Catecholamines and anxiety

6 Pages·1982·0.348 MB·English

by  Mathew RJ, Ho BT, Francis DJ, Taylor DL, Weinman ML.

Acta psychiat. scand. (1982) 65, 142-147
Texas Research Institute of Mental Sciences (Director Joseph C. Schoolur, M.D.),
Houston, Texas, U.S.A.
Catecholamines and anxiety
R. J. MATHEWB, . T. Ho, D. J. FRANCISD,. L. TAYLOARND M. L. WEINMAN
Plasma catecholamines and heart rate were determined in drug-free
groups of anxious patients and normal controls before and 20 min
after intramuscular injection of 0.01 mg/kg of V1000 diluted epine
phrine. Levels of anxiety after the injection were determined via
the State Anxiety Scale of State Trait Anxiety Inventory. Both
groups showed substantial increases in plasma levels of epinephrine
and norepinephrine and heart rate after the injection. However,
there were no significant differences between anxious patients and
controls on plasma catecholamines and heart rate before or after
the injection and post injection levels of State Anxiety. The anxious
subjects showed a significant correlation between post injection heart
rate and State Anxiety.
Key words: Anxiety - catecholamines - epinephrine- norepinephrine
-
heart rate.
Anxiety is characterised by peripheral symptoms mediated through sympathetic
adrenomedullary overactivity (Lader (1975)). Catecholamines, epinephrine and
norepinephrine, are intimately involved in this process. While most epinephrine is
secreted by the adrenalmedulla, norepinephrine in the periphery is derived from
the sympathetic post-ganglionic terminals (Frankenhueuser (1971), Cooper et al.
(1978)). Stress has been shown to increase catecholamine output in normal people
(Levi (1972)). However, patients with anxiety neurosis often report anxiety in
the absence of any identifiable stress. They also manifest excessive anxiety in
response to specific and non-specific stress. Anxiety might be mediated through
excessive catecholamine output, slow removal from the receptor sites or ex-
cessive receptor sensitivity. It is unclear as to whether the physiological and bio-
chemical differences between anxious subjects and normals are merely quantita-
tive or qualitative as well.
The present project compared patients with anxiety neurosis and normal con-
trols on their response to an intramuscular injection of epinephrine.
MATERIAL
Thirteen subjects (10 males and 3 females (mean age 45.38, s.d. 7.96)) from
the outpatient clinic of the Texas Research Institute of Mental Sciences with a
diagnosis of generalized anxiety disorder according to DSM I11 (American Psy-
chiatric Association 1980) participated in the project. None of the patients had
been on medication for a minimum of 2 weeks prior to taking part in the study
0001-690X/82/020142-06 $02.50/0 0 1982 Munksgaard, Copenhagen
143
and none gave a history of being on monoamine oxidase inhibitors or long-acting
neuroleptics. Seven non-anxious volunteers (6 males and 1 female (mean age
39.14, s.d. 5.64)) were selected from the staff at the Institute. They were inter-
viewed by a psychiatrist individually to confirm the absence of anxiety-related
problems. They were also drug-free for a minimum of 2 weeks before taking
part in the study. The age difference between the patients and controls was not
statistically significant. The research project was explained to all participants
and their informed consents obtained.
METHOD
All participants underwent a physical examination with routine laboratory tests
and standard EKG. The entire experiment was carried out in the morning be-
tween 9 and ll a.m. to minimize circadian rhythm influences (Akerstedt (1979)).
Subjects were instructed to abstain from coffee, tea and tobacco on the morning
of the experiment. First, the subjects completed an Eysenck Personality Inven-
tory (Eysenck & Eysenck (1963)) and then were taken to a semi-dark, quiet room
where the rest of the experiment was carried out. The subjects rested in the supine
position on a couch and their heart rate and EKG were recorded on a physio-
graph throughout the duration of the study. A butterfly needle with a heparin
lock (to prevent blood from clotting in the needle) was inserted into a cubital
vein. The subjects relaxed for the next 10 min with the needle in situ. At the end
of this period, a technician in the lab slowly drew a blood sample through the
butterfly needle and relocked the needle with heparin. Then the subjects received
an injection of 0.10 mg/kg body weight of 1/1000 epinephrine, given intramuscu-
larly into the deltoid muscle. A second blood sample was drawn through the
butterfly needle 20 min after the injection. Levels of anxiety experienced by the
subjects after receiving the injection were quantified via the State Anxiety Scale
of State Trait Anxiety Inventory (STAI) (Spielberger et aZ. (1970)) administered
after the experiment was over.
