Get documents about "Acetylcholine and Depression
Document Sample
www.cuwai.com
Acetylcholine and Depression*
DAVID S. JANOWSKY, MD, M. KHALED EL-YOUSEF, MD, AND JOHN M. DAVIS, MD
Physostigmine, a cholinesterase inhibitor which increases central acetylcholine levels, has been
found in man to decrease manic symptoms, antagonize methylphenidate-induced behavioral
activation, and induce severe depression and psychomotor retardation in marijuana intoxicated
normals. In the current study, physostigmine was found to increase depressed mood in patients
with an affective component to their symptoms (manics, depressives, and schizoaffectives).
Schizophrenics without an affective component did not become depressed. After physostigmine
administration, all subject groups showed a significant increase in symptoms including lethar-
gy, slowed thoughts, withdrawal, apathy, decreased energy, decreased thoughts, motor retarda-
tion, and feeling drained, indicating a state of psychomotor retardation; and all became less
cheerful, friendly, and talkative. The above information is compatible with the hypothesis that
acetylcholine may be involved in the etiology of affective disorders.
INTRODUCTION A number of cholinesterase inhibitors
have been shown to induce depression
Specific biochemical disturbances caus- and to exhibit anergic effects, presumably
ing the affective disorders have not been by increasing central acetylcholine levels.
defined. However, there is considerable Gershon reported cases of individuals
evidence suggesting that brain mono- poisoned with cholinesterase-inhibitor in-
amines, including norepinephrine, dopa- secticides who developed depression and
mine, and serotonin are significant deter- peripheral parasympathetic toxicity. He
minants of mood and behavior (1). The also noted that the incidence of depres-
cholinergic nervous system may also be sion may be higher in orchardists (4).
involved in the etiology of mania and de- Rowntree, Nevin, and Wilson (5) chroni-
pression, with depression being a disease cally administered the irreversible cholin-
of cholinergic predominance (2,3). The esterase inhibitor, diisopropylflu-
following information supports this possi- orophosphonate (DFP). Normal sub-
bility. jects and two remitted manic depress-
From the Departments of Psychiatry and Pharma- ives developed depression, irritability,
cology, the Vanderbilt University School of Medi- lassitude, apathy, and poverty or slow-
cine, Nashville, Tennessee, the Illinois Psychiatric
Institute, Chicago, Illinois, and the Department of ness of thoughts, which appeared before
Psychiatry, University of California at San Diego the onset of peripheral cholinergic symp-
School of Medicine, San Diego, California. toms. One nearly remitted hypomanic pa-
This research was supported in part by Grant GM tient became floridly manic upon DFP
15431, from the National Institute of Health, Grant
MH 11468, from the National Institute of Mental withdrawal. Two hypomanic patients im-
Health, and by research support from the State of proved with DFP. Another showed de-
Tennessee, Department of Mental Health. creased mania and was minimally de-
* Presented at the Annual Meeting of the American
Psychosomatic Society, Denver, Colorado, April, pressed after each of two courses of DFP,
1973. relapsing after DFP withdrawal. One de-
Address for reprint requests: David S. Janowsky, pressive showed a considerable increase
MD, Department of Psychiatry, University of Califor-
nia at San Diego, School of Medicine, La Jolla, Cali- in depression with DFP administration.
fornia 92037.
Received for publication April 30, 1973; revision Bowers et al. noted that the irreversible
received November 23, 1973. cholinesterase inhibitor, EA-1701, caused
248 Psychosomatic Medicine Vol. 36, No. 3 (May-June 1974)
Copyright ® 1974 by the American Psychosomatic Society, Inc.
