Effect of Lithium on Mood, Cognition, and
Personality Function in Normal Subjects
Lewis L. Judd, MD
R ecently, we have initiated and completed a series of
studies investigating the effects of various psycho-
tropic medications in normal subjects, utilizing chronic
dosage regimens that approximate those used in treating
clinical populations.'-4 We believe that methodological
advantages of this research paradigm allow psychological
and behavioral effects from these drugs to be partialed out
and identified more clearly in a normal sample than in
patient populations responsive to a particular psychotropic
medication. We have hypothesized that normative data on
the effects of psychotropic medications will be helpful in
delineating the behavioral and psychological mechanisms
that underlie and mediate desired clinical changes in
patient populations. This experimental approach is best
exemplified by the series of studies that we have conducted
over the past few years to identify the effects occurring in
normal subjects maintained at therapeutic levels.
Certain studies are available that have investigated
what mood and personality effects occur in normal individ-
uals maintained on therapeutic dosage levels of lithium
carbonate. Schou5 and referenced authors reported that
normal subjects experienced only tiredness and muscular
heaviness after lithium carbonate treatment of approxi-
mately 925 mg/day in a seven-day double-blind experi-
ment. These authors themselves took 925 mg/day for three
to six weeks and reported muscular weakness but no
subjective or objective evidence of mood or emotional
changes. When they took approximately 1,850 mg/day,
they experienced a number of symptoms-muscular heavi-
ness, increased irritability, emotional lability, increased
mental effort in initiating physical tasks (inertia), indif-
ference, malaise, passivity, increased hypersensitivity
alternating with a decreased response to environmental
stimuli, being separated from environmental stimuli by a
"glass wall," etc.
Bech et al6 have studied the effects of lithium carbonate
both in patients with affective disorder and in patients
with Meniere's disease and found basically no long-term
effects on personality functions. The study of patients
with M6niere's disease focused on the effects of six
From the Psychiatric Service, San Diego Veterans Administration Hospi-
tal, and the Department of Psychiatry, School of Medicine, University of
California at San Diego, La Jolla, Calif.
860 Arch Gen Psychiatry-Vol 36, July 20, 1979
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months' treatment with lithium carbonate in a double-
blind study on driving skills and on personality factors as
assessed by the Beck depression scale and the Marke-
Nyman personality scale. No consistent effects from
lithium carbonate on driving skills or on the personality of
these patients, as measured by the instruments, was found.
Only the side effects of tremor and increased thirst were
noted.
One of the more intriguing findings emerging from
controlled observations of lithium's effect on human
psychological functions has been the identification of
lithium-related performance deficits in a variety of senso-
ry, motor, and cognitive tasks. Linnoila et all reported a
delay in choice reaction time in normal subjects main-
tained at therapeutic serum levels of lithium and hypothe-
sized a potential information processing delay. Small et al,9
in a controlled study of ten normal subjects, noted many
physical complaints, especially those related to the CNS,
during the second and third week of therapeutic lithium
administration. This was confirmed by items from the
self-rating scales, which indicated a reduction in mental
clarity, alertness, efficiency, and pep. In addition, there
was evidence of impairment in work and school perform-
ance. In a series of studies on manic-depressive patients
receiving lithium, Demers and Heninger'°l'" have described
a lithium-related deficit in simple reaction time, a block-
turning task, the Digit Symbol subtest of the Wechsler
Adult Intelligence Test (WAIS), and a small reduction in
IQ scores. A study by Aminoff et al'2 of mentally subnor-
mal patients receiving lithium reported a significant drop
in IQ scores during lithium treatment. Finally, Marini and
Sheard," studying prisoners receiving lithium, were unable
to find performance deficits in a series of perceptual motor
tests, although it was their impression that performance
was "blunted" during the medication period.