Blood samples for catecholamine assay were collected in vacutainer tubes con-
taining EDTA with glutathione and placed immediately on ice until centrifuged
at 1,500 g for 10 min. Plasma was then separated from cells with a pipette and
placed in a glass storage tube and frozen immediately at -7OOC. The sample was
stored at this temperature until processed. Catecholamine levels were estimated
by a radioenzymatic-t.1.c. chromatographic technique based on Peuler & John-
son (1975). This assay utilized the enzyme catecholamine-0-methyl transferase
to convert the catecholamines to their 0-methylated products. Following sepa-
ration by thin layer chromatography, each labelled derivative was converted with
periodate oxidation to the acid metabolites and extracted. Values were expressed
as Pg/ml.
RESULTS
The anxious subjects obtained significantly higher neuroticism scores (EPI) as
compared to the controls (patients, mean 11.69, s.d. 5.87; controls, mean 4.17, s.d.
144
Table 1. Comparison of pre and post epinephrine injection values obtained by
the anxious patients and their controls
Pre injection* Post injection*
t P
Mean S.D. Mean S.D.
Anxious patients
Epinephrine 29.50 22,61 1248.75 691.95 6.81 < 0.001
<
Norepinephrine 331.91 159.90 654.92 375.23 2.81 0.017
Heart rate 65.16 5.96 80.18 8.91 9.05 < 0.001
Controls
Epinephrine 29.86 18.33 1386.86 1036.99 3.48 <0.013
Norepinephrine 269.43 161.07 680.00 240.05 4.25 < 0.005
<
Heart rate 60.26 7.85 80.77 14.56 5.17 0.002
* The anxious patients and controls did not show any significant between-group differ-
ences on pre and post injection catecholamine levels and heart rate.
Epinephrine and norepinephrine values are expressed as pg/d and heart rate as
beats/&.
2.93; t = 2.95, P < 0.009). The within and between group differences on plasma
epinephrine, norepinephrine and heart rate for the patient and control groups,
before and after the epinephrine injection were examined (Table 1). The two
groups did not differ significantly in degrees or direction of change of these
variables after the injection. State anxiety scores were available only for the post
epinephrine evaluation session and patients and controls did not show significant
differences on this score (patients, mean 62.69, s.d. 8.56; controls, mean 57.67,
s.d. 11.79; t = 1.06, P C 0.31). Intercorrelations between the catecholamines,
heart rate, and state anxiety before and after epinephrine injection were computed
for the anxious patients. None of the correlations reached statistical significance
except for post injection heart rate and state anxiety (t = 0.63, P < 0.01). Next,
the anxious patients were divided into heart rate responders and non-responders
using a post epinephrine injection heart rate increase of 15.5 beats/& (median
value) as the cut-off point. As was expected, the two groups showed significant
differences in post injection heart rate and state anxiety (heart rate responders,
heart rate: mean 86.27, s.d. 5.76, non-responders, mean 73.07, s.d. 6.18, t = 3.98,
<
P 0.002; heart rate responders, state anxiety: mean 67.86, s.d. 6.87, non-re-
spunders, mean 56.67, s.d. 6.19, t = 3.06, P C 0.01). However, the two groups did
not differ on post epinephrine injection plasma levels of epinephrine and nor-
epinephrine.
