CURRENT STATUS OF LITHIUM T H E R A P Y IN
A F F E C T I V E DISORDERS
MOGENS SCHOU *
Lithium was introduced into medicine more than one hundred years ago
and into psychiatry 25 years ago. In spite of this long history, it is only
within the last 510 years that the unique properties and particular advan
tages of lithium as a drug have become recognized. Its usage is now sprea
ding rapidly, and almost every month we hear of new uses being claimed
for lithium.
I want to emphasize, however, that at the present time only two uses
of lithium are fully established: the therapeutic use in mania, and the
prophylactic use in recurrent endogenous affective disorders. All other uses
are based on evidence which is not yet fully conclusive even though in some
instances it is quite strong. Systematic trials are required fox further
substantiation. We must keep our minds open to new developments in the
field, for there is presumably still much to be learned about this deceptively
simple and yet so enigmatic drug, the lithium ion.
This paper deals with indications for lithium treatment, the proven, the
tentative, and the disproven. Another paper (Schou, 1975) describes the
practical problems of lithium treatment.
Lithium medication should be continued until the time when spontaneous
remission of the manic episode could be expected. In patients with previous
manic episodes, the history may yield information as to the length of this
time period; in patients with a first manic episode, lithium administration for
12 months may be appropriate in most cases. For patients with frequent
previous manic or depressive episodes or both, prophylactic lithium treatment
should be considered; this may then be administered as a continuation of the
antimanic lithium treatment.
Depression — It has for a long time remained an open question whether
lithium exerts a direct therapeutic action in already existing depressive
illness. The first study of this question was inconclusive (Hansen et al.,
1958). Later studies have given contradictory results. The evidence avai
lable today indicates that lithium does exert a certain therapeutic action
in depression, but it is much less pronounced than the therapeutic action
in mania, and lithium seems rarely, if ever, to be the treatment of choice
for already existing depressive disorder (Mendels, 1973, 1975). Further ex
perience may show whether there are some depressed patients who with
benefit could be treated primarily with lithium.
There has been some uncertainty as to whether lithium administered
concurrently with tricyclic antidepressant drugs might counteract their the
rapeutic action in depression (Schou and Baastrup, 1967). Such a combi
nation might be considered in cases where one wants to start prophylactic
lithium treatment already during a depression in order to achieve effective
prophylaxis against further recurrences as quickly as possible. The question
was subjected to quantitative analysis in a multicenter study carried out
in Scandinavia (Lingjaerde, 1973), which showed that lithium did not diminish
the antidepressant activity of tricyclic antidepressants; on the contrary, in
some cases it seemed to potentiate it. Lithium prophylaxis can accordingly
be started already during the depressive episode when the patient is in anti
depressant treatment. Whether lithium in fact enhances the therapeutic
action is a question which requires further study. Scattered clinical obser
vations (P. C. Baastrup, personal communication, 1974; D. M. Shaw, personal
comunication, 1974) indicate that some patients who have proven refractory
to treatment with tricyclic antidepressants will respond when lithium is
added to the treatment regimen. Also a combination of lithium and a MAO
inhibitor (tranylcypromine) has been used successfully for previously intracta
ble depressions (Himmelhoch et al., 1972).
years. A consistent finding seems to be some diminution of the affective
element of the disorder, but the evidence hardly indicates any practical use
of lithium for the direct treatment of schizophrenia (reviews: Quitkin et
al., 1973; Kline and Simpson, 1975).
Recurrent endogenous affective disorders of the polar and the monopolar
type — The most controversial issue in the lithium field has been the pro
phylactic action of lithium in recurrent endogenous affective disorders, that
is, its ability to attenuate or prevent further manic and depressive episodes.
When reports of such an action first appeared, the notion of prophylaxis
was a relatively unknown one in psychiatry, and many psychiatrists found
it difficult to believe in the reality of this phenomenon. The debate ge
nerated by the first reports led to a useful clarification of methodological
and conceptual issues and to the initiation of a number of further studies
on lithium prophylaxis (reviews: Schou, 1973; Schou and Thomsen, 1975).
The evidence for a prophylactic action of lithium in recurrent endogenous
affective disorders is now very weighty and includes twogroup doubleblind
studies as well as onegroup nonblind studies. The latter were based on
certain assumptions concerning the nature and the course of recurrent endo
genous affective disorders; these assumptions have been validated.
