Hypoglycaemia induced by second generation antipsychotic agents in schizophrenic non-diabetic patientsBMJ 2009; 338 doi: https://doi.org/10.1136/bmj.a1792 (Published 26 May 2009) Cite this as: BMJ 2009;338:a1792
All rapid responses
We have read the letter by Suzuki and colleagues (1) with great
interest. It describes another potential metabolic complication in
patients with schizophrenia who are treated with a second-generation
antipsychotic, in addition to an increased risk for hyperglycemia
associated with the use of some second-generation antipsychotics (e.g. see
(2)). The letter concerns three cases of suspected reactive hypoglycemia
in whom the diagnosis was made based on symptomatology suggestive of
hypoglycemia and a demonstration of a glucose level below 3.9 mmol/l after
two hours in a 75 gram oral glucose tolerance test (OGTT). The letter
raises two important questions: 1) is there evidence for an increased
prevalence of reactive hypoglycemia in patients with schizophrenia?, and
2) do second-generation antipsychotics induce reactive hypoglycemia?
As of 2003, we have tested all patients treated with antipsychotic
medication in follow-up at the University Psychiatric Centre of the
University of Louvain (Belgium) using a standard protocol including an
OGTT (3, 4). As such, our data may help to examine the above questions. In
a sample of 707 non-diabetic patients with severe mental illness (SMI)
screened for metabolic disturbances, 2223 OGTTs were conducted over the
course of a 4-year period (November 2003 – July 2007). Of these patients,
503 were diagnosed with schizophrenia, 92 with schizoaffective disorder
and 112 with bipolar disorder (see (5) for an extensive description of
recruitment and screening procedures). The number of patients having a
glucose level below 3.9 mmol/l in any of the 2223 OGTTs was 19.2%; 10.6%
had a glucose level between 3.9 and 3.3 mmol/l, 5.9% had a glucose level
between 3.3 and 2.8 mmol/l and 2.7% had severe hypoglycemia, defined as a
glucose level below 2.8 mmol/l at 120 minutes. Using multilevel regression
to investigate predictors of hypoglycemia at 120 minutes in the OGTT using
a three-stage cut-off (‘0’: >3.9 mmol/l, ‘1’: <_3.9 and="and"/>3.3
mmol/l, ‘2’: <_3.3 and="and"/>2.8 mmol/l, ‘3’: <_2.8 mmol="mmol" l="l" we="we" found="found" that="that" neither="neither" insulin="insulin" resistance="resistance" homa-ir="homa-ir" type="type" of="of" antipsychotic="antipsychotic" medication="medication" diagnosis="diagnosis" age="age" race="race" or="or" sex="sex" was="was" associated="associated" with="with" an="an" increased="increased" risk="risk" for="for" hypoglycemia.="hypoglycemia." the="the" hypoglycemia="hypoglycemia" negatively="negatively" fasting="fasting" glucose="glucose" levels="levels" â="-0.28," se="se" _0.002="_0.002" p="p" _0.003="_0.003" p0.001="p0.001" bmi="bmi" _0.005="_0.005" and="and" a="a" worse="worse" overall="overall" metabolic="metabolic" profile="profile" as="as" indicated="indicated" by="by" presence="presence" syndrome="syndrome" according="according" to="to" adapted="adapted" atp="atp" iii="iii" criteria="criteria" _0.06="_0.06" in="in" multivariate="multivariate" regression="regression" models="models" covarying="covarying" diagnosis.="diagnosis."/> It is important to note that none of the patients presenting with a
glucose level below 3.9 mmol/l had previously received a diagnosis of
reactive hypoglycemia or had issued complaints possibly relating to
hypoglycemia prior to the OGTT. In interpreting these data therefore,
prevalence rates of hypoglycemia in asymptomatic healthy individuals need
to be considered. For example, Fariss and colleagues found that 7.4% of
military draftees had a 2-hour post-load glycemia below 2.7 mmol/l in an
OGTT (6). Occasionally, values as low as 1.9 mmol/l are found in
asymptomatic healthy individuals during the course of an OGTT (7).
Although we did not recruit a healthy control group, these data in healthy
individuals suggest that the prevalence of hypoglycemia in our sample of
707 patients with SMI was not unusually high. In addition, we were unable
to confirm that (certain) second-generation antipsychotics induce reactive
hypoglycemia, as was provocatively suggested by Suzuki and colleagues.