Our interests in the effects of lithium on normal person-
ality function were stimulated by a non-blind study in a
group of normal male subjects in whom we were assessing
the effects of lithium pretreatment on pentobarbital-
induced euphoria. During the lithium maintenance period,
we were surprised at the large number of spontaneous
complaints from the normal subjects in regard to their
personal experiences on lithium. We had anecdotally noted
during the study that there appeared to be general dulling
Lithium in Normals-Judd
 Table 1-Instruments and Experimental Tasks Used Table 2.-Self-Rated Effects of Lithium Carbonate:
in Studying Effects of Therapeutic Lithium Maintenance SHAS and POMS Combined*
on Normal Subjects
Lithium
Assessment of Affect and Mood Placebo Carbonate
Self-rated item Condition Condition t Pt
Profile of Mood States (POMS) Lethargic 1.61 2.13 2.41 .01
Subjective High Assessment Scale (Judd) Exhausted 0.48 0.87 1.68 .05
Subjective State Questionnaire Bewildered 0.17 0.52 2.91 <.01
Adverse Symptom Checklist
Independent rater observation Muddled 0.39 0.83 2.01 .03
Behavioral Observation Scale (Judd) Clearheaded 2.74 2.26 -2.42 .01
"Significant Other" Questionnaire (Judd) Ideas flow easily 2.00 1.48 -1.91 .03
Assessment of Personality Functions Good sexual feelings 1.47 1.22 -1.82 .04
California Psychological Inventory Wish it would last for
Holtzman Inkblot Technique days 1.78 1.26 -1.96 .03
Psychometric Assessment of Creative Functions Lonely 0.39 0.65 1.82 .04
Meier Aesthetic Perception Test
Meier Art Judgment Test Nauseous 1.22 1.48 2.02 .03
Christiansen-Guilford Battery Shaky 0.35 0.91 2.13 .02
Word Fluency
Ideational Fluency *SHAS, Subjective High Assessment Scale; possible range of scores is 1
Expressional Fluency (low) to 6 (high). POMS, Profile of Mood States; possible range of scores is
Associational Fluency 0 (low) to 4 (high).
Assessment of Cognitive and Sensory-Motor Functions tOne-tailed Student's t test.
Average Evoked Responses
Otis Quick-Scoring IQ Test lithium's effects on a wide spectrum of human functions. Listed in
Wechsler Adult Intelligence Scale (WAIS)
Digit Symbol Table 1 are the dependent measures that have been used to assess
Block Design the effects of two weeks of lithium administration on these normal
Trail-Making Test, A and B subjects. These are grouped into five different general categories,
Speed of Closure Test representing subtests of a psychometric inventory, a complete
Minnesota Clerical Test
Number Learning Test psychometric inventory, and rating scales developed and stan-
Standardized Serial Seven Test dardized by others or by our own research group.
Porteus Mazes In the main, the statistical procedures used to analyze the data
Simple Reaction Time Procedure from these studies were correlated t tests or analysis of variance
Posner Information Processing Task
Backward Masking Procedure-Iconic Storage for a repeated measures design. No order effects for lithium and
Assessment of Other Functions placebo presentation were found across the studies. Scores for
Sleep Log (self-rated) those few tests (WAIS-Digit Symbol Substitution and Block
Stanford Sleepiness Scale (self-rated) Design; Trail Making A and B)'4'l in which learning effects were
noted were adjusted by a learning-correction factor calculated for
and blunting of various personality functions during each test.
lithium maintenance, which was confirmed by the data RESULTS
from the self-rating scales indicating that the subjects Lithium Effects on Affect and Mood (N = 23)
experienced generalized subjective dysphoria on lithium. The data from the self-rated measures of affect and
The data reported in this paper summarize the findings mood and other subjective feeling tones in these normal
derived from a series of controlled studies, now completed, subjects reflected a consistent pattern during lithium
which were designed to assess the effects of therapeutic administration. Data from our previous study' gave a basis
maintenance levels of lithium on a wide variety of mood from which to predict in advance the direction of change of
and psychological functions in normal subjects. affect and mood in subjects receiving lithium, enabling
SUBJECTS AND METHODS one-tailed levels of significance to be reported. The items
from the Profile of Mood States (POMS)16 and Subjective
Details of the research methods have been described else- High Assessment Scale (SHAS)2 that changed significant-
where2 l; a brief summary will be presented here for purposes of
orientation. We have now studied a total of 42 young healthy men ly during the period of lithium administration are included
ranging in age from 21 to 31 years (mean, 24 years) who were in Table 2. As can be seen, the subjects reported increased
screened and selected for study participation as previously levels of lethargy, exhaustion, confusion, bewilderment,
reported. All subjects in our studies gave informed consent after and reduced clearheadedness after 14 days of lithium
having the purposes of the study fully explained. In each study a administration. In addition, mean scores on both the
double-blind, randomized, split-half crossover procedure was used Tension and Fatigue scales from the POMS were elevated.
