A P h a r m a c o g e n e t i c Case Report: Lithium-responsive Postpsychotic Antisocial Behavior J e r o m e H. L i e b o w i t z , V i c t o r R u d y , E l l i o t S. G e r s h o n . a n d A a r o n G i l l i s
U P I N ' S R E V I E W o f t h e use o f l i t h i u m in n o n m a n i c - d e p r e s s i v e c o n d i t i o n s p r o p o s e s t h a t aggressiveness and episodic Course a r e biologically r o o t e d beh a v i o r a l v a r i a b l e s t h a t c h a r a c t e r i z e all cases o f l i t h i u m - r e s p o n s i v e d i s o r d e r s . ~ S e v e r a l l a t e r studies and a n e c d o t a l c a s e r e p o r t s a r e highly s u g g e s t i v e o f a specific a n t i a g g r e s s i v e e f f e c t o f lithium. 2-4~ S e a r c h i n g f o r clinical f a c t o r s p r e d i c t i v e o f lithium r e s p o n s i v e n e s s , such studies focu~ on a least c o m m o n d e n o m i n a t o r o f clinical s y m p t o m a t o l o g y . P h a r m a c o g e n e t i c studies, on t h e o t h e r h a n d , can provide i n f o r m a t i o n on t h e r a n g e a n d q u a l i t y o f clinical s y m p t o m s t h a t pres u m a b l y a r e m a n i f e s t a t i o n s o f a single biologic d e f e c t . Fieve, reviewing t h e d a t a on t h e use o f lithium in various p s y c h i a t r i c d i s o r d e r s t h a t m i g h t r e p r e s e n t "'mixed, m a s k e d , ~m i s d i a g n o s e d or poorly-classified m a n i c - d e p r e s s i v e conditions,'" h y p o t h e s i z e d t h a t " t h e m o r e p r e d o m i n a n t t h e m a n i c c o m p o n e n t a n d t h e family history o f m a n i a in a n y o f t h e s e illnesses, t h e m o r e effective will b e the l i t h i u m therapy.'"~ P h a r m a c o g e n e t i c studies, looking at lithium r e s p o n s i v e n e s s a n d family h i s t o r y ; h a v e found l i t h i u m r e s p o n s i v e n e s s to be a s s o c i a t e d with a f a m i l y history, o f bipolar affective illness in m a n i c - d e p r e s s i v e p a t i e n t s 6.z a n d with a f a m i l y h i s t o r y o f " m o o d s w i n g s " in unipOlar depressives, s Baron et al., ~ in a s m a l l e r s a m p l e o f d e p r e s s e d p a t i e n t s , failed to find an a s s o c i a t i o n b e t w e e n family h i s t o r y o f affective d i s o r d e r and lithium r e s p o n s i v e n e s s . In t h e c a s e r e p o r t e d h e r e , a p a t i e n t with episodes o f p s y c h o s i s a n d s o c i o p a t h i c like b e h a v i o r b e t w e e n episodes was t r e a t e d with l i t h i u m in a double-blind c r o s s o v e r design. A f a m i l y h i s t o r y o f l i t h i u m - r e s p o n s i v e illness a n d r e c u r r e n t d e p r e s s i o n , as well as c e r t a i n e l e m e n t s o f his b e h a v i o r (his a g g r e s s i v e n e s s , impulsivity, a n d h y p e r a c t i v i t y ) t h a t c o n t i n u e d to c h a r a c t e r i z e him b e t w e e n his p s y c h o t i c episodes, suggested t h a t his b e h a v i o r d i s o r d e r m i g h t be r e s p o n s i v e to lithium.
T
CASE
HISTORY
T h e p a t i e n t is a 2 2 - y e a r - o l d u n m a r r i e d m a n w h o w a s first a d m i t t e d to a p s y c h i a t r i c h o s p i t a l w h e n he w a s 16 and in an a c u t e p s y c h o t i c s t a t e c h a r a c t e r i z e d by a g i t a t i o n , i n c o h e r e n c e , rapid s p e e c h , a u d i t o r y
From the Department o f Research, Jerusalem M e n t a l Health CenZer-Ezrath Nashim. Je.rusalem. Israel. J e r o m e H . Liebowitz, M . D . : Fellow in Child Psychiatry. A l b e r t Einstein College o f Medicine. Bror~x, N. 1I. (formerly. Visiting Research Fellow, Jerusalem M e n t a l Health C e n t e r - E : r a t h Nashim); V i c t o r R u d y , M . B . B . C h . : S t a f f Psychiatrist. Hillside Division-Long Island Jewish-Hillside Afedical Center. Long Island. N . Y . (former/)'. Resident, Je,'z~aIem Mental Health Center-Ezrath Nashirn); Elliot S, G e r s h o n , M , D , : Unit Chief. Section o f Psychogenetics, A d u h Psychiatr3, Branch, National Institute o f M e n t a l Health. Bethesda, Md, tformertv. Research Director, Jerusalem Mental Health Center--Ezrath Nashim£" A a r o n Gillis, M . B . , F . R . C . P . E . : Clinical Director. Jerusalem M e n t a l Health Center- E~rath Nashim. Supported in part by the Israel Center f o r Psychobiology, U S P H S Grant MH20712-03, and the l~'olfson Foundation { United Kingdom). Reprint requests should be addressed zo Dr. E, S. Gerahon, National Institutes o f Health. Building i0, R o o m 3N218, Bethesda. Md. 20014. ~ 1976 by Grune & S t r a n o n , Inc. Compfehenxive Psyctdatry. Vo|. 17. No. 5 (September/October), 1976
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hallucinations, delusions o f persecution, ideas o f reference, and some crying and suicidal t h r e a t s . H e tried to climb into the refrigerator to "'see television in his eyes" and heard terrifying voices a n d conducted conversations with them. This psychosis lasted about I 0 d a y s . He was diagnosed as schizophrenic, was l r e a t e d with chlorpromazine 800 m g / d a y , and improved rapidly. Two months after admission, he was discharged and returned to school, where h e functioned well for several months. Psychologic testing prior to discharge revealed no evidence o f psyc!