There is hardly any reason to review all the studies, but it may be of
interest to present briefly the outcome of the eight twogroup doubleblind
studies on lithium prophylaxis. They differ somewhat as regards design,
presentation of data, and statistical treatment of the results. In order to
make their results comparable, we have derived new data from those pre
sented originally by the authors and subjected them to independent statistical
assessment (Schou and Thomsen, 1975). The design and special features
of the trials are shown in Table 2, where the studies are listed in chronological
order. Their results appear from Table 3, which shows the total number
of patients in each trial; the number who completed the trials without
suffering relapse, one or more, during the trial period; and the number who
completed the trials without suffering relapse. The total number of patients
is counted here as those who entered the trial minus those who dropped out
of it for reasons other than relapse (intercurrent disease, pregnancy, side
effects). Included in the number of patients who relapsed during the trial
are those who dropped out because they relapsed as well as those who
completed the trial in spite of one or more relapses.
During recent years the assertion has occasionally been made that li
thium exerts prophylactic action in bipolar cases and no prophylactic action,
or a considerably smaller one, in monopolar cases. The statement is not
supported by the evidence of the twogroup doubleblind trials, which shows
that the prophylactic efficacy of lithium is as good in the monopolar type of
endogenous affective disorder as in the bipolar type. The misconception
about the less efficient prophylactic action of lithium in monopolar affective
disorder may have arisen from the study of Freyhan et al. (1970) : these
authors started prophylactic lithium treatment in a group of bipolar and a
group of monopolar patients and found a distinct fall in the frequency
of episodes in the former and no change in the frequency of episodes in the
latter group. Examination of their patient sample shows, however, that their
monopolar patients had a low frequency of episodes already before lithium
was given; a further fall could therefore hardly be expected.
The development of a lengthy scientific debate on the question of lithium
prophylaxis is presumably the main reason why so many extensive and
intensive doubleblind studies have been carried out. As a result, lithium
prophylaxis is now based on firmer evidence than many other uses of psychotic
drugs.
protection against further recurrences of depression (Mindham et al.
}1972,
1973; Prien et al., 1973b, 1974; Klerman et al., 1974). In the studies of
Prien et al. (1973b, 1974) imipramine was found prophylactically as effective
as lithium in monopolar cases but less effective in bipolar cases. This whole
question was recently reviewed by Schou (1975). It is to be hoped that
further studies will be carried out, preferably with larger patient groups,
longer observation periods, and attention paid also to the patient's mental
condition during the intervals between episodes. If monitoring of plasma
levels of tricyclic antidepressants turns out to be a guideline for drug
adjustment, this feature should preferably also be included in future studies.
Recurrent schizo-affective disorder — According to the first systematic
study on lithium prophylaxis (Baastrup and Schou, 1967) lithium exerts
a significant but less pronounced prophylactic action in patients with aty
pical features than in those with typical bipolar or monopolar recurrent
affective disorder. These studies have later been extended. Table 4 shows
the results of two studies in which the prophylactic efficacy of lithium in
schizoaffective disorder was compared with the efficacy in bipolar and mo
nopolar affective disorder. The data have been corrected for index episodes.
These studies also show a statistically significant but quantitatively less
pronounced prophylactic action in schizoaffective disorder than in the bipolar
and monopolar types.
This information should be supplemented by observations which in
dicate that also qualitatively the effect of lithium is less good in schizoaffec
tive disorder; usually thought disturbances, hallucinations, and paranoid de
lusions will persist even when manic and depressive mood swings are prevented
or attenuated through lithium treatment. Combination treatment with long
term administration of neuroleptic drugs sometimes leads to very satisfactory
results (Mangoni et al., 1973).
Pathological emotional instability in children and adolescents — It
is a much debated point whether manicdepressive disorder of the same kind
as that seen in adults occurs in children. Annell (1969a, 1969b), Frommer
(1968, 1972) and Feinstein (Feinstein and Wolpert, 1972, 1973; Feinstein,
1973) are among those who claim that childhood manicdepressive disorder
exists, even though it is infrequent. They point out that the disease differs
in course and symptomatology from manicdepressive disorder in adults; cy
cles have a duration of weeks or days rather than months, mania expresses
itself as hyperactivity and "naughtiness" rather than as elation, and during
depressive episodes, sadness is usually less obvious than withdrawal, school
phobia, and hypochondriasis.
needed in order to define more clearly those cases in which lithium treatment
may prove beneficial.
Some psychiatrists from New York (Rifkin et al., 1972) have described
a condition in adolescents which they term "emotionally unstable character
disorder" and which they distinguish from the hysterical or passiveaggressive
character disorder. They examined 21 patients suffering from emotionally
unstable character disorder in a sixweek doubleblind crossover comparison
of lithium and placebo and found lithium significantly superior to placebo.