in the administration of lithium carbonate and an inactive placebo Listed in Tables 3 and 4 are the self-rated items from the
(14 days each). Serum lithium levels were monitored twice weekly, Subjective State Questionnaire (SSQ)' and the Adverse
with dosages during the active medication phase adjusted to Symptom Checklist (ASC)' that changed during lithium
achieve serum levels ranging from 0.7 to 1.4 mEq/L (mean, 0.9 administration. It is clear that these items represent a
mEq/L on testing days). A sham dosage adjustment procedure consistent pattern of the subjective changes these subjects
was utilized in the placebo condition. In this experimental design,
two identical testing sessions were administered, one at the end of experienced as a result of receiving lithium. Twenty-five of
the 14-day placebo period and the other after the lithium carbon- 74 items on the SSQ showed changes induced by lithium.
ate maintenance period. These items, when grouped logically into homogenous
A broad range of tasks and instruments were used to evaluate feeling tones, revealed an interesting lithium effect. The

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 Table 3.-Self-Rated Items From Subjective State Table 4.-Items From Adverse Symptom Checklist That
Questionnaire That Changed on Lithium Carbonate Changed on Lithium Carbonate Maintenance*
Maintenance*
Lithium
Lithium Placebo Carbonate
Placebo Carbonate Item Condition Condition t Pt
Item Condition Condition t Pt Twitching 1.95 6.05 -1.96 .04
Feelings of negativism and dysphoria Numb 1.33 2.33 -1.77 .05
Helpless 2.68 3.86 -2.08 .03 Headache 2.05 6.57 -3.10 <.01
Depressed 9.50 11.95 -2.03 .03 Pain 1.48 2.67 -2.18 .02
Miserable 7.41 12.45 -3.01 <.01 Itchy 3.24 4.76 -1.74 .05
Negative toward life 7.71 10.29 -2.46 .01 Dizzy 1.33 4.62 -2.00 .03
Interested 25.90 22.82 2.86 <.01 Faint 1.91 3.67 -2.07 .03
Active 25.27 21.36 3.22 <.01 Stuffy nose 6.38 10.76 -2.10 .03
Empty 10.50 14.14 -2.02 .03 Stuffy head 4.00 7.71 -2.14 .03
Sick 7.41 11.09 -2.38 .02 Hard breathing 1.43 4.04 -2.33 .02
Feelings of tension and agitation Heart pounding 1.86 4.14 -1.97 .04
Restless 14.68 17.36 -1.88 .04
Stomach ache 1.71 3.14 -3.14 <.01
Anxious 12.45 16.95 -2.65 <.01 Dry mouth 2.38 5.38 -1.73 .05
Agitated 11.95 15.91 -3.03 <.01 Nausea 1.33 4.00 -2.59 <.01
Out of control 2.54 4.09 -2.58 <.01
Tense 9.77 14.55 -2.68 <.01 *Scoring on Adverse Symptom Checklist ranges from 1 (low) to 36
Distress 8.14 11.18 -2.19 .02 (high).
Suspicious 9.67 11.71 -2.07 .03 tOne-tailed Student's t test.