~otic processes and a high-normal intelligence. Six months later he was hospitalized againin a p s y c h o t i c stale similar to the first, with the additional features o f elevated m o o d and incessant activity. For the month prior to admission he had been without s¢If-c0nfidence, appeared to be depressed, and believed t h a t everyone Was laughing at him. During this second hospitalization, he had periods o f a week or more of immobility and catatonic posturing, during which he later reported he heard voices and believed the world had become desolate. He was again diagnosed as schizophrenic and treated with phenothiazines, but was not discharged for t year. S t a ~ i n g during, and continuing after, this hospitalization, he behaved f r e q u e n t l y in a criminal manner, forging checks and stealing money. His per/~onalit~" changed considerably from its premorbid state, in that he became manipulative, impulsive, explosive, and somewhat sexually promiscuous. He was hospitalized a third t.ime (the first in our institution) when he was 21-years-old. On that admission, his mood was elevated, and there was some psychomotor restlessness but no obvious thought disorder. H e received chlorpromazine 600 r a g / d a y and was discharged within 2 months. Approximately 2 months later, he was readmitted for 1 month, after having been imprisoned for theft. This time there was no evidence of active psychosis, and he was diagnosed as "'schizophrenic reaction with residual psychopathic traits.'" Six months later he was admitted t o o u r hospital again, under court order, having been certified incompetent to stand trial for forging checks. Clinically, he appeared much as he did during his first hospitalization, with agitation, incoherent and extremely rapid speech, and delusions of persecution and ideas o f reference. He admitted to auditory hallucinations and appeared to be immersed completely in an imaginary world, without any relationship to his surroundings. He was in constant movement, and his behavior wa s aggressive and violent. The acute psychosis was treated unsuccessfully with a maximum daily dosage of chlorpromazine, 1200 rag, plus haloperidol, 15 rag. After failure with drug treatment, he received a course o f ECT with limited success. Three months after the initiation o f t r e a t m e n t , he no longer appeared psychotic and had no affective symptoms. But he did have frequently recurring episodes of aggressive and antisocial behavior. H e was violent toward other patients, stole o t h e r patients" and hospital property (including a car). left the hospital frequently without permission, and committed numerous acts of an impulsive destructive nature, all of which appeared to be ego-syntonic. A double-blind trial o f lithium carbonate alternation with placebo was instiluted. Because o f evidence from this trial favoring the effectiveness o f lithium (see below), he v-as placed on nonblind maintenance lithium therapy at the conclusion o f this study. Approximately I month later, he was discharged f r o m the hospital and has continued to receive lithium as an outpatient. PsYchologic tests prior to discharge revealed intact intellectual functioning on a high-normal ievd. Rorschach and Other projective tests confirmed the intactness of cognitive functioning but recealed rigid control, selflimitation, and inhibition Of spontaneity. A t this writing, nearly 3 years after discharge, he is doing well, having been employed in a printing shop during ~.he entire interval and having attended and completed an evening course to become an electronics technician. Hc has stable interpersonal relations and is a source o f emotional support to his family. He is a much quieter and more self-assured pe.rson. A certain attention-demanding quality that previously characterized almost all his interpersonal behavior is now absent, and subjectively, he reports feeling better than ever.
Family History T h e patient is the older o f two children born to an Orthodox Jewish couple of European extraction. His parents were divorced when he was 12-years-old. His father remarried "without issue, and t h e r e is rio history o f psychiatric illness in him or his family. T h e patient's m o t h e r has a psychiatr/c histot3r o f mild depression in connection with the marriage dating back 20 years, in 1966, she was discovered to have a pituitary tumor after complaints o f amenorrhea, headache, and depression and was placed on steroid and thyroid hormone replacement therapy. One y e a r later she was hospitalized psychiatrically for the first time, after discontinuing the hormones, in a state of organic mental syndrome with severe depression. A chromophobe adenoma was resected in 1968. Since then, she has had several psychiatric hospitalizations for depression and has been treated successfully with tricyclic antidepressants. Her
LITHIUM-FIESPONSIVE POSTPSYCHOTIC ANTISOCIAL BEHAVIOR
657
tumor was found to have recurred in 1972. We are unable to determine to what extent her psychiatric syndrome is secondary to the pituitary t u m o r o r the hormone replacement therapy. His only sibling, a sister 3 years younger, was :treated as an outpatient with psychotherapy for neurotic anxiety and depression at age 16. Three years later, following our patient's double-blind trials, she was hospitalized with mania 2 weeks postpartum and was treated with haloperidol and ehlorpromazine with good response. H e r mania was in no way atypical and included euphoric mood, angry and demanding interpersonal behavior, sexual provocativeness, rapid speech; decreased need for sleep, distractibility, and flight of ideas. She thought God had a special interest in her and had communicated with her, but she did not hear voices or get a verbal message. She was not confused, and there were no hallucinations. After the initial therapeutic success, she relapsed into inania and was then treated with lithium on a double-blind crossover protocol with placebo and was founcl to be a =lithium-responder, with improvement after I week on lithium and relapse when lithium was discontinued. There are 20 first cousins between the a g e s o f 20 and 49, all but one of whom have.no psychiatric illness. A maternal first cousin, a 35-year-old woman, has well documented bipolar manic-depressive illness responsive to lithium. MATERIALS