They used eight measures of mood and found all eight more normal with
lithium than with placebo.
It should be noted that the ordinary hyperkinetic syndrome in psychotic
children does not respond to lithium treatment (Whitehead and Clark, 1970;
Greenhill et al., 1973).
Pathological periodic aggressiveness — Aggressiveness or assaultiveness
that occurs in episodes or bursts seems to respond favourably to lithium
maintenance treatment. This has been demonstrated in patients suffering
from mental retardation, and the effect of lithium could be noted both
on aggressiveness towards others and on selfmutilation (Dostal and Zvolsky,
1970; Dostal, 1972; Cooper and Fowlie, 1973; Naylor et al., 1974).
Another group of studies seems to have been initiated by the observation
by Weischer (1969) that lithium reduces the aggressiveness of Siamese
fighting fish. Sheard (1971) and Tupin et al. (1973) administered lithium
to psychopaths who were characterized by episodes of violent assaultive beha
viour. Lithium turned out to be clearly superior to placebo. The patients
themselves reported subjective relieff from the treatment, using such ex
pressions as "now I have lost my anger" and "now I can think whether
to hit him or not". Morrison et al. (1973) made similar observations.
These findings, interesting as they are, should be supplemented by
further studies in order to delineate the particular kind of periodic aggressi
veness that responds of lithium.
Periodic alcoholism with depression — Fries (1969) seems to have been
the first to administer lithium for periodic alcoholism. He found good effect
in only 1 out of 17 cases. Much more encouraging results were obtained
by Wren et al. (1974), who administered lithium to patients suffering from
chronic alcoholism associated with nonpsychotic depression. The design was
doubleblind. Out of 73 patients started in the trial, 30 completed it. Li
thium appeared to modify the patient's drinking habits significantly, whereas
placebo had no effect. The patients given lithium had much fewer disabling
drinking episodes than they had had before lithium and also than the patients
given placebo. It is to be hoped that this study will be supplemented by
others in which the clinical characteristics of the patients who respond to
lithium are described in more detail.
Opiate addiction — According to a single tentative report (Scher, 1972),
lithium administration to young heroine addicts led to partial or complete
blocking of the euphoric response, relief of withdrawal symptoms, and re
duction of the "heroine hunger". The report has not yet been substantiated
by further studies. We ourselves tried to give lithium to young morphine
addicts, but found them so unreliable as regards drug intake that a meaning
ful study could not be completed. A study carried out in U . S . A . was
clearly negative (Bunney, 1974, personal communication).
Obsessive-comptilsive neurosis — Any drug for which a wide variety
of indications is claimed must come under suspicion; panaceas do not exist
in the world of reality. It is therefore gratifying to present some diseases
where a lack off effect of lithium has been clearly established. Starting
from Baastrup's observation (Baastrup, 1969) that some monopolar patients
with obsessive personality features became less tense and vigilant during
lithium treatment, Geisler and Schou (1970, 1973) and Hessυ and Thorrell
(1970) carried out doubleblind crossover comparisons of lithium and placebo
in patients suffering from severe obsessivecompulsive neurosis. In none of
these studies did lithium exert better therapeutic action than placebo.
Acute anxiety — Lackroy and van Praag (1971) found lithium unable
to alleviate acute anxiety in nonpsychiatric patients who exhibited signs of
anxiety because they were to undergo myelography.
Premenstrual dysphoria — Sletten and Gershon (1966) and Rosman (1969)
administered lithium to patients suffering from premenstrual dysphoria and
obtained promising results. This indication was tested by Singer et al. (1974)
and Mattsson and von Schoultz (1973), who compared lithium and placebo
in doubleblind crossover studies. In none of the studies was lithium found
superior to placebo.
R E F E R E N C E S
1 . ANGST, J . ; DITTRICH, A . & GROF, P . — T h e course of e n d o g e n o u s a f f e c t i v e psychoses and i t s m o d i f i c a t i o n by p r o p h y l a c t i c a d m i n i s t r a t i o n of i m i p r a m i n e and l i t h i u m . Int. P h a r m a c o p s y c h i a t . 2 : 1 , 1 9 6 9 .
2 . ANGST, J . ; W E IS, P . ; GROF, P . ; B A A S T R U P , P . C. & SCHOU, M . — Li t h i u m p r o p h y l a x i s in recurrent a f f e c t i v e disorders. B r i t . J . P s y c h i a t . 116: 604, 1970.