DISCUSSION
Higher neuroticism scores in anxious subjects have been reported previously
(Lader (1975)). This score, an index of autonomic lability, is believed to indicate
predisposition to develop anxiety and other neurotic symptoms under stress (Ey-
senck & Eysenck (1963)). The absence of any difference between the anxious
subjects and their controls on resting plasma catecholamine levels contradicts
145
previous reports (Mathew et al. (1981)). However, it needs to be pointed out
that in the previous studies, blood samples for catecholamines were drawn im-
mediately following venipuncture; a well-established source of error. In the
present study, the initial peak of catecholamines following venipuncture was
avoided by delaying the sample withdrawal by 10 min after needle insertion
(Lake et al. (1976), Carruthers et al. (1970)). Both groups showed a substantial
increase in plasma catecholamine levels 20 min after epinephrine injection. Cate
cholamines in the blood at this point are likely to represent the balance between
exogenous epinephrine injected and endogenous catecholamines secreted in re-
sponse to the injection and the catecholamines removed from the blood stream
via tissue absorption, metabolism and renal excretion. Catecholamines from the
endogenous sources are likely to exceed the unmetabolised exogenous source 20
rnin after the injection, as epinephrine and norepinephrine are rapidly removed
from the blood stream (Axelrod et al. (1959), Vendsalu (1960)). Since epinephrine
was administered intramuscularly (and not subcutaneously) the consequent in-
crease in muscle blood flow would have facilitated fast removal of the drug from
the injection site (Znnes & Nickerson (1975)).
The catecholamine response to epinephrine injection cannot be due to central
mechanisms as epinephrine does not cross the blood brain barrier (Schildkraut
& Kety (1967)). Epinephrine, even when injected into the intracarotid artery does
not increase central arousal (Olesen (1972)). While adrenal medullary epinephrine
secretion is under cholinergic control, norepinephrine secreted by post ganglionic
sympathetic terminals is regulated by cholinergic ganglionic transmission (Carrier
(1972)). Therefore, the increase in endogenous catecholamines following epin-
ephrine injection cannot be explained by the direct pharmacological action of
the drug. Furthermore, it should be noted that levels of norepinephrine also in-
creased following the injection. A more plausible explanation would seem to be the
non-specific stress associated with the injection. Induction of peripheral symp-
toms by epinephrine has been reported to increase mental feelings of anxiety
(Richter (1940)). This possibility is strengthened by reports of increased central
arousal following intravenous but not intracarotid epinephrine administration
(King et al. (1925), Olesen (1972)).
Other investigators have reported progressive decline in plasma catecholamines
after 30 to 40 min of intravenous infusions of epinephrine (Cohen et al. (1959),
Vendsalu (1960)). With prolonged infusions, the subjects are likely to habituate
to the procedure and experience less stress. Upon discontinuation of the infusion
plasma, catecholamine drops because of the reductions in stress felt by the sub-
jects at that point and the associated release of endogenous catecholamines. The
anxiety induced by intravenous infusions of sodium lactate has been found to
decrease when the infusions are repeated several times (Bonn et al. (1973)).
The absence of any difference between the anxious patients and their controls
on pre and post injection catecholamine levels would seem to suggest that fac-
tors associated with the secretion and metabolism of catecholamines in the periph-
ery are not involved in the pathophysiology of anxiety neurosis. However, the
study would need to be repeated on a larger number of anxious subjects with an
equal number of age and sex matched controls and multiple serial estimations
10
146
of plasma catecholamine levels after epinephrine injection before any firm con-
clusions can be drawn in this regard.
There is general consensus that anxiety is constituted by somatic and psychic
components (Buss (1962), Fenz & Epstein (1965), Morrow & Labrum (1978)).
Extensive literature exists on the relationship between peripheral and psychic
anxieties (Tyrer (1976)). The present finding of a significant correlation between
post epinephrine heart rate and state anxiety supports the hypothesis that per-
ception of the peripheral symptoms of anxiety produces and/or augments psychic
anxiety in predisposed people (Tyrer (1976)). Propranolol, a beta-adrenergic block-
ing agent which abolishes several peripheral physiological symptoms of anxiety
including tachycardia, is a well-established anti-anxiety agent (Wheatly (1969),
Tyrer (1976)). The association between epinephrine-induced increase in heart rate
and anxiety has been reported by other investigators (Fruser & Wilson (1918),
Weurn & Sturgis (1919)).
The findings reported here indicate that anxious subjects and normals do not
differ in resting catecholamine levels or catecholamine response to epinephrine
injection. Intensity of the anxiety induced by the injection is largely determined
by the increase in heart rate, with those who experience more tachycardia report-
ing more severe anxiety. The mechanism responsible for this heart rate over-
responsiveness seems to be increased beta-adrenergic receptor sensitivity as the
tachycardia was not associated with parallel increases in plasma levels of epin-
ephrine.
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