AND
METHODS
The therapeutic trial consisted o f nine double-blind crossovers between lithium carbonate and placebo during a period of 24 weeks. The length'of each period on lithium or placebo varied randomly between 8 and 23 days. "I~erapeutic blood levels were reached generally 2 or 3 days after taking 1800 rag/day and were maintained between 0.9 and 1.3 mEq/liter. The patient's behavior, thinking, and affect were rated three times per week on the BeigeI-Murphy Manic Rating Scale t° on the basis of his psychiatric state during the previous 24 hr, as related in nursing reports and systemaiie interviews by the blind observer (EG). i~e was also ,seen in individual psychotherapy sessions and was afforded t h e ward milieu therapy and occupational therapy. Systematic family histor3~ interviews, using a modification of the method of Winokur et al., ~= were performed on patient, sister, mother, father, and maternal aunt. Case summaries were obtained from the hospital or treating physician in each instance where psychiatric illness was indicated by the family study. R ESU LTS
The patient's ratings were grouped and averaged separately for each week of t r e a t m e n t . F i g u r e I p r e s e n t s t h e a v e r a g e s c o r e s f o r e a c h o f t h e 2 2 w e e k s in w h i c h ratings were made. The scores invariably improved while on lithium and worsened while on placebo, also reflecting the general staff impression of the patient's behavior during these periods. A gradual improvement with time, irrespective of medication, can also be noted. For statistical analysis, the ratings were grouped according to effective lithium periods (defined as beginning 7 days after starting lithium and ending 2 days after starting placebo) or placebo periods. These revealed a significant difference b e t w e e n t h e t w o g r o u p s b y t t e s t ( p < 0 . 0 5 , t = 2 . 0 7 , df = 6 1 ) , w i t h t h e o v e r a l l average of the lithium group (46.1, SD = 30.4) almost 20 points lower than that of the placebo group (65.1, SD = 41.1). The effect of autocorrelation on the t test, c o n s i d e r i n g t h e o b v i o u s l o n g - t e r m t r e n d in t h e r a t i n g s , is n o t c l e a r . H o w e v e r , a n e c d o t a l e v i d e n c e , in t h e f o r m o f n u r s i n g n o t e s , c o n f i r m s t h i s f i n d i n g , in t h a t e a c h o f t h e s e v e r a l e p i s o d e s Of V i o l e n t , a g g r e s s i v e b e h a v i o r t h a t r e q u i r e d i n t r a m u s c u l a r sedation for control occurred during effectiveplaceb0 periods. In:addition, each t i m e t h e m e d i c a t i o n w a s c h a n g e d , t h e c l i n i c a l s t a t u s c h a n g e d in t h e d i r e c t i o n predicted by drug change (p < 0.002 for 9 crossovers, binomial sign test). Analysis of the individual subscores--the ratings of'the 26 items combined to f o r m t h e t o t a l s c o r e r ° - - - - r e v e a l s t h a t c h a n g e s in m e d i c a t i o n w e r e c o r r e l a t e d w e l l
658
UEBOWJTZ ET AL.
180 ! 170
=First dcly serum Li >0SmF-J:i/L. =F,rst day serum Li *;05 rnUq/L. = =No ratings ovczikable-pl.in joil. • = :No ratings-protocol temporar~y d=scontinued.
~ lf~ ]
100 90 80
[] [] ~
=LITHII.~ PERIOD =PLACEBO PERIOD
$
70 60
H
1 2 3 4 5 6 7 8
Fig. •.
9 10 11 12 13 1/. 15 16 WEEK
18 19 20 21 22 23 2Z,
Extended d o u b l e - b l i n d c l i n i c a l t r i a l o f l i t h i u m carbonate. B e i g e I - M u r p h y rating scale is used status.
to assess clinical
with p o o r j u d g m e n t , c o m b a t i v e n e s s a n d d e s t r u c t i v e n e s s , d e c r e a s e d i m p u l s e control, and h y p e r a c t i v i t y . It is intel:esting to note t h a t c h a n g e s in mood and affect did not c o r r e l a t e with c h a n g e s in m e d i c a t i o n . N e e d for a t t e n t i o n ( d e m a n d i n g c o n t a c t o r seeking o t h e r s ) , sexual p r e o c c u p a t i o n , and g r a n d i o s i t y also fluctuated without any a p p a r e n t correlation. DISCUSSION
T h i s p a t i e n t m a n i f e s t e d a r e c u r r e n t psychotic d i s o r d e r , which, during two admissions, satisfied minimal c r i t e r i a for mania, 12 b u t during his o t h e r a d m i s s i o n s p r e s e n t e d . a s a typical schizophrenic psychosis. T h e p i c t u r e p r e s e n t e d in a psychotic s t a t e a l w a y s included " s c h i z o p h r e n i c ' " s y m p t o m s , and the p e r s o n a l i t y deterioration seen between p s y c h o t i c episodes w a s also suggestive o f a chronic schizophrenic process. T h e behavior d i s o r d e r resulting f r o m this p e r s o n a l i t y c h a n g e (as m e a s u r e d by o v e r t a g g r e s s i v e n e s s and r a t i n g s o f poor j u d g m e n t , c o m b a t i v e n e s s a n d d e s t r u c t i v e n e s s , d e c r e a s e d i m p u l s e control, and h y p e r a c t i v i t y ) i m p r o v e d m a r k e d l y during double-blind lithium t r e a t m e n t . T h e s c h i z o p h r e n i f o r m psychosis w a s also p r o b a b l y r e s p o n s i v e to lithium, since it also has not r e c u r r e d in the 3 y e a r s he h a s been on lithium. T h e effect o f lithium in schizophrenic s t a t e s is o f g r e a t i n t e r e s t . A l t h o u g h excited schizophrenic patients a r e g e n e r a l l y not lithium-responsive, ~8-~9 lithium is r e p o r t e d to be as effective as c h l o r p r o m a z i n e in s o m e (mildly active) schizoaffectires. ~a T h e r e a r e also several a n e c d o t a l a n d nonblind r e p o r t s o f s o m e o f t h e s e p a t i e n t s being responsive to lithium, z. J 2 . ~ - ~ 6 T h e prediction o f clinical r e s p o n s e to a p s y c h o p h a r m a c o l o g i c a g e n t is g e n e r a l l y b a s e d on t h e c a s e diagnosis o r on c u r r e n t l y active t a r g e t s y m p t o m s . Lithium app e a r s to be effective in a r e s t r i c t e d r a n g e o f v a r y i n g clinical s t a t e s . T h e h y p o t h e s i s t h a t this specificity m a y be r e l a t e d to a specific biologic a l t e r a t i o n in t h e s e clinical