3 . A N N E L L , A . L . — L i t h i u m in t h e t r e a t m e n t of children a n d a d o l e s c e n t s . A c t a p s y c h i a t . s c a n d . s u p p l . 207:19, 1 9 6 9 a .
4 . A N N E L L , A . L . — M a n i c d e p r e s s i v e i l l n e s s in children and effect of t r e a t m e n t w i t h l i t h i u m c a r b o n a t e . A c t a p a e d o p s y c h i a t . 36:292, 1 9 6 9 b .
5 . B A A S T R U P , P . C. & SCHOU, M . — L i t h i u m as a p r o p h y l a c t i c a g e n t . I t s effect a g a i n s t recurrent depressions and m a n i c d e p r e s s i v e p s y c h o s i s . Arch, gen. P s y c h i a t . 16:162, 1967.
6. BAASTRUP, P . C. — P r a c t i c a l clinical v i e w p o i n t s r e g a r d i n g t r e a t m e n t w i t h l i t h i u m . A c t a p s y c h i a t . s c a n d . s u p p l . 207:12, 1 9 6 9 .
8 . BUENO, J . R . ; COSTA E SILVA, J . A . ; F R E I T A S , C. M . ; LOYELLO, W . ; V I A N N A FILHO, R O B A L I N H O , R. & D A SILVA, J. C. — E x p e r i κ n c i a clνnica e r e s u l t a d o s t e r a p κ u t i c o s do uso c o n t i n u a d o de c a r b o n a t o de litio na psicose m a n i a c o d e p r e s s i v a . J . B r a s i l . P s i q u i a t . 22:45, 1 9 7 3 .
9 . CADE, J . F . J . — L i t h i u m s a l t s in t h e t r e a t m e n t of p s y c h o t i c e x c i t e m e n t . M e d . J . A u s t . 36:349, 1 9 4 9 .
1 0 . COOPER, A . F . & FOWLIE, H . C. — Control of gross s e l f m u t i l a t i o n w i t h l i t h i u m c a r b o n a t e . B r i t . J . P s y c h i a t . 122:370, 1 9 7 3 .
1 1 . COPPEN, A . ; NOGUERA, R . ; BAILEY, J . ; B U R N S , B . H . ; SWANI, M . S . ; HARE, E . H . ; GARDNER, R . & MAGGS, R . — P r o p h y l a c t i c l i t h i u m in a f f e c t i v e disorders. Controlled t r i a l . L a n c e t 11:275, 1 9 7 1 .
1 2 . CUNDALL, R . L . ; BROOKS, P . W . & MURRAY, L . G. — A c o n t r o l l e d e v a l u a t i o n of l i t h i u m p r o p h y l a x i s in a f f e c t i v e disorders. P s y c h o l . M e d . 2:308, 1 9 7 2 .
1 3 . DAOU, B . ; CONDOTTA, J . L . ; D E F R E I T A S , A . P . ; DORETTO, M . C. & D E PΑDUA, F . C. — R e v i s γ o bibliográfica e e x p e r i κ n c i a com c a r b o n a t o de l i t i o . J . P s i c o l . profunda a p l i c a d . 3 : 9 1 , 1 9 7 4 .
1 4 . DOSTAL, T . — A n t i a g g r e s s i v e e f f e c t of l i t h i u m s a l t s in m e n t a l l y retarded a d o l e s c e n t s . In D e p r e s s i v e S t a t e s in Childhood and A d o l e s c e n c e — Anell, A. L. ( e d . ) . A l m q v i s t a n d W i k s e l l , S t o c k h o l m , 1972, p a g . 4 9 1 .
1 5 . DOSTAL, T . & ZVOLSKY, P . — A n t i a g g r e s s i v e effect of l i t h i u m s a l t s in s e v e r e m e n t a l l y retarded a d o l e s c e n t s . Int. P h a r m a c o p s y c h i a t . 5:203, 1 9 7 0 . 1 6 . DYSON, W . L . .& BARCAI, A . — T r e a t m e n t of children of l i t h i u m r e s p o n d i n g
p a r e n t s . Curr. T h e r . R e s . 12:286, 1 9 7 0 .
1 7 . EGLI, H . — E r f a h r u n g e n m i t der L i t h i u m p r o p h y l a x e p h a s i s c h e r a f f e k t i v e r E r k r a n k u n g e n in einer p s y c h i a t r i s c h e n Poliklinik. E l f o l g e u n d N e b e n w i r k u n g e n . S c h w e i z . m e d . W s c h r . 101:157, 1 9 7 1 .
