Case Report of Dramatic Resolutio n of
Psychotic Symptoms During Cro ss-over to
Clozapine
Leo Sher, M.D. and Alan Mendelowitz, M.D.
Abstract
Clozapine is thefirst antipsychotic drug with proven superiority overconventional antipsychotics in the management of treatment-resistant patients. vVe describe a case of treatment-resistant
schieoaffectioe disorder in a y oung woman who improved rapidly on clozapine. The patient was
started on a low dose ofclozapine whilefluph enaeine was decreased. S he improved significantly
during thefirst several days oftreatment. This improvement tookplace well before the expected ifJect
of clozapine. Possible explanations fo r this unusual response include: J) the placebo ifJect; 2)
fluphena zine dose-response curve; 3) acute clorapi ne neurochemical mechanisms; 4) inaccurate
original diagnosis. Better understanding ofthe mechanisms ofaction ofantipsychotic drugs may
considerably improvepatient care.
C loza pine is th e first a n tipsyc ho tic age n t wit h proven superior ity over conve nti on al a n tipsyc ho tics in te rm s of it s efficacy in t reatm ent- resist ant patie nts (1,2). In
pati ent s with poor or parti al resp on se to co nve n tional neu rol ep tics, cloza pine is th e
treatm ent of choice . We wish to rep ort a nd to di scuss a cas e of t he rapid a nd
subs ta n tia l improvem ent of a patient who was started on c1ozapi ne.
PRESENT I IG PROBLEM AND PATIENT DESCRIPTIO N
Ms. C. was a 34 year old whit eJ ewish fem al e with 13 yea r hist or y of schizoaffective di sorder. At th e tim e of admi ssion th e pati ent report ed a ud itory hallu cin a tions,
refer entia l delusions (th e pati ent felt that other peop le were mak ing refe rence to
her), a nd th e bel ief that sh e was abl e to read th e minds of peopl e a ro u nd her. T he
Leo Sh er , M.D. is a fellow at th e National Inst itu te of Ment al Health , Bethesda , Ma ryla nd. At
th e tim e of writ ing this article, he was a resid ent a t Hill sid e H ospit al , Psychi atric Division of
Lon g Isla nd J ewish Medi ca l Center , th e Lon g Isla nd Cam pus for th e Albert Ein st ein Co llege of
Medi cin e, G len Oaks, New York.
Alan Mendelowitz , M.D. is C hief of th e Resid en cy Train ing a nd Resea rch Unit at H illside
Hospital, Psychi atric Division of Lon g IslandJewish Medi cal Ce nter , th e Lon g Island Campus
for th e Albert Ein st ein Coll eg e of Medi cin e, Gl en O ak s, New York , and Assis tant Professor of
Psychi at ry, Albert Einst ein Coll ege of Medi cin e, Bronx , New York.
The cor respond ing a ut hor: Leo Sh er , M.D. , NIMH, Bldg. 10, Rm 3S-23 I, 9000 Rockville Pike,
Bethesd a , MD 20892, T el : 30 1-496-2 14 1, Fax : 30 1-496-5439, E-ma il: LSHER@B O XL.NIH.GOV
41
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J EFFERSO N J O URNA L OF PSYCH IATR Y
patient also reported sa d mood a nd so me a nx ie ty. She was tea rfu l with a constricted
a ffect. Ms. C . showed good in sight int o he r illn ess (s he was aware of her illn ess, a nd
und erst ood th at her sym pto ms a nd soc ia l probl em s were du e to her own di st urbances), a nd expressed a strong d esi re to ge t rid of he r sym ptoms. Th is, d esp it e t he
fact th at th e male voice whi ch was " ta lking to he r" sou nd ed fri endly. (She s ta te d that
th e a bility to hear this voice was a bno rmal.) During th e ini tia l in te rview Ms. C . also
di spl a yed some d ep endent features including th e need s for he r parents to assum e
res pons ibility for decision s in her life. We had a n opport u nity to in te rview t he
pati ent 's parent s a nd learned th at th e patient always had d ep e nd e nt traits.