L I T H I U M - R E S P O N S I V E POSTPSYCHOTtC A N T I S O C I A L B E H A V I O R
65~
states naturally suggests itself: l.~r As a corollary hypothesis, o n e would predict that a c o m m o n factor (possibly a clinical and behavioral finding, but not necessarily so) could be d e m o n s t r a t e d in all the lithium-responsive states. Our patient manifested the aggressiveness and episodic course suggested by Tupin, ~as well as the impulsitivity (going directly from stimulus to response) postulated by S h a d e r et al. ~ It is not clear, however, whether such a group o f lithium-responsive patients could ever be defined solely on the basis of clinical and behavioral observations. O t h e r types of observations m a y be needed. A family history of bipolar affective disorder a n d / o r lithium responsiveness m a y be a heuristic device for revealing sy n d r o m e s that share lithium responsiveness. This m a y be especially useful for disorders that are generally not responsive to lithium. A systematic study of lithium response in patients with s y m p t o m s that satisfy criteria for both m a n i a and schizophrenia has not been reported, but excited schizophrenic patients a r e generally not good candidates for lithium. ~s.j° Similarly, the hyperkinetic synd r o m e of childhood seems generally unresponsive to lithium, 2° but two children with this syndrome, chosen on the basis of family history of bipolar affective disorder, were found to be responders, albeit on a nonblind basis. 2~ This p a p e r suggests that antisocial behavior ma y be responsive to lithium in patients (whatever the clinical psychiatric diagnosis) with a family history of bipolar affective illness a n d / o r lithium responsiveness. It also suggests a similar correlation for schiz0Phreniform (schizoaffective) psychosis. A set of behavior states m a y be defined that are worth investigating for shared biologic and behavioral characteristics. T h a t is, a single genetically d e t e r m i n e d etiologic factor m a y be present in subgroups of patients in all the disorders in which a family history of affective disorder and lithium responsiveness has been found. T h e s e include.bipolar and unipolar affective disorder, acute schizophrenia-schizoaffective disorder, emotionally unstable character disorder, cyclothymic personality, hyperkinetic s y n d r o m e of childhood, and sociopathy. In addition, the responsiveness to lithium of two (or three) a ppa r e ntly different disorders in one family suggests pleiotropisrn of genes for bipolar illness r a th e r than two genetically distinct disorders. It is our suggestion that patients and their relatives in these lithium-responsive subgroups are especially worth investigation clinically, biologically, and p h a r m a cologically. T he search for genetically related psychiatric disorders m a y be enhanced by such a study, and the biologic and phenomenologic understanding o f the disorders themselves may also be advanced. SUMMARY
A double-blind crossover study was p e r f o r m e d with lithium c a r b o n a t e in a 22year-old man with a 6-year course of schizophrenic-like psychotic episodes and personality deterioration manifested by antisocial behavior. A family history of lithium-responsive manic-depressive illness, as well as certain aspects o f his behavior (aggressiveness, impulsivity, and hyperactivity), prompted the trial. Lithium was found to be effective in reducing overt antisocial behavior, as well as poor j u d g m e n t , hyperactivity, impulsivity, and destructiveness, during a time
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660
when he was no longer psychotic. It also has been effective prophylactically against the previously recurrent schizophreniform psychosis. Use of family history is discussed as a heuristic device for revealing a spectrum of lithium-responsive disorders. REFERENCES 12. Taylor MA, Abrams R: The phe1. Tupin JP: Lithium use in nonmanic depresnomenology of mania. Arch Gen Psychiatry sive conditions. Compr Psychiatry 13: 29:520-522, 1973 209-214, 1972 2. Shader RI, Jackson AH, Dodes LM: The 13. Prien RF, Caffey EM Jr, Klett C J: A comantiaggressive effects of lithium in man. Psycho- parison of lithium carbonate and chi0rp'romazinc pharmacolo~a 40:17=24, 1974 in the treatment of excited schizoaffectives. Arch 3. Sheard MH: Lithium in the treatment of Gen Psychiatry 27:182-189, 1972 aggression. J Nerv Ment Dis 16: ! 08-118, 1975 14. Prien RF, K l e t t C J, Caffey EM Jr: 4. Tupin JP, Smith DB, Ciasson TL, et ai: Lithium carbonate and imipramine in prevention Long term use Of lithium in aggressive prisoners. of affective episodes. Arch Gen Psychiatry Compr Psychiatry 14:311-317, 1973 29:420-425, 1973 5. Fieve RR: Overview of therapeutic and 15. Lipkin KM, Dyrud J, Meyer GG: The prophylactic trials with lithium in psychiatric many faces of mania. Arch Gen Psychiatry patients, in Gershon S, Shopsin B (eds): Lithium: 22:262-267, 1970 Its Rote In Psychiatric Research and Treatment. 