Published by American Elsevier Publishing Company, Inc.
www.cuwai.com
ACETYLCHOLINE AND DEPRESSION
decreased energy, depressed mood, lethar- effect in causing depressive symptoms in patients
gy, decreased enthusiasm, and decreased with or without an affective component to their psy-
chiatric illness—a study not previously reported. The
friendliness in normal volunteers (6). subjects consisted of: (a) 8 floridly ill schizophrenics
We have recently conducted a series of without marked affective symptoms (2 chronic undif-
experiments exploring the role of the ferentiated, 4 paranoid type, and 2 acute schizo-
cholinergic nervous system in human be- phrenic episode), (b) 6 acutely ill schizoaffective pa-
tients (2 depressed and 4 excited) with prominent
havior. Based in part on these, we have affective symptoms, (c) 8 manic-depressive patients,
hypothesized a "cholinergic-adrenergic manic type, and (d) 2 depressed patients. Diagnosis
balance hypothesis of mania and depres- and assessment of the severity of the clinical state
sion" (2). To date, we have reported that was based on the consensus of three psychiatrists,
physostigmine, a centrally acting cholin- using diagnostic criteria outlined in the American
Psychiatric Association Diagnostic and Statistical
esterase inhibitor, administered to patients Manual (DSM-II).
with hypomanic symptoms, causes a de-
Each patient was pretreated with methylscopola-
crease in specific manic symptoms (3) and mine (0.75-1.0 mg i.m.), a noncentrally acting
an increase in psychomotor retardation. anticholinergic agent, to partially block the
Some subjects also show a depressed peripheral cholinomimetic effects of physostigmine
mood (3). In another study, we demon- or neostigmine. An intravenous infusion of dextrose
and water was started 30 min after
strated that marijuana intoxicated normal methylscopolamine administration. A varying
volunteers, given physostigmine, develop number of placebo injections, followed by a
a profound depressive reaction (7). As a sequence of 0.25 mg or 0.50 mg per dose of either
corollary, we found that tetrahydrocanna- physostigmine or neostigmine (a peripheral acting
cholinomimetic agent), respectively, followed by
binol increases the toxicity of physostig-
placebo, was given through the rubber tubing of the
mine given to rats (8). Furthermore, we intravenous unit every 5 min until a behavioral
have presented preliminary evidence that change occurred or a total of 3.0 mg physostigmine
physostigmine decreases activation and or 1.5 mg neostigmine had been given. Only one
induces psychomotor retardation in schi- cholinomimetic agent (either physostigmine or
neostigmine) was administered per experiment. The
zophrenic patients, without actually de- individual and cumulative dose given depended on
creasing psychotic thoughts and hallucin- clinical factors such as the patients' reaction to the
ations (9). We have also reported that me- drugs administered. Pulses and blood pressures were
thylphenidate (Ritalin®) induced behav- monitored every 5 min. In the study, two types of
ioral activation consisting of increased talk- controls were utilized. First, in 13 of the patients,
neostigmine, a cholinesterase inhibitor which does
ativeness and interactions, as well as in- not effectively pass the blood-brain barrier and
creased psychotic symptoms in psychotic which is 2-3 times as potent as physostigmine in
patients, can be antagonized or prevented the periphery, was used as an active placebo (11)
by administration of physostigmine (9). instead of physostigmine. Second, the patient and
the rating nurse did not know which of a series of
Similarly, methylphenidate-induced ster- injections was placebo and which was active drug.
eotyped behavior in rats is decreased or Thus, the participants were blind as to which drug
prevented by physostigmine (10). Con- was being administered in a given experiment and
versely, the anergic syndrome induced by when in the injection sequence active drug was sub-
physostigmine is readily reversed by in- stituted for placebo.
jection of methylphenidate (9). On the basis of previous studies, a rating scale was
developed to evaluate the general "anergic-
inhibitory" effects of physostigmine. Subjects were
METHODS rated on a 0-5 point continuum for the following
items: 1—irritable, 2—lethargic, 3—dysphoric, 4—
In the present study, we have attempted to deter- has slow thoughts, 5—does not want to say anything,
mine whether or not physostigmine has a differential 6—hostile, 7—withdrawn, 8—wants to be alone, 9—
Psychosomatic Medicine Vol. 36, No. 3 (May-June 1974) 249
www.cuwai.com
DAVID S. JANOWSKY, MD, et al.