1 8 . F E I N S T E I N , S. C. — D i a g n o s i s and t h e r a p e u t i c a s p e c t s of m a n i c d e p r e s s i v e i l l n e s s in e a r l y c h i l d h o o d . E a r l y Childhood D e v e l o p m e n t and Care 3 : 1 , 1973. 1 9 . F E I N S T E I N , S. C. & WOLPERT, E . A . — L a m a l a d i e m a n i a c o d ι p r e s s i v e j u
v e n i l e . Considerιrations c l i n i q u e s e t t h ι r a p e u t i q u e s . P s y c h i a t . Enf. 15:133, 1 9 7 2 .
2 0 . F E I N S T E I N , S. C. •& W O L P E R T , E . A . — J u v e n i l e m a n i c d e p r e s s i v e i l l n e s s : clinical and t h e r a p e u t i c c o n s i d e r a t i o n s . J . A m e r . A c a d . Child P s y c h i a t . 12: 123, 1 9 7 3 .
2 1 . F I E V E , R . R . ; P L A T M A N , S. R . & PLUTCHIK, R. R. — The u s e of l i t h i u m in a f f e c t i v e disorders: p r o p h y l a x i s of depression in chronic r e c u r r e n t a f f e c t i v e disorder. A m e r . J . P s y c h i a t . 125:492, 1 9 6 8 .
2 2 . F R E Y H A N , F . A . ; O'CONNELL, R . A . & MAYO, J . A . — T r e a t m e n t of mood disorders w i t h l i t h i u m c a r b o n a t e . I n t . P h a r m a c o p s y c h i a t . 5:137, 1970. 2 3 . FRIES, H . — E x p e r i e n c e w i t h l i t h i u m c a r b o n a t e t r e a t m e n t a t a psychiatric d e p a r t m e n t in t h e period 19641967. A c t a p s y c h i a t . s c a n d . s u p p l . 207:41, 1969.
2 4 . FROMMER, E . A . — D e p r e s s i v e i l l n e s s in c h i l d h o o d . In R e c e n t D e v e l o p m e n t s in A f f e c t i v e Disorders — Coppen, A . & Walk, A . ( e d s . ) . Headley, London, 1968, p á g . 117.
2 5 . FROMMER, E . A . — D i a g n o s i s and T r e a t m e n t in Clinical P s y c h i a t r y . W i l l i a m H e i n e m a n n , London, 1972, pp. 45, 53, 1 7 2 .
2 6 . GEISLER, A . •& SCHOU, M . — L i t h i u m ved t v a n g s n e u r o s e r . E n dobbeltblind t e r a p e u t i s k u n d e r s o g e l s e . N o r d . P s y k i a t . T . 23:493, 1 9 7 0 .
2 7 . GEISLER, A . & SCHOU, M . — L i t h i u m t r e a t m e n t of o b s e s s i v e c o m p u l s i v e n e u r o s i s : a doubleblind t h e r a p e u t i c trial w i t h n e g a t i v e r e s u l t . F o r e i g n P s y c h i a t . 2:90, 1 9 7 3 .
2 9 . GRAM, L . F . & R A F A E L S E N , O. J . — L i t h i u m t r e a t m e n t of p s y c h o t i c children and a d o l e s c e n t s . A c t a p s y c h i a t . s c a n d . 48:253, 1 9 7 2 .
3 0 . GRAM, L . F . & R A F A E L S E N , O. J . — L i t h i u m t r e a t m e n t of psychotic c h i l d r e n . In D e p r e s s i v e S t a t e s in Childhood and A d o l e s c e n c e — A n n e l l , A. L. ( e d . ) . A l m q v i s t and Wiksell, S t o c k h o l m , 1972, pág. 4 8 8 .
3 1 . G R E E N H I L L , L . L . ; R I E D E R , R . O . ; W E N D E R , P . H . ; BUCHSBAUM, M. •& ZAHN, T . P . — L i t h i u m c a r b o n a t e in t h e t r e a t m e n t of h y p e r a c t i v e children. A r c h . g e n . P s y c h i a t . 28:636, 1 9 7 3 .
3 2 . GROF, P . & VINAR, O. — M a i n t e n a n c e and prophylactic i m i p r a m i n e doses in recurrent d e p r e s s i o n s . A c t i v . n e r v . S u p . ( P r a h a ) 8:383, 1 9 6 6 .
3 3 . H A N S E N , C. J . ; R E T B 0 L L , K. & SCHOU, M. — Unpublished d a t a concer n i n g a doubleblind trial on t h e t h e r a p e u t i c effect of lithium in depression 1958), quoted in Schou, M. — P s y c h o p h a r m a c o l o g i a Berlin 1:65, 1969.