16. Dempsey GM, Tsuang MT, Struss A, et New York, Plenum, 1973, pp 317-350 al: Treatment of schizoaffective disorder. Compr 6. Mendtewicz J, Fieve RR, Staltone F: RelaPsychiatry 16:55-59, 1975 tionship between the effectiveness of lithium 17. Singer I, Rotenburg D: Mechanisms of therapy and family history. Am J Psychiatry lithium action. N Engl J Med 289:254-260, 1973 130:1011-1013, 1973 18. Johnson G, Gershon S, Burdock El, et ai: 7. Prima RF, Caffey EM Jr, Klett CJ: Factors Comparative effects of lithium and chlorproassociated with treatment success in lithium carbonate prophylaxis. Arch Gen Psychiatry 31: mazine in the treatment of acute manic states. Br J Psychiatry 119:267-276, 1971 189-192, 1974 19. Shopsin B, Kim SS, Gershon S: A con8. Kupfer D J, Pickar D, Himmelhoch JM. et al: Are there two types of unipolar depression? trolled study of lithium vs. chlorpromazine in acute schizophrenics. Br J Psychiatry 119: Arch Gen Psychiatry. 32:866-871, 1975 9. Baron M, Gershon ES, Rudy V, et al: Lith- 435-440, 1971 20. Greenhill LL, Rieder RO, Wender PH, et ium carbonate response in depression. Arch Gen al: Lithium carbonate in the treatment of Psychiatry 32:1107-1111, 1975 I0. Beigel A, Murphy DL, Bunney WE Jr: The hyperactive children. Arch Gen Psychiatry manic-state rating scale. Arch Gma Psychiatry 28:636-640, 1973 21. Dyson WL, Barcai A: Treatment of 25"256-262, 197l 11. ~qnokur G, Clayton PJ, Reich T: Manic children of lithium-responding parents. Curr "l'her Res 12:286-290, 1970 Depressive Illness. St. Louis, C V Mosley, 1969
U P I N ' S R E V I E W o f t h e use o f l i t h i u m in n o n m a n i c - d e p r e s s i v e c o n d i t i o n s p r o p o s e s t h a t aggressiveness and episodic Course a r e biologically r o o t e d beh a v i o r a l v a r i a b l e s t h a t c h a r a c t e r i z e all cases o f l i t h i u m - r e s p o n s i v e d i s o r d e r s . ~ S e v e r a l l a t e r studies and a n e c d o t a l c a s e r e p o r t s a r e highly s u g g e s t i v e o f a specific a n t i a g g r e s s i v e e f f e c t o f lithium. 2-4~ S e a r c h i n g f o r clinical f a c t o r s p r e d i c t i v e o f lithium r e s p o n s i v e n e s s , such studies focu~ on a least c o m m o n d e n o m i n a t o r o f clinical s y m p t o m a t o l o g y . P h a r m a c o g e n e t i c studies, on t h e o t h e r h a n d , can provide i n f o r m a t i o n on t h e r a n g e a n d q u a l i t y o f clinical s y m p t o m s t h a t pres u m a b l y a r e m a n i f e s t a t i o n s o f a single biologic d e f e c t . Fieve, reviewing t h e d a t a on t h e use o f lithium in various p s y c h i a t r i c d i s o r d e r s t h a t m i g h t r e p r e s e n t "'mixed, m a s k e d , ~m i s d i a g n o s e d or poorly-classified m a n i c - d e p r e s s i v e conditions,'" h y p o t h e s i z e d t h a t " t h e m o r e p r e d o m i n a n t t h e m a n i c c o m p o n e n t a n d t h e family history o f m a n i a in a n y o f t h e s e illnesses, t h e m o r e effective will b e the l i t h i u m therapy.'"~ P h a r m a c o g e n e t i c studies, looking at lithium r e s p o n s i v e n e s s a n d family h i s t o r y ; h a v e found l i t h i u m r e s p o n s i v e n e s s to be a s s o c i a t e d with a f a m i l y history, o f bipolar affective illness in m a n i c - d e p r e s s i v e p a t i e n t s 6.z a n d with a f a m i l y h i s t o r y o f " m o o d s w i n g s " in unipOlar depressives, s Baron et al., ~ in a s m a l l e r s a m p l e o f d e p r e s s e d p a t i e n t s , failed to find an a s s o c i a t i o n b e t w e e n family h i s t o r y o f affective d i s o r d e r and lithium r e s p o n s i v e n e s s . In t h e c a s e r e p o r t e d h e r e , a p a t i e n t with episodes o f p s y c h o s i s a n d s o c i o p a t h i c like b e h a v i o r b e t w e e n episodes was t r e a t e d with l i t h i u m in a double-blind c r o s s o v e r design. A f a m i l y h i s t o r y o f l i t h i u m - r e s p o n s i v e illness a n d r e c u r r e n t d e p r e s s i o n , as well as c e r t a i n e l e m e n t s o f his b e h a v i o r (his a g g r e s s i v e n e s s , impulsivity, a n d h y p e r a c t i v i t y ) t h a t c o n t i n u e d to c h a r a c t e r i z e him b e t w e e n his p s y c h o t i c episodes, suggested t h a t his b e h a v i o r d i s o r d e r m i g h t be r e s p o n s i v e to lithium.
T
CASE
HISTORY
T h e p a t i e n t is a 2 2 - y e a r - o l d u n m a r r i e d m a n w h o w a s first a d m i t t e d to a p s y c h i a t r i c h o s p i t a l w h e n he w a s 16 and in an a c u t e p s y c h o t i c s t a t e c h a r a c t e r i z e d by a g i t a t i o n , i n c o h e r e n c e , rapid s p e e c h , a u d i t o r y
From the Department o f Research, Jerusalem M e n t a l Health CenZer-Ezrath Nashim. Je.rusalem. Israel. J e r o m e H . Liebowitz, M . D . : Fellow in Child Psychiatry. A l b e r t Einstein College o f Medicine. Bror~x, N. 1I. (formerly. Visiting Research Fellow, Jerusalem M e n t a l Health C e n t e r - E : r a t h Nashim); V i c t o r R u d y , M . B . B . C h . : S t a f f Psychiatrist. Hillside Division-Long Island Jewish-Hillside Afedical Center. Long Island. N . Y . (former/)'. Resident, Je,'z~aIem Mental Health Center-Ezrath Nashirn); Elliot S, G e r s h o n , M , D , : Unit Chief. Section o f Psychogenetics, A d u h Psychiatr3, Branch, National Institute o f M e n t a l Health. Bethesda, Md, tformertv. Research Director, Jerusalem Mental Health Center--Ezrath Nashim£" A a r o n Gillis, M . B . , F . R . C . P . E . : Clinical Director. Jerusalem M e n t a l Health Center- E~rath Nashim. Supported in part by the Israel Center f o r Psychobiology, U S P H S Grant MH20712-03, and the l~'olfson Foundation { United Kingdom). Reprint requests should be addressed zo Dr. E, S. Gerahon, National Institutes o f Health. Building i0, R o o m 3N218, Bethesda. Md. 20014. ~ 1976 by Grune & S t r a n o n , Inc. Compfehenxive Psyctdatry. Vo|. 17. No. 5 (September/October), 1976
655
656
LIEBC)WlTZ El" AL.