apathetic, 10—crying, 11—sadness (Bunney- ponent to their illness. Six of the eight
Hamburg subitem (12)), 12—lacks energy, 13—is manics and both depressives showed in-
sleepy, 14—drained, 15—hypoactive, 16—lacks
thoughts, 17—psychomotor retardation, 18—
creased depressed mood after receiving
psychotic, 19—angry, and 20—emotional with- physostigmine (manic's increased depres-
drawal. They were also rated on 1—cheerful, 2— sion rating = p < 0.02; manic's increased
friendliness, 3—interacting, and 4—talkativeness. An sadness rating = P < 0.01, N = 8). Like-
"activation" scale and an "inhibitory" scale as des- wise, five of the six schizoaffectives
cribed previously (3) were derived from certain of showed depression after physostigmine
the above items. Patients also were rated on a 0-5
point continuum for global depression using the
infusion (increased depression rating =p<
Bunney-Hamburg rating scale (12). Ratings were 0.005; increased sadness rating = P <
completed every 5 min. 0.007, N = 6). In contrast, of the eight
The baseline ratings taken during the initial place- schizophrenics without an affective com-
bo phase for each patient were compared with the ponent to their symptoms, physostigmine
ratings following administration of physostigmine or caused depression in only one of the pa-
neostigmine. The changes in ratings were evaluated tients (increased depression rating = NS;
for each specific group of patients using the Stu-
dent's one Tailed t-Test for paired observations. In- increased sadness rating = NS, N = 8).
creases over placebo-baseline scores for the sadness Thus, increased depression ratings and
and depression ratings for the manic and schizoaffec- sadness ratings over baseline for the man-
tive groups respectively, and for the entire group of ic and schizoaffective groups and for the
patients with affective symptoms (manics, schizoaf- entire group of patients with affective
fectives, depressives) were compared with the in- symptoms (manics, depressives, schizoaf-
creases in sadness and depression ratings for the
schizophrenic group of patients who had no signifi- fectives) were statistically significant. This
cant affective symptoms, using the Student's one contrasted with the lack of a significant
Tailed t-Test (unpaired). increase in ratings in the schizophrenic
group without affective symptoms. The
increases in depression and sadness rat-
RESULTS ings in each of the groups are summarized
in Table 1.
The results indicate that virtually all Table 1 also directly compares the in-
patients receiving physostigmine exhibit creases in depression and sadness ratings
symptoms consistent with a state of psy- for the schizophrenic group without affec-
chomotor retardation. In addition, most tive symptoms with those of other groups
patients with an affective component to of patients with affective symptoms. The
their symptoms exhibit increased de- schizoaffective group had a significantly
pressed mood following physostigmine greater increase in depression and sadness
administration. Significantly, the patient ratings, as compared with the schizo-
group (manics, schizophrenics with affec- phrenic group without affective symp-
tive symptoms, schizophrenics without af- toms. Similarly, the increases in depres-
fective symptoms, and all patients with af- sion and sadness ratings for the entire
fective symptoms) had average baseline- group of patients with affective symptoms
placebo depression and sadness ratings was significantly greater than the increase
which did not differ statistically from in these ratings in the schizophrenic
each other. group without affective symptoms. Al-
Physostigmine, but not neostigmine, though the manic patient group had a sig-
appeared capable of inducing a depressed nificant increase in depression and sad-
mood in patients with an affective com- ness over its own baseline values, this
250 Psychosomatic Medicine Vol. 36, No. 3 (May-June 1974)
www.cuwai.com
ACETYLCHOLINE AND DEPRESSION
TABLE 1. Sadness and Depression Ratings Change Scores in Patients with and without Affective Symptoms
Following Administration of Physostigmine
Schizophrenics without Schizophrenics with All patients with
affective symptoms affective symptoms affective symptoms0
(N=8) (N = 6) (N=16)
Depression^ 0.23 ±.48 1.60±.39() 0.79±.27 1.16±.24a
Sadnessrf 0.23±.48 1.48±.40b 0.81 ±.26 1.25±.24b
3
< 0.05 and b < 0.02. All values represent significance of comparisons of differences in increases in depression
and sadness ratings in the schizophrenics without affective symptoms and other groups with affective symptoms,
includes 8 manics, 2 depressives, and 6 schizophrenics with affective symptoms.