3 4 . HESSO, R . & THORELL, L . H . — L i t i u m b e h a n d l i n g vid t v a n g s n e u r o s e r . E n liten k l i n i s k t e r a p e u t i s k p i l o t u n d e r s υ k n i n g a v dubbelblind crossover typ. Nord. psykiat. 23:496, 1 9 7 0 .
3 5 . HIMMELHOCH, J . M . ; DETRE, T . ; KUPFER, D . J . ; SWARTZBURG, M. & BYCK, R . — T r e a t m e n t of p r e v i o u s l y i n t r a c t a b l e depressions w i t h t r a n y l c y promine and l i t h i u m . J . n e r v . m e n t . D i s . 155:216, 1 9 7 2 .
3 6 . H O R D E R N , A . ; BURT, C. G.; W . F . & HOLT, N . F . — A m i t r i p t y l i n e in d e p r e s s i v e s t a t e s : s i x m o n t h t r e a t m e n t r e s u l t s . B r i t . J . P s y c h i a t . 110:641, 1 9 6 4 .
3 7 . HULLIN, R . P . ; M c D O N A L D , R . & ALLSOPP, M . N . E . — P r o p h y l a c t i c li t h i u m in recurrent a f f e c t i v e disorders. L a n c e t 1:1044, 1 9 7 2 .
3 8 . KLERMAN, G. L . ; DIMASCIO, A . ; WEISSMAN, M . ; PRUSOFF, B . & P A Y KEL, E . S. — T r e a t m e n t of depression by d r u g s and p s y c h o t h e r a p y . A m e r . J . P s y c h i a t . 131:186, 1974.
3 9 . K L I N E , N . S. & SIMPSON, G. — L i t h i u m in the t r e a t m e n t of conditions o t h e r t h a n a f f e c t i v e disorders. In L i t h i u m R e s e a r c h and T h e r a p y — Johnson, F . N . ( e d . ) . A c a d e m i c Press, London, 1975.
4 0 . LACKROY, G. H . •& V A N PRAAG, H . M . — L i t h i u m s a l t s as s e d a t i v e s . A n i n v e s t i g a t i o n into t h e possible effect of l i t h i u m on a c u t e a n x i e t y . A c t a p s y c h i a t . s c a n d . 47:163, 1 9 7 1 .
4 1 . L I N G J A E R D E , O. — S y n e r g i s t i c effect of tricyclic a n t i d e p r e s s a n t s and l i t h i u m c a r b o n a t e in e n d o g e n o u s d e p r e s s i o n . L a n c e t 11:1260, 1 9 7 3 .
4 2 . LΣPEZIBOR ALIΡO, J . J . & LΣPEZIBOR ALIΡO, J . M . — I n d i c a t i o n s of l i t h i u m s a l t s in p s y c h o s o m a t i c m e d i c i n e . I n t . P h a r m a c o p s y c h i a t . 5:187, 1 9 7 0 . 4 3 . MANGONI, A . ; CAZZULLO, C. L . ; A N D R E O L I , V . ; CABIBBE, F . ; MEANI, E . & V I L L A N I , F . — C l i n i c a l b i o l o g i c a l c o r r e l a t i o n s in S c h i z o a f f e c t i v e p a t i e n t s t r e a t e d w i t h l i t h i u m c a r b o n a t e and h a l o p e r i d o l . R e v . s p e r . f r e n i a t . 97: 731, 1973.
4 4 . MATTSSON, B . & VON SCHOULTZ, B . — L i t h i u m vid p r e m e n s t r u e l l s p a n n i n g . N o r d . p s y k i a t . 27:406, 1 9 7 3 .
4 5 . MELIA, P . I . — P r o p h y l a c t i c l i t h i u m in recurrent a f f e c t i v e disorders: four y e a r s t u d y . J . Irish Med A s s . 63:353, 1970.
4 6 . MENDELS, J . — L i t h i u m a n d d e p r e s s i o n . In L i t h i u m . I t s R o l e in P s y c h i a t r i c R e s e a r c h and T r e a t m e n t — Gershon, S. & Shopsin, B. ( e d s . ) . P l e n u m , N e w York and London, 1973, pág. 2 5 3 .
4 7 . MENDELS, J . — L i t h i u m in t h e a c u t e t r e a t m e n t of depresive s t a t e s . In L i t h i u m R e s e a r c h and T h e r a p y — J o h n s o n , F . N . ( e d . ) , A c a d e m i c Press, L o n don, 1 9 7 5 .