hallucinations, delusions o f persecution, ideas o f reference, and some crying and suicidal t h r e a t s . H e tried to climb into the refrigerator to "'see television in his eyes" and heard terrifying voices a n d conducted conversations with them. This psychosis lasted about I 0 d a y s . He was diagnosed as schizophrenic, was l r e a t e d with chlorpromazine 800 m g / d a y , and improved rapidly. Two months after admission, he was discharged and returned to school, where h e functioned well for several months. Psychologic testing prior to discharge revealed no evidence o f psyc!~otic processes and a high-normal intelligence. Six months later he was hospitalized againin a p s y c h o t i c stale similar to the first, with the additional features o f elevated m o o d and incessant activity. For the month prior to admission he had been without s¢If-c0nfidence, appeared to be depressed, and believed t h a t everyone Was laughing at him. During this second hospitalization, he had periods o f a week or more of immobility and catatonic posturing, during which he later reported he heard voices and believed the world had become desolate. He was again diagnosed as schizophrenic and treated with phenothiazines, but was not discharged for t year. S t a ~ i n g during, and continuing after, this hospitalization, he behaved f r e q u e n t l y in a criminal manner, forging checks and stealing money. His per/~onalit~" changed considerably from its premorbid state, in that he became manipulative, impulsive, explosive, and somewhat sexually promiscuous. He was hospitalized a third t.ime (the first in our institution) when he was 21-years-old. On that admission, his mood was elevated, and there was some psychomotor restlessness but no obvious thought disorder. H e received chlorpromazine 600 r a g / d a y and was discharged within 2 months. Approximately 2 months later, he was readmitted for 1 month, after having been imprisoned for theft. This time there was no evidence of active psychosis, and he was diagnosed as "'schizophrenic reaction with residual psychopathic traits.'" Six months later he was admitted t o o u r hospital again, under court order, having been certified incompetent to stand trial for forging checks. Clinically, he appeared much as he did during his first hospitalization, with agitation, incoherent and extremely rapid speech, and delusions of persecution and ideas o f reference. He admitted to auditory hallucinations and appeared to be immersed completely in an imaginary world, without any relationship to his surroundings. He was in constant movement, and his behavior wa s aggressive and violent. The acute psychosis was treated unsuccessfully with a maximum daily dosage of chlorpromazine, 1200 rag, plus haloperidol, 15 rag. After failure with drug treatment, he received a course o f ECT with limited success. Three months after the initiation o f t r e a t m e n t , he no longer appeared psychotic and had no affective symptoms. But he did have frequently recurring episodes of aggressive and antisocial behavior. H e was violent toward other patients, stole o t h e r patients" and hospital property (including a car). left the hospital frequently without permission, and committed numerous acts of an impulsive destructive nature, all of which appeared to be ego-syntonic. A double-blind trial o f lithium carbonate alternation with placebo was instiluted. Because o f evidence from this trial favoring the effectiveness o f lithium (see below), he v-as placed on nonblind maintenance lithium therapy at the conclusion o f this study. Approximately I month later, he was discharged f r o m the hospital and has continued to receive lithium as an outpatient. PsYchologic tests prior to discharge revealed intact intellectual functioning on a high-normal ievd. Rorschach and Other projective tests confirmed the intactness of cognitive functioning but recealed rigid control, selflimitation, and inhibition Of spontaneity. A t this writing, nearly 3 years after discharge, he is doing well, having been employed in a printing shop during ~.he entire interval and having attended and completed an evening course to become an electronics technician. Hc has stable interpersonal relations and is a source o f emotional support to his family. He is a much quieter and more self-assured pe.rson. A certain attention-demanding quality that previously characterized almost all his interpersonal behavior is now absent, and subjectively, he reports feeling better than ever.
Family History T h e patient is the older o f two children born to an Orthodox Jewish couple of European extraction. His parents were divorced when he was 12-years-old. His father remarried "without issue, and t h e r e is rio history o f psychiatric illness in him or his family. T h e patient's m o t h e r has a psychiatr/c histot3r o f mild depression in connection with the marriage dating back 20 years, in 1966, she was discovered to have a pituitary tumor after complaints o f amenorrhea, headache, and depression and was placed on steroid and thyroid hormone replacement therapy. One y e a r later she was hospitalized psychiatrically for the first time, after discontinuing the hormones, in a state of organic mental syndrome with severe depression. A chromophobe adenoma was resected in 1968. Since then, she has had several psychiatric hospitalizations for depression and has been treated successfully with tricyclic antidepressants. Her
LITHIUM-FIESPONSIVE POSTPSYCHOTIC ANTISOCIAL BEHAVIOR
657
tumor was found to have recurred in 1972. We are unable to determine to what extent her psychiatric syndrome is secondary to the pituitary t u m o r o r the hormone replacement therapy. His only sibling, a sister 3 years younger, was :treated as an outpatient with psychotherapy for neurotic anxiety and depression at age 16. Three years later, following our patient's double-blind trials, she was hospitalized with mania 2 weeks postpartum and was treated with haloperidol and ehlorpromazine with good response. H e r mania was in no way atypical and included euphoric mood, angry and demanding interpersonal behavior, sexual provocativeness, rapid speech; decreased need for sleep, distractibility, and flight of ideas. She thought God had a special interest in her and had communicated with her, but she did not hear voices or get a verbal message. She was not confused, and there were no hallucinations. After the initial therapeutic success, she relapsed into inania and was then treated with lithium on a double-blind crossover protocol with placebo and was founcl to be a =lithium-responder, with improvement after I week on lithium and relapse when lithium was discontinued. There are 20 first cousins between the a g e s o f 20 and 49, all but one of whom have.no psychiatric illness. A maternal first cousin, a 35-year-old woman, has well documented bipolar manic-depressive illness responsive to lithium. MATERIALS