d
The increases in depression and sadness ratings over baseline values are statistically significant for the group of
schizophrenics with affective symptoms, the manic patient group and the group consisting of all the patients with
affective symptoms. The group of schizophrenic patients without affective symptoms did not show a significant
increase in depression and sadness ratings.
group did not show a significant increase "inhibitory" score and a decrease in the
in these values when compared to the group's "activation" score occurred fol-
slight, statistically insignificant, increase lowing physostigmine administration.
in these values found in the schizophrenic In contrast, neostigmine did not cause
group without affective symptoms. Al- a significant change in the patient group's
though this difference between the change behavior. It is very likely that neostig-
scores did not reach statistical signifi- mine, which poorly crosses the blood-
cance, the magnitude of the increase in brain barrier, served as an "active place-
depression and sadness ratings in the bo." First, this drug has been found to be
manic group exceeded that of the schizo- 2-3 times more potent in the periphery
phrenic group without affective symp- than is physostigmine (11). Also, in our
toms. studies, we frequently noted that the peri-
As summarized in Table 2, as a general pheral effects of neostigmine, including
effect, physostigmine caused a psychomo- antagonism of methylscopolamine's ef-
tor inhibitory state similar to that seen in fects, bradycardia, perspiration, and mus-
patients with retarded depression. Statisti- cle fasiculations occurred without accom-
cally significant increases in lethargy, panying behavioral changes, and that
slow thoughts, withdrawal, drained feel- these effects occurred in a higher percen-
ings, lack of energy, hypoactivity, dys- tage of neostigmine treated patients than
phoria, apathy, and drowsiness occurred in physostigmine treated patients.
in the subjects. Physostigmine did not Neither the schizoaffective patients nor
produce marked sedation, slurred speech, the schizophrenics without an affective
or ataxia. No patients fell asleep, such as component to their illness showed a signi-
might have occurred with sedative- ficant change in the quality of their psy-
hypnotic drugs. Decreases in the subjects' chotic symptoms following physostigmine
cheerfulness, friendliness, interacting, and administration. Psychomotor retardation
talkativeness scores occurred. A signifi- and a blunting of symptoms did occur,
cant increase in the patient group's causing the symptoms to be less promin-
Psychosomatic Medicine Vol. 36, No. 3 (May-June 1974) 251
www.cuwai.com
DAVID S. JANOWSKY, MD, et al.
TABLE 2. Effects of Intravenous Physostigmine and Neostigmine on Various Symptoms in All Patients
Change Score Change Score
(Baseline-Physostigmine) (Basel i ne- Neostigmi ne)c
18 Subjects 13 Subjects
Inhibitory Scalea 8.68+1.33 = <0.00001 0.40±1.37 = NS
Lethargy 1.15+0.19 <0.00001 0.07±0.24 NS
Has slow thoughts 0.83+0.21 <0.0005 0.13+0.11 NS
Does not want
to say anything 0.50+0.16 <0.005 -0.18±0.15 NS
Withdrawn 0.92+0.16 <0.00001 0.01+0.14 NS
Apathetic 0.31+0.17 <0.05 -0.09+0.15 NS
Lacks energy 1.00+0.18 <0.00001 0.23+0.20 NS
Drained 1.03+0.23 <0.00005 0.12±0.23 NS
Hypoactive 1.03+0.20 <0.00001 0.23+0.23 NS
Lacks thoughts 0.51+0.18 <0.01 0.00±0.12 NS
Depressed 0.43+0.21 <0.03 -0.03±0.15 NS
Psychomotor
retardation 1.23+0.19 <0.00001 -0.09±0.22 NS
Emotional withdrawal 0.57+0.19 <0.005 -0.20±0.23 NS
Activation Scale*" -3.09+0.48 <0.00001 0.39±0.76 NS
Cheerful -0.85±.16 <0.00001 0.04 ±0.06 NS
Friendliness -0.73±.19 <0.0005 0.05±0.17 NS
Interacting -0.83+.15 <0.00001 -0.10±0.22 NS
Talkativeness -0.68±.19 <0.001 0.11+0.25 NS
a
"Inhibitory Scale" includes sum of the next 12 items.