This is in line with the clinical description of two of the three cases,
in whom mild hypoglycemia persisted after antipsychotic medication was
changed. Thus, the data leave open the possibility that second-generation
antipsychotics aggravate pre-existing (mild) reactive hypoglycemia, but
the examination of more than 2000 OGTTs indicates that there is little
evidence to suggest these agents actually induce reactive hypoglycemia in
The authors declare they do not have competing interests.
1. Suzuki Y, Watanabe J, Fukui N, Ozdemir V, Someya T. Hypoglycaemia
induced by second generation antipsychotic agents in schizophrenic non-
diabetic patients. BMJ 2009;338:a1792.
2. van Winkel R, De Hert M, Wampers M, Van Eyck D, Hanssens L, Scheen A,
et al. Major changes in glucose metabolism, including new-onset diabetes,
within 3 months after initiation of or switch to atypical antipsychotic
medication in patients with schizophrenia and schizoaffective disorder. J
Clin Psychiatry 2008;69(3):472-9.
3. De Hert MA, van Winkel R, Van Eyck D, Hanssens L, Wampers M, Scheen A,
et al. Prevalence of the metabolic syndrome in patients with schizophrenia
treated with antipsychotic medication. Schizophr Res 2006;83(1):87-93.
4. van Winkel R, De Hert M, Van Eyck D, Hanssens L, Wampers M, Scheen A,
et al. Screening for diabetes and other metabolic abnormalities in
patients with schizophrenia and schizoaffective disorder: evaluation of
incidence and screening methods. J Clin Psychiatry 2006;67(10):1493-500.
5. van Winkel R, van Os J, Celic I, Van Eyck D, Wampers M, Scheen A, et
al. Psychiatric diagnosis as an independent risk factor for metabolic
disturbances: results from a comprehensive, naturalistic screening
program. J Clin Psychiatry 2008;69(8):1319-27.
6. Fariss BL. Prevalence of post-glucose-load glycosuria and hypoglycemia
in a group of healthy young men. Diabetes 1974;23(3):189-91.
7. Brun JF, Fedou C, Mercier J. Postprandial reactive hypoglycemia.
Diabetes Metab 2000;26(5):337-51.
Competing interests: No competing interests
The Maudsley guidelines have no reference to hypoglycaemia as a side
effect of anti-psychotics(1). What is unfortunately expected is the
The three case studies on hypoglycaemia in schizophrenic patients
indicate a reaction that is dose dependent, and varies according to which
drug is deployed (2).
The mystery nowadays is: are atypical antipsychotics directly
producing insulin resistance, through some putative receptor X (3)? The
alternative is that they are indirectly establishing it through weight
gain in the metabolic syndrome.
The implication of the three case studies is that antipsychotics can
disrupt insulin response in both directions- so either hyperglycaemia or
hypoglycaemia may result. There is proposed some sort of metabolic tug of
war. How were these patients different? What else was wrong with them ,
apart from the glucose levels?
Without fruitful idiosyncracies such as these three cases, we cannot
pull the solution out of a general medical problem.
Historically, insulin coma therapy actually was the artificial, cruel
and deliberate induction of hypoglycaemia in a patient (4). Also, even
before anti- psychotic drugs were devised in the 1950's, there was a
putative association between schizophrenia and diabetes (5).
Chlorpromazine, the initial archetypal anti- psychotic, became linked
subsequently to diabetes (6).
This article by Yutaro Suzuki et al is, then, part of the extended
tension between schizophrenia and sugar.
(1)The Maudsley Prescribing Guidelines. 9th Edition. 2007.
(2)Drug Point: Hypoglycaemia induced by second generation
antipsychotic agents in schizophrenic non- diabetic patients. BMJ
(3)Which comes first: atypical antipsychotic treatment or
cardiometabolic risk? S.M. Stahl, L.Mignon, J.M.Meyer. Acta Psychiatr
Scand 2009:119:pg. 175.
(4) Mad In America. Bad Science, Bad Medicine, and the Enduring
Mistreatment of the Mentally Ill. Robert Whitaker. Perseus. 2002. Pg.85.
(5)Diabetes mellitus and schizophrenia: historical perspective. D.
Kohen. s64. B J Psych Vol. 184 Supplement 47.
(6)Cardiovascular Risk Associated with Schizophrenia and its
treatment. Ed. J. Camm. Galliard. 2003. Pg. 33. (Adverse metabolic effects
of atypical antipsychotics by Ali Dana and Michael Marber)
Competing interests: No competing interests