AND
METHODS
The therapeutic trial consisted o f nine double-blind crossovers between lithium carbonate and placebo during a period of 24 weeks. The length'of each period on lithium or placebo varied randomly between 8 and 23 days. "I~erapeutic blood levels were reached generally 2 or 3 days after taking 1800 rag/day and were maintained between 0.9 and 1.3 mEq/liter. The patient's behavior, thinking, and affect were rated three times per week on the BeigeI-Murphy Manic Rating Scale t° on the basis of his psychiatric state during the previous 24 hr, as related in nursing reports and systemaiie interviews by the blind observer (EG). i~e was also ,seen in individual psychotherapy sessions and was afforded t h e ward milieu therapy and occupational therapy. Systematic family histor3~ interviews, using a modification of the method of Winokur et al., ~= were performed on patient, sister, mother, father, and maternal aunt. Case summaries were obtained from the hospital or treating physician in each instance where psychiatric illness was indicated by the family study. R ESU LTS
The patient's ratings were grouped and averaged separately for each week of t r e a t m e n t . F i g u r e I p r e s e n t s t h e a v e r a g e s c o r e s f o r e a c h o f t h e 2 2 w e e k s in w h i c h ratings were made. The scores invariably improved while on lithium and worsened while on placebo, also reflecting the general staff impression of the patient's behavior during these periods. A gradual improvement with time, irrespective of medication, can also be noted. For statistical analysis, the ratings were grouped according to effective lithium periods (defined as beginning 7 days after starting lithium and ending 2 days after starting placebo) or placebo periods. These revealed a significant difference b e t w e e n t h e t w o g r o u p s b y t t e s t ( p < 0 . 0 5 , t = 2 . 0 7 , df = 6 1 ) , w i t h t h e o v e r a l l average of the lithium group (46.1, SD = 30.4) almost 20 points lower than that of the placebo group (65.1, SD = 41.1). The effect of autocorrelation on the t test, c o n s i d e r i n g t h e o b v i o u s l o n g - t e r m t r e n d in t h e r a t i n g s , is n o t c l e a r . H o w e v e r , a n e c d o t a l e v i d e n c e , in t h e f o r m o f n u r s i n g n o t e s , c o n f i r m s t h i s f i n d i n g , in t h a t e a c h o f t h e s e v e r a l e p i s o d e s Of V i o l e n t , a g g r e s s i v e b e h a v i o r t h a t r e q u i r e d i n t r a m u s c u l a r sedation for control occurred during effectiveplaceb0 periods. In:addition, each t i m e t h e m e d i c a t i o n w a s c h a n g e d , t h e c l i n i c a l s t a t u s c h a n g e d in t h e d i r e c t i o n predicted by drug change (p < 0.002 for 9 crossovers, binomial sign test). Analysis of the individual subscores--the ratings of'the 26 items combined to f o r m t h e t o t a l s c o r e r ° - - - - r e v e a l s t h a t c h a n g e s in m e d i c a t i o n w e r e c o r r e l a t e d w e l l
658
UEBOWJTZ ET AL.
180 ! 170
=First dcly serum Li >0SmF-J:i/L. =F,rst day serum Li *;05 rnUq/L. = =No ratings ovczikable-pl.in joil. • = :No ratings-protocol temporar~y d=scontinued.
~ lf~ ]
100 90 80
[] [] ~
=LITHII.~ PERIOD =PLACEBO PERIOD
$
70 60
H
1 2 3 4 5 6 7 8
Fig. •.
9 10 11 12 13 1/. 15 16 WEEK
18 19 20 21 22 23 2Z,
Extended d o u b l e - b l i n d c l i n i c a l t r i a l o f l i t h i u m carbonate. B e i g e I - M u r p h y rating scale is used status.
to assess clinical
with p o o r j u d g m e n t , c o m b a t i v e n e s s a n d d e s t r u c t i v e n e s s , d e c r e a s e d i m p u l s e control, and h y p e r a c t i v i t y . It is intel:esting to note t h a t c h a n g e s in mood and affect did not c o r r e l a t e with c h a n g e s in m e d i c a t i o n . N e e d for a t t e n t i o n ( d e m a n d i n g c o n t a c t o r seeking o t h e r s ) , sexual p r e o c c u p a t i o n , and g r a n d i o s i t y also fluctuated without any a p p a r e n t correlation. DISCUSSION
T h i s p a t i e n t m a n i f e s t e d a r e c u r r e n t psychotic d i s o r d e r , which, during two admissions, satisfied minimal c r i t e r i a for mania, 12 b u t during his o t h e r a d m i s s i o n s p r e s e n t e d . a s a typical schizophrenic psychosis. T h e p i c t u r e p r e s e n t e d in a psychotic s t a t e a l w a y s included " s c h i z o p h r e n i c ' " s y m p t o m s , and the p e r s o n a l i t y deterioration seen between p s y c h o t i c episodes w a s also suggestive o f a chronic schizophrenic process. T h e behavior d i s o r d e r resulting f r o m this p e r s o n a l i t y c h a n g e (as m e a s u r e d by o v e r t a g g r e s s i v e n e s s and r a t i n g s o f poor j u d g m e n t , c o m b a t i v e n e s s a n d d e s t r u c t i v e n e s s , d e c r e a s e d i m p u l s e control, and h y p e r a c t i v i t y ) i m p r o v e d m a r k e d l y during double-blind lithium t r e a t m e n t . T h e s c h i z o p h r e n i f o r m psychosis w a s also p r o b a b l y r e s p o n s i v e to lithium, since it also has not r e c u r r e d in the 3 y e a r s he h a s been on lithium. T h e effect o f lithium in schizophrenic s t a t e s is o f g r e a t i n t e r e s t . A l t h o u g h excited schizophrenic patients a r e g e n e r a l l y not lithium-responsive, ~8-~9 lithium is r e p o r t e d to be as effective as c h l o r p r o m a z i n e in s o m e (mildly active) schizoaffectires. ~a T h e r e a r e also several a n e c d o t a l a n d nonblind r e p o r t s o f s o m e o f t h e s e p a t i e n t s being responsive to lithium, z. J 2 . ~ - ~ 6 T h e prediction o f clinical r e s p o n s e to a p s y c h o p h a r m a c o l o g i c a g e n t is g e n e r a l l y b a s e d on t h e c a s e diagnosis o r on c u r r e n t l y active t a r g e t s y m p t o m s . Lithium app e a r s to be effective in a r e s t r i c t e d r a n g e o f v a r y i n g clinical s t a t e s . T h e h y p o t h e s i s t h a t this specificity m a y be r e l a t e d to a specific biologic a l t e r a t i o n in t h e s e clinical