b
"Activation Scale" score includes cheerful, friendliness, interacting, talkativeness scores.
c
Statistically significant differences between baseline-physostigmine change scores and baseline-neostigmine change
scores occurred for all items.
ent. Thus, delusions, hallucinations, and baseline-placebo phase with moderate
bizarre behavior continued, although in anger and irritability, increased interac-
subdued and muted form. In addition, cer- tions, and increased talkativeness. He
tain of the schizophrenic subjects showed showed moderate flight of ideas and was
increased irritability and dysphoria fol- very manipulative of staff members. He
lowing physostigmine administration. was moderately euphoric. After receiving
The following case examples are illus- a total of 3.0 mg of physostigmine i.v., the
trative of the effects of physostigmine on patient abruptly showed a complete cessa-
the various patient subgroups: tion of his manic symptoms. He became
depressed, sad, and dysphoric. He stated
that he was "no good" and began to cry.
Manic He then ceased to be active and did not
A 40-year-old married Caucasian male wish to communicate. He stopped talking
with a 10-year history of bipolar manic- except when spoken to and asked to be
depressive illness presented during the left alone. He said he felt moderately
252 Psychosomatic Medicine Vol. 36, No. 3 (May-June 1974)
www.cuwai.com
ACETYLCHOLINE AND DEPRESSION
drained and sad. He was apathetic, with- injection, the patient had returned to his
drawn, and lethargic, and showed psycho- baseline state.
motor retardation. Irritability and anger
increased as the patient became depressed.
One half hour after the last physostigmine DISCUSSION
injection, the patient had returned to his
baseline manic state. The above data provides evidence that
increasing central acetylcholine levels
Depressive with the cholinesterase inhibitor, physos-
tigmine, causes a general anergic syn-
A depressed 48-year-old woman
drome. Furthermore, physostigmine
showed mild psychomotor retardation, de-
creased energy, feelings of hopelessness, causes symptoms characteristic of a de-
pessimism, worthlessness, and sadness. pressed mood in many patients with an
After receiving a total of 1.0 mg of physos- affective component to their illness. In
tigmine, the patient exhibited increased contrast, neostigmine does not cause sig-
psychomotor retardation, drained feeling, nificant behavioral changes.
apathy, and withdrawal. She stated that Related to the results reported in this
she felt more depressed, hopeless, worth- paper are those of our previously reported
less, and pessimistic. She said that she felt study (7) indicating that marijuana and
similar to the time when her depression physostigmine, given together, cause a
had been most severe. Administration of profound depressive syndrome in nor-
atropine, 1.0 mg i.v., restored the patient mals. Although reported elsewhere (7),
to her baseline condition. reiteration of this study is worthwhile to
develop the argument supporting acetyl-
Schizophrenic Without an Affective choline's possible role in the etiology of
Component depression. In the latter pilot study, we
administered physostigmine to two nor-
A 28-year-old Negro male had a 2- mal college-age, marijuana intoxicated
month history of hearing "God's" voice. subjects who arrived for "treatment" of
He claimed that he was King David and their marijuana "high" and volunteered to
that he could read minds. He also claimed receive physostigmine. The following
telepathy with God. He spoke calmly, in description summarizes the observations:
a slow, rather pedantic voice. He was The first subject, a female, arrived ap-
courteous and snowed a rather flat affect. parently intoxicated on marijuana. She
He was not depressed or elated. Adminis- stated "I am 13/15th's as high as I have
tration of physostigmine 1.5 mg caused ever been." She was garrulous, cheerful,
the patient to become psychomotor re- full of hilarity, showing flight of ideas and
tarded. He stated that he had "no talkativeness. She described this as her
thoughts," felt drained, and did not want usual response to marijuana. After receiv-
to talk. He felt that his level of communi- ing 1.25 mg of physostigmine, her clinical
cation with God had decreased, but that state had progressed until she reported
this capability still existed. He said God and appeared to be lethargic, drained, and
was still talking to him—yet softly—and sad. She was extremely depressed and felt
still maintained that he was King David. hopeless, useless, and worthless. She
Within one hour of the last physostigmine sobbed, cried, manifested extreme psycho-
Psychosomatic Medicine Vol. 36, No. 3 (May-June 1974) 253
www.cuwai.com
DAVID S. JANOWSKY, MD, et al.