BACKGRO UND INFORMATION
Ms . C. did well academically in th e Elementary,junior Hi gh , an d Hi gh Schools.
Sh e skipped two school years and grad ua te d from th e Hi gh Schoo l in 10 yea rs instead
of 12 years. Sh e e n te re d th e Coll ege, a nd she was close to com ple ting he r Bachelor
Degr ee, wh en at th e age of 21, Ms . C. d eveloped psych otic sym pto ms includ ing
a ud itory hallucin ation s a nd ideas of referen ce. H er level of fu nct ion ing d eclin ed
consid e ra bly, and th e patient had to drop ou t of th e College . T he pati en t was
hospit ali zed on ce a t th e tim e of her fir st break , and th en she has bee n in out pa tient
treatm ent for 13 yea rs . The cou rs e of her illn ess was som ewhat unusual : it wen t for 13
years fro m onse t to th e first co ns ide ra ble rel ap se. She has been on ha lop eri dol for a
lon g ti m e wit h a part ial res po nse (t he level of he r social fun cti oni ng was low, and,
some times, she had mild psych ot ic sym pto ms) . Six months prior to ad m ission, th e
pa ti ent 's co nd ition d et eriorat ed , she d evelop ed persist e nt a ud itory hallucin ation s
a nd referential d elu sion s, and she was switc h ed from hal ope ridol to fluph en azine.
Fluphe naz ine was gradua lly incr eas ed to 40 mglday. Howeve r, th e clinica l res ponse
was te m po rary a nd limited . The pat ien t con tinue d to d et e riorat e, a nd he r psychiat rist referred her to th e hospital for inpatient t rea tm en t.
HOSPITAL COU RSE
Ms. C . was eva lua te d a nd felt to m eet crite ria for no nres po nse to sta ndard
a n tipsyc hotic treatm ent , a nd was offe red cloz apine t reat m e nt. Sh e was told t ha t
cloz apine was a very effec tive drug, it helped many patient s, who were part ial
respond ers , and that it could improve th e pati ent 's qu ality of life. Ms. C. ag reed with
cons id e ra ble e n t husiasm . On th e fir st day of th e t reatm ent she received 12.5 mg of
clozapine wh ile fluph en azin e was tap ered to 20 mg. On t he next d ay the pa tie nt
repo rte d improvement, s ta ting th at h er a udito ry hallucin ation s we re less d isturbing,
a nd th at she was free of th e hallucin ation s for two hou rs in th e morning. On t he fifth
day of th e treatm ent , wh en th e clo zapine dose was 25 mg bid a nd fluph e nazine dose
contin ue d a t 20 rng/d ay, Ms. C . re ported marked im prove me nt, t he patient stated
th at she felt mu ch bette r, tot all y free fro m refere n tial id eas. She rep ort ed t hat t he
hallucin atory voice was quiet, less di stu rbing, a nd a pa rt of t he day she d id not hear it
a t all. She a lso felt reli ef from a nxie ty. O ver th e following d ays Ms. C. reported
CROSS-OVER TO CLOZAPINE
43
improvement almost every day, sh e tol erated cloza pine well, a nd t hree wee ks aft er
her admission she was discharged with very conside ra ble improvem ent. At th e time of
discharge patient was not getting fluph enazine, and her clozapine dose was 200
mg /day.
DISCUSSION
This quick and remarkable response to cloza pine treatm ent in thi s patient
requires further evalua tion. It ca n be expla ine d in part by a placeb o effect which is
probably involv ed in every therapeutic maneuver. A number of fact or s whic h may
predict a good response in this patient may include th e patient 's stron g desi re to get
better, relatively good insight into h er illness, a relatively high level of ed ucation, the
patient's high degree of suggestibility, th e pr es en ce of d ep end ent pe rsonal it y features , th e d esire to be a "good patient," a nd th e fact th at th e m ed icat ion was given by
ca ring and confide nt physicians cou ld cont ribute to thi s effect.
