripiprazole as the offending drug.
So, aripiprazole was withdrawn (dechallenge) and the
other drugs were continued for 2 weeks and the patient did
not experience any hypoglycemic symptoms. His glycemic
status then was assessed and found to be normal:
1. Fasting blood glucose 100 mg/dL (5.56 mmol/L)
2. Two hours postprandial blood glucose: 118 mg/dL
(6.56 mmol/L)
The patient was rechallenged with a reduced dose
(5 mg/day) of oral aripiprazole. Other drugs were continued
as usual. After 6 days of therapy, the patient started to
re-experience symptoms of hypoglycemia and on the seventh
day his glycemic status was as follows:
1. Fasting blood glucose 62 mg/dL (3.44mmol/L)
2. 2 hours postprandial blood glucose: 71 mg/dL
(3.94 mmol/L)
Aripiprazole was immediately discontinued, and the
patient was treated with oral glucose. After 7 days of stopping
aripiprazole, and continuing the other drugs, his hypoglyce-
mic symptoms disappeared and glycemic status reverted back
to normal as follows:
1. Fasting blood glucose 102 mg/dL (5.67 mmol/L)
2. Two hours postprandial blood glucose: 115 mg/dL
(6.39 mmol/L)
The patient is now being treated with oral olanzapine
10 mg daily for psychosis.
TDM CONSULTANT
After excluding other attributable factors for hypoglyce-
mia such as drug interactions, ethanol ingestion, neoplasm, and
liver diseases, aripiprazole was suspected to be the offending
drug. Naranjo adverse drug reaction probability scale9 suggests
that there is a denite relationship between administration of
aripiprazole and onset of hypoglycemic events. This is proba-
bly the rst reported case report of oral aripiprazole induced
severe hypoglycemia.
Further, a MEDLINE search yielded no reports of sig-
nicant drug interactions between aripiprazole and patients
concomitant medications that could have resulted in hypogly-
cemia. Neither any pharmacodynamic interactions have been
found as a potential cause for the same.
Metabolic abnormalities have been associated with
schizophrenia since long before the era of antipsychotic
medications.10 The recent introduction of newer congeners
of atypical antipsychotics and their possible association
with the metabolic abnormalities such as weight gain,
hyperglycemia, and hypertriglyceridemia are of major
concern owing to the additive effect on morbidity and
2012 Lippincott Williams & Wilkins
Ther Drug Monit  Volume 34, Number 3, June 2012
mortality in a population with already increased prevalence
of obesity, type 2 diabetes mellitus, and cardiovascular
disease.1113
The exact mechanism of how atypical antipsychotics
promote the development of hyperglycemia and diabetes is
unknown. The development of diabetes and resultant hyper-
glycemia, however, is likely a complex interplay of the
atypical antipsychotics likelihood of promoting weight gain
(eg, olanzapine and clozapine) through the involvement of
multiple mechanisms. These mechanisms involve, but are
not limited to, antagonism at 5-HT receptors (serotonin recep-
tors) mainly involving 5-HT2C, which is involved in regula-
tion of food intake; antagonism at central histamine H1
receptors; development of insulin resistance through effects
on cellular glucose transporters; compromised insulin secre-
tion; and alterations in leptin levels.1416 Sympathetic activa-
tion by second-generation antipsychotics in a mouse study
seemed to promote hyperglycemia.16
Extensive literature survey on metabolic impact sug-
gests favorable metabolic prole of aripiprazole both on
glucose homeostasis and serum lipids over other second-
generation atypical antipsychotics. However, 2 cases of
diabetic ketoacidosis were reported in people with schizo-
phrenia after starting aripiprazole.1719
A 33-year-old male with schizophrenia presented with
fatigue, dyspepsia, and epigastric pain. The patient was found
to have hyperglycemia, diabetic ketoacidosis, and hyper-
lipasemia. The patient was started on aripiprazole treatment
18 months before this episode and had progressive weight
gain since then. Imaging studies of the pancreas were normal
and work up for other causes of pancreatitis was negative.19 In
another case report, 3 patients schizophrenic patients suffered
second-generation antipsychotics-induced hypoglycemia.
Interestingly, case 2 was co-prescribed aripiprazole in
response to the hypoglycemic episode.20
Aripiprazole-induced hypoglycemia had also been de-
scribed in a case report of a patient who developed type-2
diabetes mellitus while on second-generation antipsychotic
treatment. When admitted to hospital, he was switched from
olanzapine/risperidone combination therapy to aripiprazole
and suffered hypoglycemic episodes. Antidiabetic treatment
was stopped although on aripiprazole, and blood glucose was
stabilized.21
So, although, hyperglycemia or diabetes mellitus is
more expected with these drugs, it is indeed paradoxical in
this case, that aripiprazole has caused hypoglycemic episodes.
The cause of hypoglycemic episode due to aripiprazole in this
patient of discussion could be multifactorial in origin,
involving lowered energy reservoir, failed glucose homeosta-
sis (hypoglycemic unawareness and blunt counter regulatory
responses), and a probable direct glucose-lowering effect of
aripiprazole. These, obviously, are few hypotheses that
require further investigations and studies.
The exact insight of the increased risk for metabolic
abnormalities is uncertain, but their prevalence must be corre-
lated as hypoglycemia is a serious medical condition and can
cause serious medical condition like seizures, permanent
neurological damage, or even serious morbidity.2 The likeli-
hood of developing severe metabolic disease should also be
2012 Lippincott Williams & Wilkins
Aripiprazole-Induced Severe Hypoglycemia
an important consideration. When prescribing aripiprazole, a
commitment to baseline screening and follow-up monitoring
is essential to mitigate the likelihood of developing either
hypoglycemia or hyperglycemia and their associated
complication.
Clinical adverse events from aripiprazole-induced
hypoglycemia in psychotic patient alone or in combination
with any other oral hypoglycemic agent or any other
drugs with potential of causing hypoglycemia remain an
issue with spontaneity and lack of predictability. Until more
clinical information becomes available in this matter, close
unlimited active observation by physicians and health care
professionals are warranted with the use of aripiprazole.
Physicians should keep this rare adverse drug reaction
in mind when prescribing this drug. Also patients taking this
drug should be made aware of the symptoms of hypoglycemia
and their blood glucose level should be monitored regularly if
they exhibit such symptoms. There should be provisions for
early withdrawal of aripiprazole, and emergency oral or
intravenous glucose or dextrose should be administered to
prevent and treat a hypoglycemic episode.
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