motor retardation, and reported having no cholinesterase inhibitors. Overlapping
thoughts. She stated that she had never symptoms include apathy, lassitude,
been so depressed in her life, yet could slowed down thinking, psychomotor re-
offer no reasons to explain her feelings. tardation, lack of interest, fatigue, lethar-
She stated that she would have committed gy, nightmares, and depression. Indeed,
suicide had she not known that the syn- reserpine has been reported to have cen-
drome was due to the drug. She appeared tral cholinergic properties (13). Thus,
to be as depressed as any patient the au- reserpine-induced depression could be
thors have observed. Within 1 min of atro- due to a combination of monoamine de-
pine administration the patient com- pletion and cholinergic activation, shift-
mented that she felt better and improve- ing adrenergic-cholinergic balance to
ment progressed over the next 0.5 hr. The cholinergic predominance. Similarly, tri-
second patient, a male, arrived stating that cyclic antidepressant induced manic reac-
he was "high." He showed increased tal- tions and antidepressant effects could be
kativeness, friendliness, and interactions. due to a combination of decreased central
He was slightly euphoric, but somewhat cholinergic activity and increased central
apprehensive and anxious. He reported adrenergic activity. Significantly, a few
feeling closer to people and demonstrated uncontrolled studies have indicated that
vivid reminiscent thoughts and descrip- anticholinergic drugs do alleviate depres-
tions about previous pleasant experiences. sion. However, evaluation of the efficacy
With administration of 1.0 mg of physos- of these agents is limited by the develop-
tigmine, this progressed into a profound ment of central anticholinergic behavioral
depression. The patient exhibited extreme toxicity in subjects receiving them and by
psychomotor retardation. He was sad, de- a lack of controls in these studies (14,15).
jected, drained, apathetic, weak, and de- Furthermore, it is reported that scopola-
pressed. He spontaneously said he felt mine causes euphoria in normals (16). It
useless, worthless, and hopeless and that has also recently been reported that the
he wished he could die. He stated that he cholinesterase reactivator, dipyroxine,
felt he could understand how depressed causes increased central stimulation, talk-
people felt and wondered why they all ativeness, and euphoria in man (17), pos-
didn't kill themselves. He claimed virtual- sibly by decreasing acetylcholine levels.
ly no thoughts and spent much time with Table 3 summarizes the above informa-
eyes closed, moaning weakly "oh, oh." tion.