Feelings of interpersonal detachment or placebo administration on the 18 individual scales. Of
Want excitement 24.50 22.27 1.95 .03
Be with people 24.55 20.68 2.71 <.01 the 22 possible scoring dimensions in the Holtzman Inkblot
Want attention 22.36 19.05 3.38 <.01 Technique,'8 only two were significantly changed during
Want physical contact 23.32 19.82 2.01 .03 lithium administration. Lithium induced a longer delay in
Feelings of cognitive inefficiency response to the stimulus inkblot (P = .022, two-tailed), and
Attentive 26.59 23.59 2.49 .01 the subjects receiving lithium were more likely to respond
Rapidly changing with a popular response (P = .048, two-tailed). Thus, only
thoughts 7.59 12.05 -2.61 <.01
Easy to remember 25.05 20.68 2.24 .02 two of a possible 40 scoring variables were influenced by
Confusion 7.27 10.27 -1.72 .05 lithium. Since these effects could have occurred by chance
Can't function 2.73 4.68 -2.75 <.01 alone, we have concluded that there were no significant
Drug effect 7.14 13.29 2.89 <.01 alterations on these personality inventories due to
*Scoring on Subjective State Questionnaire ranges from 1 (low) to 3fi lithium.
{high). Effects of Lithium on Psychometric Assessment of
tOne-tailed Student's t test. Creative Functions (N = 22, N = 14)
first grouping of items indicated increased negativism and Due to varying opinions expressed as to lithium's poten-
depression. The second grouping indicated increased feel- tial influence on creativity, we attempted to assess this
ings of agitation, anxiety, restlessness, and tension. The area using standardized tests that tap aspects of one's
third grouping reflected feelings of withdrawal from capacity in this area of function. No differences from the
contact with others and from interpersonal and environ- subjects' normal performances were noted during lithium
mental demands. The last group was composed of items administration on either of the Meier Art Tests."' Further,
indicating feelings of inefficiency and disrupted cognition. there were no differences between the scores obtained on
A significant number of subjective side effects, as rated on the four Christensen-Guilford Verbal Fluency Tests during
the ASC (Table 4), were also found. Fourteen of the lithium and placebo administration.2"' Thus, lithium did not
possible 32 items on this scale were experienced as being affect performance in semantic creativity or the capacity
changed during or after lithium administration. While a to judge the artistic efforts of others.
number of these items have been commonly reported by Effects of Lithium on Cognitive and Sensory-Motor
patients receiving lithium, several new effects were Performance (N = 22)
observed. It was interesting that trained independent
observers were unable to detect any behavioral changes in Table 5 lists the mean performance scores from the
the subjects induced by lithium, whereas individuals close various cognitive motor tasks contrasting the results
to the subjects (friends, roommates, girlfriends, etc) were obtained during lithium and placebo administration. In
able to identify lithium-related behavioral changes on a general, these results indicate performance deficits seen
questionnaire directed to them. These observed effects after 14 days of lithium carbonate administration. The one
included increased levels of drowsiness and lowered ability exception is the Speed of Closure test,2' on which the
to work hard and to think clearly. subjects receiving lithium scanned fewer letters but made
fewer errors than they did while receiving placebo. It
Effects of Lithium on Psychometric Tests of Personality should be noted that although lithium-related decrements
Function (N = 23) in performance were small, they nonetheless were consist-
No differences were found on the California Psychologi- ent enough to reach statistical significance. In examining
cal Inventory"' in the mean scores achieved during lithium this data more closely, it appeared to us that the deficit

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 Table 5.-Comparison of Scores From Cognitive and
Motor Performance Tests in Lithium Carbonate and
850
Placebo Conditions
Lithium
Testing Instrument Placebo Carbonate P
t 8
Otis 10 Test (10 Score) 120.75 118.54 2.25 .018 800
WAIS Block Design Test 14.38 14.42 -0.05 NS
WAIS Digit Symbol Test 15.09 12.91 2.02 .028 5
Halstead-Reitan Trail Making
A (time, s) 20.15 22.31 -1.82 .041 .S 750
Halstead-Reitan Trail Making
B (time, s) 49.04 52.28 -1.14 NS
Porteus Maze
Time, s 71.00 67.60 -0.21 NS * 700
Errors 4.85 5.35 0.20 NS
Serial 7
No. completed 38.80 37.75 -0.59 NS
No. correct 37.50 37.10 -0.21 NS
650
Speed of closure
No. of letters scanned 358.65 346.45 -0.68 NS
No. of errors 3.60 2.70 -2.07 .025
% Errors 14.73 11.50 -1.87 .034
Minnesota Clerical 600
No. completed 156.50 142.45 -4.02 .001 Simple (AA) Complex (Aa)
No. correct 153.30 137.40 -4.83 <.0001
Cognitive Processing Task Analysis: (N = 22)
'One-tailed Student's t test.
