Risperidone and clozapine in the treatment of drug-resistant schizophrenia and neuroleptic-induced supersensitivity psychosis

Prq.

Neur~PsychophcmmcoI.

C%Rid. F’sychiat. Copyrtght

Pergamon

1994.

VIII. IX. pp.

ci 1994 Elsetier

1129-l

141

Sclrnc~

Ltd

F’rtnted in Great Hrttatn. All rights reserved 0278 - 5X46/94

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RISPERIDONE AND CLOZAPINE IN THE TREATMENT OF DRUG-RESISTANT SCHIZOPHRENIA AND NEUROLEPTIC-INDUCED SUPERSENSITMTY PSYCHOSIS Guy Chouinardt.2, Juana L. Vainer2, Marie-Claire BClanger2, Luc Tumiert, Paul Beaudry2. Jean-Yves Royt, and Robert Millers tPsychiatric Research Cenue, Louis-H. Lafontaine Hospital, University of Montreal; Flinical

Psychopharmacology

Unit, Allan Memorial Institute, Royal Victoria Hospital, Department of Psychiatry, McGill University; Montreal, Canada, and Wniversity of Otago Medical School, Duncdin, New Zealand. (Final Form, December 1993)

Abstract Guy Chouinard, Juana L. Vainer, Marie-Claire BClanger, Luc Turnier, Paul Bcaudry, Jean-Yves Roy, and Robert Miller: Risperidone and Clozapine in the Treatment of Drug-Resistant Schizophrenia and Neuroleptic-Induced Supersensitivity Psychosis. frog. Neuro-Psychopharmacol. andBiol. Psychiat. 1994, ts(7): 1129-t 141

1. Supersensitivity psychosis (SSP) has emerged as a potential side effect of long-term neuroleptic therapy similar to tardive dyskinesia (I’D). 2. Six schizophrenic patients with SSP, considered to be drug-resistant, were treated with risperidone, while another 5 were treated with clozapine. 3. The 6 risperidone-treated patients (all women) were rated on the Clinical Global Impression Improvement Scale as at least very much improved. Among the 5 clozapine-treated patients, all 4 men were found to have a marked response to clozapine, while the female patient was judged to be minimally improved. 4. It is hypothesized that not only TD but also SSP arise from destruction of cholinergic interneurons in the striatum as a consequence of prolonged neuroleptic administration. Thus, the drug-induced parkinsonism, which was proposed as mediating the antipsychotic effect of dopamine D2 blocking drugs, depends on the integrity of these cholinergic neurons. If these neurons are destroyed, drugs such as haloperidol lose their therapeutic effect. 5. In contrast, atypical neuroleptics like clozapine and risperidone reduce dopamine release in the striatum independently of prior production of extrapyramidal symptoms and, in this way, may be effective in psychotic illnesses unresponsive to classical anti-D2 neuroleptics. 6. In the present sample of patients, it is worth noting that schizophrenic men were good responders to clozapine. In comparison, risperidone was found to be efficacious in schizophrenic women. Kevwords:

atypical neuroleptics,

Abbreviations:

clozapine, risperidone,

serotonin (5HT), supersensitivity

schizophrenia,

tardive dyskinesia

psychosis (SSP), tardive dyskinesia

1129

(TD)

1130

G. Choumard

The efficacy of classical antipsychotics benefit

to a substantial

chronically

proportion

is limited in that they fail to provide significant

of schizophrenic

treated young schizophrenic

treatment following

their NIMH-index

themselves

hospitalization

as compared

colleagues

(1978) described

neuroleptic

therapy.

the worsening

of psychotic

neuroleptic

and showed

dyskinesia

administration

new

1993).

of cholinergic

symptoms

alone.

associated

Chouinard

and

with long-term

has not been found to

schizophrenic

symptoms

or worsening

of previous

psychosis (SSP) is hypothesized cells in the striatum

Miller and Chouinard

and eventual

as a consequence

of dopamine

degeneration

(1993) suggested

of prolonged

that the predisposition

receptor proliferation

to tardive

but results, in part, from the

of the striatal intemeurons.

cholinergic cellular damage would be the prolonged overactivation removal by neuroleptics

as resulting from the

in the same way that tardive dyskinesia (TD) is thought to develop (Miller

is not the consequence

overactivation

of the illness

(Chouinard and Jones 1980a).

of a population

and Chouinard

is due to the effects of the

illness; for example, certain patients relapsed rapidly upon

The clinical syndrome termed supersensitivity destruction

or poor responders,

Psychotic relapse in a number of patients on neuroleptics

in dosage

psychopathology

It was found that only 20% of

(Breier et al 1991). At present, it is not clear

to the progression

follow the usual course of schizophrenic reduction

patients.

long-term

patients had a good outcome after 2 to12 years of follow-up

what proportion of patients, classified as drug-resistant neuroleptics

et aL

The putative cause of this

of these neurons resulting from the

of the inhibition normally exerted by spontaneous release of dopamine in the

striatum acting at the DZ receptors.

