BRIEF REPORTS

BRIEF
AmREPORTS
J Psychiatry 155:7, July 1998

Effect of Acute Metabolic Stress on Pituitary-Adrenal Axis

Activation in Patients With Schizophrenia
Igor Elman, M.D., Caleb M. Adler, M.D., Anil K. Malhotra, M.D.,
Christopher Bir, B.S., David Pickar, M.D., and Alan Breier, M.D.

Objective: Although several lines of evidence suggest that stress plays a role in the course
of schizophrenia, studies that have assessed stress-relevant neurobiological measures have not
produced consistent results. The authors examined the effects of acute metabolic stress induced
by 2-deoxy-D-glucose (2-DG) on pituitary-adrenal axis activation. Method: Thirteen patients
with schizophrenia and 11 healthy comparison subjects were administered pharmacological
doses of 2-DG (40 mg/kg). The subjects arterial plasma was then assayed for levels of adrenocorticotropic hormone (ACTH) and cortisol. Results: 2-DG induced significant increases
in the measured hormones in both groups, and ACTH elevations were significantly greater in
patients with schizophrenia than in comparison subjects. Conclusions: Patients with schizophrenia have an exaggerated ACTH response to acute metabolic stress exposure.
(Am J Psychiatry 1998; 155:979981)

everal lines of evidence suggest that stress plays a

role in the course of schizophrenia. Illness onset (1)
and relapse (2) are associated with environmental
stress. Stress-reducing behavioral (3) and pharmacological treatments (4) may improve the symptoms of
schizophrenia. Moreover, hypercortisolism, e.g., elevated plasma cortisol (5) or cortisol nonsuppression after dexamethasone administration (5, 6), has been reported in schizophrenia and is potentially related to
stress and arousal (5, 7, 8).
Relatively few studies have exposed patients with
schizophrenia to laboratory-induced stress to determine
if there are neurobiological correlates to stress response,
and these studies have yielded inconsistent results (9, 10).
One method of acute stress induction is administration
of pharmacological doses of 2-deoxy-D-glucose (2-DG).
2-DG is a glucose analog that blocks glycolysis by inhibition of glucose-6-phosphate dehydrogenase, thus preventing neuronal glucose utilization and resulting in a
clinical state similar to hypoglycemia (11). Although
metabolic stress may be distinct from the environmental
stress implicated in the schizophrenia literature, it offers
the advantage of activation of stress-related neurochemical and neuroendocrine systems, including the pituitaryadrenal axis (12), and may provide unique information
Received July 15, 1997; revisions received Dec. 24, 1997, and Feb.
6, 1998; accepted Feb. 16, 1998. From the Experimental Therapeutics
Branch, NIMH, National Institutes of Health, Bethesda, Md. Address
reprint requests to Dr. Elman, Massachusetts General Hospital, Harvard Medical School, West End House, 16 Blossom St., Boston, MA
02114; elman.igor@mgh.harvard.edu (e-mail).
The authors thank Lisa Picken, Kingsley Turner, Jerry Rotter, and
Allan Clifton for their contribution to this study and Marilyn Duncan
for editorial assistance.

Am J Psychiatry 155:7, July 1998

pertaining to regulatory mechanisms of hormonal synthesis, release, and clearance.

The present study investigated the effects of 2-DG administration on arterial plasma levels of the pituitary-adrenal axis hormones ACTH and cortisol in patients with
schizophrenia and healthy comparison subjects. The advantage of arterial sampling is that it is less affected by
local peripheral metabolism, as suggested by preclinical
studies demonstrating that muscle and skin tissues remove more than 70% of intravenously injected radioactive-labeled ACTH within 1 minute (13). Arterial plasma
is used in endocrine research of the sympathoneural system; therefore, it may have heuristic value in the investigation of the anatomically and functionally related hypothalamic-pituitary-adrenal axis (14).
METHOD
Thirteen outpatients who met DSM-IV criteria for schizophrenia
(mean age at appearance of DSM-IV criterion A symptoms of schizophrenia=22.5 years, SD=3.5; mean duration of the illness=15.7 years,
SD=9.3) and 11 healthy comparison subjects participated in this study.
The patients were diagnosed by two research psychiatrists using a bestestimate format that uses all available sources of information, including
clinical history, interview, and the Structured Clinical Interview for
DSM-III-R. The patients were tested while receiving stable doses of typical antipsychotic drugs for a minimum of 2 weeks (except for one patient, who had received the drug for 8 days). Drugs and doses (chlorpromazine equivalent mean=748.54 mg/day, SD=501.31, range=
3332000) were varied to achieve a stable clinical condition. Comparison subjects were recruited through the normal volunteer program of
the National Institutes of Health (NIH) and had no psychiatric history.
All individuals were in good physical health and gave written informed
consent to a protocol approved by the NIH Institutional Review Board.
On the morning of the procedure, subjects were admitted to the
4 East Unit of NIH, having fasted and refrained from alcohol, to-

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FIGURE 1. Effects of 2-Deoxy-D-Glucose on the Pituitary-Adrenal Axis Activation in Patients With