Task Complexity (Simple vs Complex) F= 50.619; df= 1,21; P<.001
Lithium Effect (Overall) F= 5.524; df= 1,21; P= .029
produced by lithium is due to a lithium-related slowing of Lithium x Task Complexity Interaction F= 6.765; df= 1,21; P= .017
performance rather than a reduction of accuracy levels. Simple Task (M)-
The data from these performance tests did not allow us to Lithium vs Placebo NS
partial out whether lithium's effect was due to a simple Complex Task (Aa)- F=9.815; df= 1,17; P= .006
motor slowing or if it was related to an actual slowing of Mean response times in milliseconds for two conditions of
cerebral processing. information processing task comparing lithium and placebo main-
To answer this question, another study was designed to tenance periods in normal subjects.
identify the locus of lithium's action on cognition by using
a simple reaction time procedure and an information
processing task. The information processing task, de- cating that the lithium-induced delay in response time is
scribed by Posner,22 is a letter-matching task in which present during the more complex and higher level of
tachistoscopically presented letter pairs are presented and cognitive processing. This was confirmed by a post hoc
the subjects are asked to indicate whether the pairs are the examination of the lithium factor using the test on simple
same or different. Evidence is now available that suggests main effects, which revealed' that a significant lithium
that a systematic manipulation of the letter pair stimuli effect occurred only during the complex condition of the
can tap two different types and levels of cognitive process- information processing task.
ing. A simpler, swifter type of cognitive processing occurs
when the letter pairs are physically identical, but when Effects of Lithium on Circadian Rhythm of Sleep
non-physically identical pairs are presented, a more (N = 20)
complete, higher level and significantly slower rate of Each morning during the four-week study, subjects
processing occurs. recorded, on awakening, the precise times they had slept
There were no significant differences between the during the previous 24 hours. A standardized sleep log
lithium maintenance and placebo conditions in the simple questionnaire was used that divided the full 24-hour period
reaction time data. The subjects had slightly slower mean into 15-minute intervals. In addition, they filled out the
reaction times after 14 days of lithium administration Stanford Sleepiness Scale,24 which asks specific questions
(192.55 ms) than when receiving placebo (180.61 ms), but about the quantity and quality of sleep and level of
the difference was not significant (t = 1.59, NS). Data alertness on awakening. Complete and usable data was
from the information processing task were analyzed using obtained in 20 of the 22 subjects.25
a within-subjects, two-way analysis of variance with drug Data from the self-report sleep log were analyzed by two
condition (lithium vs placebo) as one factor and the cogni- statistical methods. First, the median point of nocturnal
tive processing task-complexity (physically identical vs sleep was calculated for each of the last seven nights
non-physically identical) as a second factor. The results are during the lithium condition and during the placebo condi-
graphed in the Figure. There is a task complexity effect, tion. These median points were averaged for each subject
which confirms Posner's original observations.22 An overall to obtain the mean midsleep points during lithium and
effect for lithium was found in which the mean processing placebo administration. Secondly, a best-fitting 24-hour
rate is slower during lithium administration. In addition, cosine curve was computed from the sleep log data for the
there was a lithium-by-task complexity interaction, indi- last seven days of lithium and placebo, using the least-

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 squares method. The peak of the fitted curve (the acro-
phase) was selected as an estimate of the peak of the
24-hour sleep-wake rhythm. Both methods agreed closely,
although nocturnal awakenings were weighted somewhat
differently. Daytime naps were included in the cosine fits
but were ignored in the analysis of the nocturnal sleep
medians.
During lithium administration, the subjects' mean
median point of sleep was approximately 14.2 minutes
later than the median point obtained during placebo
administration (correlated t test, t = 2.39, df = 19,
P = .027, two-tailed). Similarly, the 24-hour acrophases
were 3.640 later during lithium as contrasted to placebo
administration (correlated t test, t = 2.37, df = 19,
P = .029, two-tailed), where 3.64° corresponded to 14.6
minutes. Approximately identical significance values were
obtained using the nonparametric Wilcoxon Signed-Rank
test. Since all sleep midpoints and acrophases were
grouped in the early morning hours, a linear model was
justified, and the hypothetically circular distribution of
these data was ignored. Nine of 20 subjects reported some
daytime naps that averaged a total of 19 minutes a day.