Administration of atropine 1.0 mg caused The above findings and reviewed infor-
noticeable improvement in symptoms mation are consistent with the hypothesis
within 1 min which progressed over the that depressives have a relative or true ex-
next hour. cess of central acetylcholine in those areas
In further support of a hypothesis im- of the brain regulating emotion. It is thus
plicating acetylcholine in the etiology of possible that patients with a presumed ex-
depression is the observation that the cen- cess of central acetylcholine are more vul-
tral effects of the monoamine depletor, re- nerable to the effects of physostigmine,
serpine, the mood depressing effects of since they have a relative surplus of ace-
which have been used to support the mo- tylcholine which can accumulate when
noamine hypothesis of depression (12), cholinesterase is inhibited. Possibly, pa-
are remarkably similar to those of the tients with an affective component to their
254 Psychosomatic Medicine Vol. 36, No. 3 (May-June 1974)
www.cuwai.com
ACETYLCHOLINE AND DEPRESSION
TABLE 3. Evidence that Acetylcholine May Cause Depression
Human Evidence
(1) Cholinesterase inhibitor insecticides (parathione, etc.) cause depression in poisoned workers
(2) The cholinesterase inhibitor diisopropylflurophosphonate (DFP):
(a) causes depression in normals
(b) intensifies depression in depressives
(c) causes depression and j mania in manics
(3) The cholinesterase inhibitor (EA-1701) causes depression in normals
(4) The reversible cholinesterase inhibitor, physostigmine:
(a) | manic symptoms
(b) antagonizes and prevents methylphenidate stimulation in man
(c) causes psychomotor retardation in all subjects
(d) causes depression in many subjects with an affective component to their syndrome
(e) causes severe depression in marijuana intoxicated subjects
(5) Reserpine and cholinesterase inhibitors cause similar symptoms (apathy, slowed-down thinking, motor
retardation, nightmares, fatigue, depression, Cl stimulating effects, lacrimation, nausea, miosis, bradycardia,
etc.)
(6) Dipyroxime (a cholinesterase reactivator) has euphoriant, antidepressant and stimulant properties, possibly
due to J. acetylcholine levels
Animal Evidence
(1) Cholinesterase inhibitors, like reserpine, cause motor retardation, and j self stimulation in rats and prevent
and antagonize \ locomotion and stereotyped behavior caused by methylphenidate
(2) Reserpine has central parasympathetic effects in animals
illness, be they manics, depressives, or illness, may be a continuum ranging be-
schizoaffectives have a lability, sensitivi- tween "inhibition inactivation" and "ex-
ty, or overreactivity of central cholinergic citation activation." Increasing choliner-
mechanisms in those areas of brain- gic activity may shift behavior in the dir-
regulating affect. This may lead to exces- ection of inhibition and inactivation. Re-
sive cholinergic activity following cholin- lated to this, we have found, in a patient
esterase inhibition. Possibly, schizophren- group including manics and schizophren-
ic patients without an affective compon- ics, that "inhibitory" symptoms caused by
ent to their illness have a less labile, sensi- physostigmine, consisting of lethergy,
tive, or reactive central cholinergic system drained feelings, slow thoughts, with-
than patients with an affective component drawal, apathy, lack of energy, motor re-
to their illness. tardation, and emotional withdrawal were
Concerning the more general anergic ef- rapidly reversed by the amphetaminelike
fects of increasing central acetylcholine psychostimulant, methylphenidate (9).
levels, the results presented suggest that This presumably occurred through an in-
one parameter of human behavior, occur- crease in central adrenergic activity rela-
ring in both affective and schizophrenic tive to central cholinergic activity. Con-
Psychosomatic Medicine Vol. 36, No. 3 (May-June 1974) 255
www.cuwai.com
DAVID S. JANOWSKY, MD, et al.
versely, i.v. methylphenidate induced disorders are caused by an alteration of
central activation, consisting of increased norepinephrine, dopamine, or serotonin.
thoughts, talkativeness, interactions, and The data presented in this paper, for ex-
associations was antagonized by physos- ample, is based on pharmacologic manip-
tigmine. Thus, an amphetaminelike psy- ulations, and may or may not reflect endo-
ch ostimulant and physostigmine antagon- genous events. Furthermore, the nonspeci-
ized each other and had opposite effects fic ability of an agent, such as physostig-
on a behavioral continuum ranging be- mine or reserpine, to cause depression as
tween "excitation activation" and "inhib- a side effect of its psychomotor retardation
ition inactivation." Increasing central ace- inducing effects has not been defined.
tylcholine levels with physostigmine Also, the data presented above was gener-
would seem to shift behavior toward the ally obtained from patients with moderate
"inhibition inactivation" pole of the con- rather than severe affective symptoms.