Schizophrenia and Normal Comparison Subjectsa

effects of group (F=10.58, df=1, 22, p<0.01), time (F=20.32, df=3, 22, p<0.01; =0.51),
and group-by-time interaction (F=5.51, df=3, 22, p<0.01; =0.51) for ACTH. Significant time effect
(F=115.49, df=3, 22, p<0.01; =0.62) but no group effect (F=1.92, df=1, 22, p=0.18) or group-by-time
interaction (F=2.1, df=3, 22, p=0.11; =0.62) for cortisol.

aSignificant

bacco, caffeine, and physical activity for at least 10 hours. An arterial line was placed under local anesthesia with 1% lidocaine.
After a 90-minute rest period, 2-DG (40 mg/kg, maximal dose
4000 mg) was administered as an intravenous bolus. Blood samples
were obtained at 30 minutes before (30 minutes), immediately
prior (0 minutes), and 20, 40, and 60 minutes following 2-DG administration. The assays for ACTH and cortisol were performed as
described elsewhere (15).
The data were analyzed by using the statistical package SuperANOVA (16). Baseline hormonal levels were determined from the mean
of hormonal levels at the 30-minute and 0-minute time points. Analyses were conducted by using two-way analysis of variance (ANOVA)
with repeated measures design. Diagnosis was a grouping factor, and
time was the within-subject factor. When group-by-time interactions
were significant, post hoc Newman-Keuls t tests were performed. All
ANOVAs were interpreted with the Greenhouse-Geisser conservative F
test to account for sphericity. All analyses were two-tailed. A p value less
than 0.05 defined statistical significance. Group data were summarized
as means and standard deviations.

RESULTS

There were no significant differences between patients

with schizophrenia and comparison subjects in age
(mean=37.9 years, SD=8.7, versus mean=32.4 years, SD=
6.5) (t=1.7, df=22, p=0.10), gender (10 men and three
women versus nine men and two women) (2=0.09, df=1,
p=0.77), and weight (mean=81.5 kg, SD=13.5, versus
mean=78.2 kg, SD=18.4) (t=0.5, df=22, p=0.61).
Patients with schizophrenia and comparison subjects
both demonstrated robust increases in plasma ACTH
levels (mean change from baseline: 797% versus
386%). Patients demonstrated significantly higher 2DG-induced ACTH levels than comparison subjects
(figure 1). Post hoc Newman-Keuls t tests revealed no
differences between groups in ACTH levels at baseline
(mean=28.68 pg/ml, SD=17.37, versus mean=40.23 pg/
ml, SD=15.91) (p=0.77) but did show significantly
higher ACTH levels for patients at 20 minutes (p<0.01),

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40 minutes (p<0.01), and 60

minutes (p<0.01) after the administration of 2-DG.
Analyses of cortisol data
revealed similar baseline levels in patients and comparison subjects (mean=13.99
g/dl, SD=8.19, versus mean=
13.52 g/dl, SD=5.17). 2-DG
produced a significant time
effect but no group effect or
group-by-time interaction
(figure 1). All subjects demonstrated usual behavioral
and clinical responses to 2DG administration (12).
DISCUSSION

The major finding of this

study is that patients with
schizophrenia had significantly greater 2-DG-induced plasma ACTH levels but
not cortisol levels than healthy comparison subjects. To
our knowledge, this is the first report of exaggerated
ACTH response to pharmacological challenge in patients with schizophrenia.
Our findings are consistent with other reports of pituitary-adrenal axis abnormalities in schizophrenia,
such as basal hypercortisolemia (5) and cortisol nonsuppression after dexamethasone (8). Our results contrast with the finding of a clinical study using 2-DG as
a metabolic stressor. Breier (12) found that 2-DG did
not induce significantly different ACTH responses in
patients with schizophrenia and comparison subjects.
These contrasting data might be accounted for by differences in study design, patient selection, method of
2-DG administration (bolus versus infusion), and sampling of arterial rather than venous blood.
The unexpected lack of significant group differences
in 2-DG-induced cortisol elevations in the face of
ACTH response may have been due to a ceiling effect. Cortisol elevations exceeded the threshold for
maximal adrenal response (17), and cortisol levels
reached the 95th percentile value achieved in healthy
comparison subjects on a standard ACTH stimulation
test (18). This hypothesis, however, requires further investigation given the small number of subjects in our
study and evidence that cortisol levels did appear to be
higher, although not statistically significantly higher, in
the patients. In addition, this study assessed only acute
stress response, and a longer study period may have
yielded different results because cortisol levels were still
rising at the end of the experiment.
The following caveats should be considered in interpreting our results. Because of the magnitude of the 2DG response and the lack of group differences in hormonal levels at baseline, it is unlikely that basal endocrine status contributed to the 2-DG-induced endocrine

Am J Psychiatry 155:7, July 1998

BRIEF REPORTS

effects. It is also unlikely that antipsychotic drugs affected the ACTH response to 2-DG. Clinical and preclinical studies have shown that chronic antipsychotic
drug treatment is not associated with ACTH elevations
(5, 19) but might have a dampening effect on pituitaryadrenal axis activity (5). Nonetheless, a study of antipsychotic-drug-free patients may be warranted.
In conclusion, 2-DG-induced metabolic stress elicited
a heightened ACTH response in patients with schizophrenia. These data suggest that elucidation of the
mechanisms underlying the metabolic stress response
may provide information that would help us understand the pathophysiology and treatment of the illness.
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