4 8 . MINDHAM, R . H . S . ; H O W L A N D , C. & S H E P H E R D , M . — C o n t i n u a t i o n t h e r a p y w i t h tricyclic a n t i d e p r e s s a n t s in depressive i l l n e s s . L a n c e t 11:854, 1972.
5 0 . MORRISON, S. D . ; E R W I N , C. W . ; GIANTURCO, D . T . & GERBER, C. J . — T h e effect of l i t h i u m on c o m b a t i v e b e h a v i o r in h u m a n s . D i s . N e r v . S y s t . 34: 186, 1 9 7 3 .
5 1 . NAYLOR, G. J . ; D O N A L D , J . M . ; LE P O I D E V I N , D . & REÍD, A . H . — A doubleblind trial of l o n g t e r m l i t h i u m t h e r a p y in m e n t a l d e f e c t i v e s . Brit. J . P s y c h i a t . 124:52, 1 9 7 4 .
5 2 . OLTMAN, J . E . & F R I E D M A N , S . — R e l a p s e s f o l l o w i n g t r e a t m e n t w i t h a n t i d e p r e s s a n t d r u g s . D i s . N e r v . S y s t . 25:699, 1 9 6 4 .
5 3 . PEET, M. — L i t h i u m in t h e a c u t e t r e a t m e n t of m a n i a . In L i t h i u m R e s e a r c h and T h e r a p y — Johnson, F . N . ( e d . ) . A c a d e m i c Press, London, 1975. 5 4 . PLATMAN, S. R . — Comparison of l i t h i u m c a r b o n a t e and i m i p r a m i n e in
p r e v e n t i o n of m a n i c d e p r e s s i v e d i s e a s e . D i s . N e r v . S y s t . 31:132, 1 9 7 0 . 5 5 . P R I E N , R. F . ; CAFFEY, E . M . & KLETT, J . — P r o p h y l a c t i c efficacy of
l i t h i u m c a r b o n a t e in m a n i c d e p r e s s i v e i l l n e s s . A r c h . G e n . P s y c h i a t . 28:337, 1973a.
5 6 . P R I E N , R. F . ; KLETT, C. J . & CAFFEY, E . M. — L i t h i u m c a r b o n a t e and i m i p r a m i n e in p r e v e n t i o n of a f f e c t i v e e p i s o d e s : a c o m p a r i s o n in recurrent a f f e c t i v e i l l n e s s . A r c h . G e n . P s y c h i a t . 29:420, 1 9 7 3 b .
5 7 . P R I E N , R. F . ; KLETT, C. J . & CAFFEY, E . M. — L i t h i u m p r o p h y l a x i s in recurrent a f f e c t i v e i l l n e s s . A m e r . J . P s y c h i a t . 131:198, 1 9 7 4 .
5 8 . QUITKIN, F . M . ; R I F K I N , A . & K L E I N , D . F . — L i t h i u m in o t h e r psy c h i a t r i c disorders. In L i t h i u m . Its R o l e in P s y c h i a t r i c R e s e a r c h and T r e a t m e n t — Gershon, S. & Shopsin, B . ( e d s . ) . P l e n u m , N e w York, 1973, p á g . 2 9 5 .
5 9 . REVUSKY, S. — Some laboratory p a r a d i g m s for c h e m i c a l a v e r s i o n t r e a t m e n t of a l c o h o l i s m . J . B e h a v . T h e r . E x p . P s y c h i a t . 4:15, 1 9 7 3 .
6 0 . R I F K I N , A . ; QUITKIN, F . ; CARRILLO, C ; BLUMBERG, A . G. & K L E I N , D . F . — L i t h i u m in e m o t i o n a l l y u n s t a b l e c h a r a c t e r disorder. A r c h . Gen. P s y c h i a t . 27:519, 1 9 7 2 .
6 1 . ROSMAN, C. — Discussion ( w i t h d a t a on l i t h i u m a d m i n i s t r a t i o n a g a i n s t pre m e n s t r u a l t e n s i o n ) . A c t a p s y c h i a t . s c a n d . s u p p l . 207:89, 1969.
6 2 . SCHER, J . M. — L i t h i u m c a r b o n a t e in o p i a t e d e t o x i f i c a t i o n : a p r e l i m i n a r y report. P a p e r presented a t t h e 2n d
I n t e r n a t i o n a l S y m p o s i u m on D r u g Abuse, M a y 29, 1972, J e r u s a l e m .
6 3 . SCHOU, M. & B A A S T R U P , P . C. — L i t h i u m t r e a t m e n t of m a n i c d e p r e s s i v e disorder. D o s a g e and c o n t r o l . J . A m e r . M e d . A s s . 201:696, 1967.