Nap duration was not significantly different during the
lithium and placebo conditions. No differences between
lithium and placebo were found on the following dependent
measures: the amplitudes of the fitted 24-hour cosines (a
measure of the peak-trough magnitude of the rhythms);
the mesors of the cosines (a measure of total 24-hour sleep
duration); and the level of sleepiness or alertness on
awakening in the morning. In summary, there was a small
but consistent delay (14.6 minutes and 3.64°) in the sleep-
wake circadian rhythm of these normal subjects during the
lithium condition.
DISCUSSION
The various possible caveats that this particular research
design raises have been discussed in detail in other publi-
cations2 3 and therefore will not be included in this discus-
sion. The data that have been derived from the group of
studies summarized and reported in this paper strongly
suggest that maintenance at therapeutic lithium levels
induces subtle but distinct alterations in certain psycholog-
ical and cognitive functions of normal subjects. Specifical-
ly, there is evidence that lithium produces consistent
changes in the subjective state of healthy normal male
subjects. The feeling tones induced by lithium are those of
lethargy and lassitude, anxiety and tension, and feelings of
loss of clearheadedness with an inability to concentrate.
These findings agree with the anecdotal report of Schoul
and with the study reported by Small et al.9 It is
interesting that these subjective changes were not observ-
able to trained independent observers; they were notice-
able to individuals, blind to the drug condition, who were
more intimately acquainted with the subjects. The impres-
sions of the "significant other" were completely consonant
with the self-rated changes as reported by the subjects
themselves.
No pattern of lithium-related changes were noted in the
two psychometric personality instruments used in our
studies (the California Psychological Inventory and Holtz-
man Inkblot Technique). This is consistent with the find-
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ings of Bech et al,6 who reported no lithium effect on the
Neiman-Mark scale. In addition, lithium did not affect
performances on either of the psychometric instruments
used to assess the subjects' capacity for aesthetic apprecia-
tion and verbal fluency and creativity."20
Whereas these instruments difinitely are limited and do
not evaluate the spectrum of creative efforts, nonetheless
the performance scores indicate that those capacities and
capabilities tapped by these instruments were not
influenced by lithium maintenance.
Both the subjects themselves and their "significant
others" did identify a lithium-related impairment in cogni-
tive functions. These subjective impressions were con-
firmed, since a deficit in performance behavior on a
variety of cognitive sensory motor tasks was found. This is
in agreement with the reports of Heninger," Linnoila et
al,8 and Aminoff et al,12 in which similar deficits were also
noted. A closer examination of our data revealed that speed
of performance was affected by lithium, whereas accuracy
levels were not. Another study was initiated in an attempt
to identify where lithium's effect on performance was
primarily being manifested. The data from the study of
information processing suggest that lithium does affect
the rate at which information is processed. This is
supported by the fact that lithium did not alter perform-
ance on the simple reaction time test or the simple task of
the information processing procedure. Since the motor
component of the response is essentially identical for each
of the tasks and the lithium-related slowing was primarily
manifested during the more complex cerebral processing
component, this would indicate that lithium exerts a
central effect by slowing the rate of cognitive process-
ing.
It is our feeling that this slowing of central cognitive
processing could be one of the behavioral mechanisms by
which lithium exerts a therapeutic effect during manic and
hypomanic states in patients with bipolar affective illness.
Since one of the more distinctive characteristics of the
state is very rapid, pressured, highly distractible speech
and cognition, it is our hypothesis that lithium, by slowing
cognitive processes, may specifically correct the cognitive
disordering that is characteristic of the manic patient. This
will remain speculative until data are available in manic
patients who are tested under these experimental condi-
tions.