The " placebo effec t" is an outstanding exam ple of mind-bod y re la tions hips, a
case of transformation of psychological effec ts into biological processes (3,4) . Pa tien ts
with schizophrenia may respond to placebos (5-8) . A st riking d ep end ence on a
placebo in a periodically catatonic schizophrenic wom an has been re por te d in th e
lit erature (5). An un expect ed placebo response was found during a doubl e-blind drug
study in a patient with treatm ent-resistant tardive diskinesia (6). Schulz and colleagu es reported a n exce ssive beta-endorphin response to placebo in schizophren ic
pati ents (7) . Pickar and associat es found incr eas es in plasma opi oid ac tivity after the
intravenous administration of placebo in patients with sch izoph re nia (8).
In 1978 Levine a nd as sociates who st ud ied th e a nalge sic effec t of placebo
proposed that endorphin rel eas e m edi ates a pla cebo respons e (9). Several stud ies
were cond uc te d to test th e hypothesis that beta-endorphins are e ndogenous subst an ces with neuroleptic-like activity and th at di sturbances in th e bet a- endorphin
fra gm entation may con t ribu te to th e pathogen esis of psychotic di sord e rs ( 10- 12).
Thes e studies showed th at e ndor phins ca n poss ess neurol eptic pr op erti es. H e nce, it
ca n be argued th at placebo m ay ca use a rel eas e of e ndoge nous subs ta nces with
neuroleptic-like activity and produce an antipsychotic effec t.
Decr eas e in fluph enazine dos e could also play a part in th e pa ti ent 's quick and
substantial improvement. Clinical information on th e th erapeutic do sage of antipsychotics remains controversial. It has been proposed that neuroleptics may have a
bell-shaped dos e-respons e cu rve (13). Possibly, in this ca se 20 mg of fluph e nazine per
day could give a bett er clinical response than 40 mg/day. It is also possible t hat
decr ease in fluph enazine caused reduction in ex t ra pyram idal sym ptoms, and th e
improvem ent was from the decreas e in th es e symptoms.
Anoth er possible expla na tion can be con nec te d with mon oamin e a nd am ino acid
transmission in different brain regions aft er ac ute cloza pine ad m inist rat ion . Th e
expe rime n ts on ra ts showed that the acute administration of 10- 30 mg/ kg of
cloza pine increased dopamine and glutamat e in th e m edial pr efrontal cortex, and
produced a gr eat er incr ease com pa re d with haloperidol, in ga m ma-am inobutyric ac id
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JEFFERSON JOURNAL OF PSYCHIATR Y
efflux within the ventral pa llidum (14). Th ese change s were obs erved 1- 2 hou rs after
the clozapine administration. Combined dysfunction of dopamine and N-m et hyl-Daspartate glutamate receptors with th e involv em ent of GABA ergic neurons has bee n
implicat ed in pathophysiological m echanism of sch izophrenia, a nd it has been
suggested t ha t som e antipsychotic drugs , including c1ozapin e, ca n pr eve nt th ese
pat ho log ical changes in the br ain (I5).
There is a possibility that th e original diagnosis was in accurat e. Th e unu su al
course of th e pati ent 's illn ess (it went for 13 years from ons et to fir st se rious rela pse)
and the unusually rapid improvem ent aft er th e inpati ent ad m issio n mi gh t be rela ted
to th e in correct original di agnosis.
CONCLUSION
Ov er th e past de cad es we have witnessed con sid erab le pro gr ess in th e psychopha rmacological treatm ent of psychotic disorders. Antipsych oti c m edi cat ions hel p man y
patients. Bett e r understanding of th e m ech anisms of ac tion of psych ot ro pic dr ugs
may significantly improve patient ca re .
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