6 4 . SCHOU, M . — L i t h i u m in p s y c h i a t r i c t h e r a p y and p r o p h y l a x i s . A r e v i e w w i t h special regard to its use in c h i l d r e n . In D e p r e s s i v e S t a t e s in Childhood and A d o l e s c e n c e — Annell, A . L . (ed.) . A l m q v i s t and Wiksell, S t o c k h o l m , 1972, pág. 4 7 9 .
6 5 . SCHOU, M. —• P r o p h y l a c t i c l i t h i u m m a i n t e n a n c e t r e a t m e n t in recurrent e n d o g e n o u s a f f e c t i v e disorders. In L i t h i u m . I t s R o l e in P s y c h i a t r i c R e s e a r c h and T r e a t m e n t — Gershon, S. & Shopsin, B . ( e d s . ) . P l e n u m , N e w York and London, 1973, p á g . 2 6 9 .
6 6 . SCHOU, M . & THOMSEN, K. — L i t h i u m in t h e p r o p h y l a c t i c t r e a t m e n t of recurrent a f f e c t i v e disorders. In L i t h i u m R e s e a r c h and T h e r a p y — Johnson, F . N . ( e d . ) . A c a d e m i c Press, London, 1975.
6 7 . SCHOU, M . (1975) — P r o p h y l a c t i c and m a i n t e n a n c e t h e r a p y in recurrent a f f e c t i v e disorders. P a p e r read a t The T u l a n e I n t e r n a t i o n a l S y m p o s i u m on Depression, N o v e m b e r 1 9 7 4 . (To be p u b l i s h e d ) .
6 8 . SEAGER, C. P . & BIRD, R . L . — I m i p r a m i n e w i t h electrical t r e a t m e n t in depression: a controlled t r i a l . J . M e n t . S c i . 108:704, 1 9 6 2 .
6 9 . S H E A R D , M. H . — Effect of l i t h i u m on h u m a n a g g r e s s i o n . N a t u r e 230:113, 1971.
7 0 . SINGER, K . ; CHENG, R . & SCHOU, M. — A controlled e v a l u a t i o n of l i t h i u m in t h e p r e m e n s t r u a l t e n s i o n s y n d r o m e . B r i t . J . P s y c h i a t . 124:50, 1974. 7 1 . SLETTEN, I . W . & GERSHON, S. — The p r e m e n s t r u a l s y n d r o m e : a discussion
7 2 . STALLONE, F . ; SHELLEY, E . ; MENDLEWICZ, J . & F I E V E , R . R . — T h e use of l i t h i u m in a f f e c t i v e disorders: a doubleblind s t u d y of p r o p h y l a x i s in bipolar i l l n e s s . A m e r . J . P s y c h i a t . 130:1006, 1 9 7 3 .
7 3 . TUPIN, J . P . ; SMITH, D . B . ; CLANON, T . L . ; KIM, L . I . ; N U G E N T , A. & GROUPE, A . — T h e l o n g t e r m use of l i t h i u m in a g g r e s s i v e prisoners. Com p r e h e n s . P s y c h i a t . 14:311, 1 9 7 2 .
7 4 . U D D E N B E R G , G. — D i s c u s s i o n w i t h d a t a on l i t h i u m t r e a t m e n t in children. A c t a p s y c h i a t . s c a n d . s u p p l . 207:31, 1969.
7 5 . VYBOROVA, L . & N Á H U N E K , K. — Clinical e x p e r i e n c e w i t h o c t o c l o t h e p i n e and l i t h i u m in child i n s t a b i l i t y . A c t i v . n e r v . s u p . ( P r a h a ) 15:104, 1 9 7 2 . 7 6 . WEISCHER, M. L . — Ober die a n t i a p r e s s i v e W i r k u n g v o n L i t h i u m . P s y c h o
p h a r m a c o l o g i a (Berlin) 15:245, 1 9 6 9 .
7 7 . W H I T E H E A D , P . L . & CLARK, L . D . — Effect of l i t h i u m c a r b o n a t e , p l a c e b o and t h i o r i d a z i n e on h y p e r a c t i v e c h i l d r e n . A m e r . J . P s y c h i a t . 127:824, 1 9 7 0 . 7 8 . W R E N , J . C ; K L I N E , N . S. ; COOPER, T . B . ; VARGA, E . & CANAL, O.
— E v a l u a t i o n of l i t h i u m t h e r a p y in chronic a l c o h o l i s m . Clin. Med. 8 1 : 3 3 , 1974.