tinuum, regardless of diagnosis, while in- Nevertheless, the observation that physos-
creasing central adrenergic activity would tigmine can decrease manic symptoms, in-
seem to cause a shift toward the "excita- crease depression in patients with an af-
tion activation" pole. fective component to their illness, and
A definite interpretation of the role of cause a generalized inhibitory state raises
the cholinergic nervous system in affec- the possibility that a "single
tive disorders cannot be made until more neurotransmitter-single mental disease"
is known of the role of acetylcholine in model of psychopathology may be an in-
normal behavior and psychopathologic complete explanation of the cause of emo-
states. Evidence for the involvement of the tional disorders and that acetylcholine
central cholinergic nervous system in af- may be also important in the regulation
fective disorders, as reviewed above, is in- of affect.
direct, as is most evidence that affective
REFERENCES
1. Davis JM: Theories of biological etiology of affective disorders. Int Rev Neurobiol 12:145-175, 1970
2. Janowsky DS, El-Yousef MK, Davis JM, et al: A cholinergioadrenergic hypothesis of mania and depres-
sion. Lancet 1:632-635, 1972
3. Janowsky DS, El-Yousef MK, Davis JM, et al: Parasympathetic suppression of mania by physostigmine.
Arch Gen Psych 28:542-547, 1973
4. Gershon S, Shaw FH: Psychiatric sequelae of chronic exposure to organophosphorus insecticides. Lancet
1:1371-1384, 1961
5. Rowntree DW, Nevin S, Wilson A: The effects of diisopropylfluorophosphonate in schizophrenia and
manic depressive psychosis. J Neurol Neurosurg Psychiat 13:47-62, 1950
6. Bowers MB, Goodman E, Sim VM: Some behavioral changes in man following anticholinesterase admin-
istration. J Nerv Ment Dis 138:383-389, 1964
7. El-Yousef MK, Janowsky DS, Davis JM, et al: Induction of severe depression by physostigmine in mari-
juana intoxicated individuals. In Press, Br J Addict (in press)
8. Rosenblatt JE, Janowsky DS, Davis JM, et al: The augmentation of physostigmine toxicity in the rat
by A9-tetrahydrocannabinol. Res Com Chem Path Pharm 3:478-482, 1972
9. Janowsky DS, El-Yousef MK, Davis JM, et al: Antagonistic effects of physostigmine and methylphenidate.
Presented at the 1973 Annual Meeting of the American Psychiatric Association, Amer J Psychiat (in
press)
256 Psychosomatic Medicine Vol. 36, No. 3 (May-June 1974)
www.cuwai.com
ACETYLCHOLINE AND DEPRESSION
10. Janowsky DS, El-Yousef MK, Davis JM, Sekerke HJ: Cholinergic antagonism of methylphenidate-induced
stereotyped behavior. Psychopharmacologia 27:295-303, 1972
11. Stark P, Boy ES: Effects of cholinergic drugs on hypothalamic self-stimulation response in dogs. Amer
12. Bunney WE, Jr, Hamburg DA: Methods for reliable longitudinal observations of behavior. Arch Gen
Psych 9:114-128, 1963
13. Sulser F, Bickel MH, Brodie BB: The action of desmethylimipramine in counteracting sedation and
cholinergic effects of reserpine-like drugs. J Pharm Exp Ther 321-330, 1964
14. Meduna LJ, Abood LG: Studies of a new drug (ditran) in depressive states. J Neuropsychiat 11:20-23,
1959
15. English DC: Reintegration of affect and psychic emergence with ditran. J Neuropsychiat 3:304-310,
1962
16. Safer DJ, Allen RP: The central effects of scopolamine in man. Biol Psychiat 3:437-455, 1971
17. Ramkhen VF: Use of diproxime, a reactivator of cherase, for the treatment of mental patients.
Neuropat Psychiat Korsakov 71:1872-1877, 1971
Psychosomatic Medicine Vol. 36, No. 3 (May-June 1974) 257
Related docs