L I T H I U M - R E S P O N S I V E POSTPSYCHOTtC A N T I S O C I A L B E H A V I O R
65~
states naturally suggests itself: l.~r As a corollary hypothesis, o n e would predict that a c o m m o n factor (possibly a clinical and behavioral finding, but not necessarily so) could be d e m o n s t r a t e d in all the lithium-responsive states. Our patient manifested the aggressiveness and episodic course suggested by Tupin, ~as well as the impulsitivity (going directly from stimulus to response) postulated by S h a d e r et al. ~ It is not clear, however, whether such a group o f lithium-responsive patients could ever be defined solely on the basis of clinical and behavioral observations. O t h e r types of observations m a y be needed. A family history of bipolar affective disorder a n d / o r lithium responsiveness m a y be a heuristic device for revealing sy n d r o m e s that share lithium responsiveness. This m a y be especially useful for disorders that are generally not responsive to lithium. A systematic study of lithium response in patients with s y m p t o m s that satisfy criteria for both m a n i a and schizophrenia has not been reported, but excited schizophrenic patients a r e generally not good candidates for lithium. ~s.j° Similarly, the hyperkinetic synd r o m e of childhood seems generally unresponsive to lithium, 2° but two children with this syndrome, chosen on the basis of family history of bipolar affective disorder, were found to be responders, albeit on a nonblind basis. 2~ This p a p e r suggests that antisocial behavior ma y be responsive to lithium in patients (whatever the clinical psychiatric diagnosis) with a family history of bipolar affective illness a n d / o r lithium responsiveness. It also suggests a similar correlation for schiz0Phreniform (schizoaffective) psychosis. A set of behavior states m a y be defined that are worth investigating for shared biologic and behavioral characteristics. T h a t is, a single genetically d e t e r m i n e d etiologic factor m a y be present in subgroups of patients in all the disorders in which a family history of affective disorder and lithium responsiveness has been found. T h e s e include.bipolar and unipolar affective disorder, acute schizophrenia-schizoaffective disorder, emotionally unstable character disorder, cyclothymic personality, hyperkinetic s y n d r o m e of childhood, and sociopathy. In addition, the responsiveness to lithium of two (or three) a ppa r e ntly different disorders in one family suggests pleiotropisrn of genes for bipolar illness r a th e r than two genetically distinct disorders. It is our suggestion that patients and their relatives in these lithium-responsive subgroups are especially worth investigation clinically, biologically, and p h a r m a cologically. T he search for genetically related psychiatric disorders m a y be enhanced by such a study, and the biologic and phenomenologic understanding o f the disorders themselves may also be advanced. SUMMARY
A double-blind crossover study was p e r f o r m e d with lithium c a r b o n a t e in a 22year-old man with a 6-year course of schizophrenic-like psychotic episodes and personality deterioration manifested by antisocial behavior. A family history of lithium-responsive manic-depressive illness, as well as certain aspects o f his behavior (aggressiveness, impulsivity, and hyperactivity), prompted the trial. Lithium was found to be effective in reducing overt antisocial behavior, as well as poor j u d g m e n t , hyperactivity, impulsivity, and destructiveness, during a time
LIEBOWITZ ET AL.
660
when he was no longer psychotic. It also has been effective prophylactically against the previously recurrent schizophreniform psychosis. Use of family history is discussed as a heuristic device for revealing a spectrum of lithium-responsive disorders. REFERENCES 12. Taylor MA, Abrams R: The phe1. Tupin JP: Lithium use in nonmanic depresnomenology of mania. Arch Gen Psychiatry sive conditions. Compr Psychiatry 13: 29:520-522, 1973 209-214, 1972 2. Shader RI, Jackson AH, Dodes LM: The 13. Prien RF, Caffey EM Jr, Klett C J: A comantiaggressive effects of lithium in man. Psycho- parison of lithium carbonate and chi0rp'romazinc pharmacolo~a 40:17=24, 1974 in the treatment of excited schizoaffectives. Arch 3. Sheard MH: Lithium in the treatment of Gen Psychiatry 27:182-189, 1972 aggression. J Nerv Ment Dis 16: ! 08-118, 1975 14. Prien RF, K l e t t C J, Caffey EM Jr: 4. Tupin JP, Smith DB, Ciasson TL, et ai: Lithium carbonate and imipramine in prevention Long term use Of lithium in aggressive prisoners. of affective episodes. Arch Gen Psychiatry Compr Psychiatry 14:311-317, 1973 29:420-425, 1973 5. Fieve RR: Overview of therapeutic and 15. Lipkin KM, Dyrud J, Meyer GG: The prophylactic trials with lithium in psychiatric many faces of mania. Arch Gen Psychiatry patients, in Gershon S, Shopsin B (eds): Lithium: 22:262-267, 1970 Its Rote In Psychiatric Research and Treatment. 16. Dempsey GM, Tsuang MT, Struss A, et New York, Plenum, 1973, pp 317-350 al: Treatment of schizoaffective disorder. Compr 6. Mendtewicz J, Fieve RR, Staltone F: RelaPsychiatry 16:55-59, 1975 tionship between the effectiveness of lithium 17. Singer I, Rotenburg D: Mechanisms of therapy and family history. Am J Psychiatry lithium action. N Engl J Med 289:254-260, 1973 130:1011-1013, 1973 18. Johnson G, Gershon S, Burdock El, et ai: 7. Prima RF, Caffey EM Jr, Klett CJ: Factors Comparative effects of lithium and chlorproassociated with treatment success in lithium carbonate prophylaxis. Arch Gen Psychiatry 31: mazine in the treatment of acute manic states. Br J Psychiatry 119:267-276, 1971 189-192, 1974 19. Shopsin B, Kim SS, Gershon S: A con8. Kupfer D J, Pickar D, Himmelhoch JM. et al: Are there two types of unipolar depression? trolled study of lithium vs. chlorpromazine in acute schizophrenics. Br J Psychiatry 119: Arch Gen Psychiatry. 32:866-871, 1975 9. Baron M, Gershon ES, Rudy V, et al: Lith- 435-440, 1971 20. Greenhill LL, Rieder RO, Wender PH, et ium carbonate response in depression. Arch Gen al: Lithium carbonate in the treatment of Psychiatry 32:1107-1111, 1975 I0. Beigel A, Murphy DL, Bunney WE Jr: The hyperactive children. Arch Gen Psychiatry manic-state rating scale. Arch Gma Psychiatry 28:636-640, 1973 21. Dyson WL, Barcai A: Treatment of 25"256-262, 197l 11. ~qnokur G, Clayton PJ, Reich T: Manic children of lithium-responding parents. Curr "l'her Res 12:286-290, 1970 Depressive Illness. St. Louis, C V Mosley, 1969