The data from the daily self-report questionnaires on
sleep are interesting but should be considered preliminary
in nature. Specifically, it is clear that information of this
nature, derived from self-report rather than from direct
empirical and electrophysiological monitoring, warrants
only the most tentative conclusions. Self-report data are
always subject to inadvertent errors of recall and are
vulnerable to a variety of other influences that could not be
identified or controlled in this particular design. Despite
these limitations, lithium did appear to induce a small but
significant delay in the sleep-wake circadian rhythm of
these normal subjects. Given the fact that environmental
and social synchronizers should be equivalent in both the
lithium and placebo conditions, it tentatively suggests that
the sleep-wake phase delay may be related to lithium's
effect on an endogenous biological oscillator. This would
Lithium in Normals-Judd
 appear to be more likely, since neither the quantity nor
quality of sleep and napping were affected. Basic research
in Meriones, a rodent, and kalanchoe, a plant with a
prominent circadian rhythm phenomenon, has demon-
strated a lithium-related slowing of circadian oscillators.2'
Further, it has been suggested from studies in the few
bipolar depressive patients in a manic state that desyn-
chronization of circadian rhythms may be a feature of this
illness, in which free-running circadian rhythms are more
rapid (eg, one cycle per 22 hours vs the normal 24-hour
cycle).27 In addition, it is postulated that one of the
effects of lithium carbonate may be to slow the circadian
oscillators in patients with bipolar affective illness.2' These
preliminary self-report data on the sleep-wake circadian
rhythm are consistent with these hypotheses and findings,
and if true, may delineate another behavioral mechanism
underlying lithium's clinical effectiveness. It is our feeling
that the initial results are promising enough to warrant
further investigation using more traditionally objective
methods for the study of biological rhythms.
These studies of lithium's effects in normal subjects
have enabled us to hypothesize two specific behavioral
mechanisms by which clinical changes are mediated in
patients with lithium-responsive disorders. It is our
impression that lithium's effect on cognition and biological
rhythms, observed in normal subjects, would not have been
as easily identified in a patient subject sample as it was in
a normal subject sample. Invariably patients afflicted with
major psychiatric disorders are so discomforted and
distracted by the disease process itself that it often
obfuscates the identification of subtle psychological mech-
anisms altered by the various psychotropic drugs used in
treating mental illness. We feel relatively certain that the
lithium-related effects reported here could only have been
identified in the relative psychological quietude and stabil-
ity of a normal subject who is not experiencing the
dysphoria and disruption of a serious mental disorder. We
are convinced that the study of the effects of each class of
psychotropic drugs, administered in a dosage range and
schedule that approximates their clinical use, in normal
subject samples, is a potentially rewarding and interesting
direction for future clinical psychopharmacological re-
search.
Interpretation of the clinical relevance of Dr Judd's very interest-
ing results in normal subjects requires some consideration of
time-frames. The data in normals were collected during two weeks
of lithium administration. Clinical experience with lithium
suggests that subjective awareness ofcognitive effects is greatest at
the initiation of treatment, and diminishes with time. Thus, the
marked functional effects of lithium noted by Dr Judd may not be
predictive of what patients experience. on long-term maintenance
treatment. Dr Judd makes the interesting point that the cognitive
slowing seen in his study may provide a way of understanding the
beneficial effect of lithium in hypomania. However, a cognitive
slowing mechanism seems more difficult to invoke in understand-
ing the demonstrated antidepressant effect of lithium. (See the
report by Mendels et al, p 845 this issue.) Here again, attention to
the time-frame may be important. The acute effect of lithium on
hypomania is often rapid, that is, within afew days. On the other
hand, the acute antidepressant effects of lithium are often more
gradual, with maximal improvement often not occurring until the
fourth week. It is possible that the initial effects observed by Dr
Judd attenuate, or even rebound at later times.-ED.
Arch Gen Psychiatry-Vol 36, July 20, 1979
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The author wishes to acknowledge the important contributions made by
the following collaborators to each of the individual studies that are
summarized and reported in this communication: Bruce Hubbard, MD,
Leighton Huey, MD, David S. Janowsky, MD, and Daniel F. Kripke, MD.
Nonproprietary Name and Tradmarks of Drug
Lithium carbonate-Eskalith, Lithane, Lithonate, Lithotabs, PFI-
Lithium.
References
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