The process of cell destruction

would be similar to excitotoxic

processes induced by excitatory amino acids which can destroy neurons in several parts of the central nervous

system,

degenerative

and which have been held responsible

for neuronal

loss in a variety

of other

disorders of the central nervous system. This overactivity of central cholinergic

systems

could also be involved in the production of akinetic and motor retarded depression

and in the

Risperidone and clozapine in supersensitivity

predisposition

towards L-DOPA-induced

Supersensitivity

psychosis

potentially

persistent.

striatal intemeurons antagonists

like clozapine,

therapeutically

effective

schizophrenia,

have similar predisposing

These two conditions following

1131

peak-dose dyskinesia in Parkinson’s disease.

and drug-resistant

associated with tardive dyskinesia,

psychosis

chronic

two syndromes

which are commonly

factors and pharmacology,

would also be a result of degeneration

dopamine

D2 antagonist

as well as other atypical

in such treatment-refractory

neuroleptic

neuroleptics

schizophrenic

and both are of choline@

administration.

like risperidone,

should

is a new dopamine-D2

that risperidone

and serotoninS2

had a marked antidyskinetic

receptor antagonist.

neuroleptics. of psychotic

was administered

Similarly, clozapine, symptoms

chronic schizophrenic Association: developed

to these

patients

it would be useful in patients with

as an alternative

treatment

to classical

which has been found to produce marked improvement

(Kane et al 1988) but also of TD (Naber et al 1989; Liebemran patients, was also administered to schizophrenic

and were used to distinguish

SSP from co-existing

et al 1989) in

patients (American

schizophrenic

not only

Psychiatric criteria were

psychopathology

(Table

1990).

In a previous

paper, the authors reported

treatment of chronic schizophrenia cases compared neuroleptics.

Based on the observation

DSM III R 1987) who met criteria for SSP. Specific research diagnostic

1) (Chouinard

symptoms.

effect (Chouinard et al 1993) in chronic schizophrenic

patients with TD, and on the theory that by the same mechanism SSP, risperidone

be

patients by reducing dopamine

release in the striatum in a manner not dependent on the prior production of extrapyramidal Risperidone

Dr

the prevalence

of SSP in their outpatient

(Chouinard et al 1986). It was found to be high, 22% for definite

to 45% for TD among 224 schizophrenic

outpatients

chronically

As with TD, the severe cases are less frequent (Chouinardl990).

have a poor outcome despite high doses.

clinic for the

with standard anti-D2 neuroleptic

treatment,

treated

with

Severe cases of SSP

often requiring

hospitalization

1132

G. Chouinard

et aL

Table 1 Chouinard Research Diagnostic Criteria For Supersensitivity

(A)

The patient must have a 3 month history of receiving antipsychotics.

(B)

At least one of the following major criteria must be present:

Psychosis1

(1) reappearance

(2) (3) (4) (5) (6) (7)

of psychotic symptoms upon decrease or discontinuation of neuroleptic medication during the last 5 years - within 6 weeks for oral medication, 3 months for i.m. depot medication; greater frequency of relapse (acute psychotic exacerbation) during continuous treatment with neuroleptics; tolerance to the antipsychotic effect of the neuroleptic (overall increase in dose by 20% or more during the last 5 years); extreme tolerance: increased neuroleptic dosages do not mask the psychotic symptoms anymore; psychotic symptoms upon decrease of medication are new schizophrenic symptoms (not previously seen) OR are of greater severity; psychotic relapse occurs upon sudden decrease (2 10%) of medication but not if same decrease is gradual; presence of drug tolerance in the past but presently treated with high doses of neuroleptics on at least a b.i.d. regimen.

(C)

At least one of the following minor criteria must be present if only one major criterion is present: (1) tardive dyskinesia (a standard examination must be used); (2) rapid improvement in psychotic symptoms when the neuroleptic dose is increased after a decrease or discontinuation; (3) clear exacerbation of psychotic symptoms by stress; (4) appearance of psychotic symptoms at the end of the injection interval (for patients on long-acting intramuscular medication); (5) high levels of prolactin or neuroleptic activity (twice normal - at least once within the last 2 years).

(D)

Exclusion criteria: (1) patients in the first acute phase of illness; (2) patients with continuous severe psychosis unresponsive

to neuroleptics.

Risperidone ,md clozapine in supersensitivity psychosis

1133

Table I (Cont’d)

Subtypes: Stage I:

Withdrawal type: reversible when the onIy major criteria present are no. 1 and/or no. 6:

Stage II: IL4 IIB UC -

Tardive type: masked and mostly reversible when the only major criterion present is no. 3; masked and mostly irreversible when the only major criterion present is no. 7; overt and mostly irreversible when major criterion no. 1 is present with any other major criteria (other than no. 6);

Stage III: Severe type: when major criterion no. 4 is present. 1Adapted from Chouinard (1990)

Meth~s

Subjects In this paper we report on 1I schizophrenic patients who met the criteria for SSP, 6 of whom were treated with the atypical neuroleptic risperidone and S with clozapine. Patients were required to give infotmed written consent for the experimental part of their treatment with risperidone.

Of the 6

schizophrenic women treated with risperidone 8 to 12 mg per day (mean: 9.3) for a period of 2 to 25 months (mean: 9), 2 were rated as extremely improved by the treating physician and 4 as very much improved on the Clinical Global Impression Improvement Scale (Table 2). Of the 5 patients (4 men and 1 woman) treated with clozapine SO to 250 mg per day (mean: 170) for a period of 7 to 16 months (mean: 13 months), all 4 men were found to have a marked response to clozapine and the woman to be animally

improved (Table 3).

The clinical characteristics of the patients are given in Tables 2 and 3. For the risperidone-treated patients, the mean age was 46 years (range 32 - S I}, the mean daily halope~do1 units mg per day was

50

54

32

45

32.51 (46)

F

F

F

D

E

F

Rase

Meall

50

F

C

8-12

6-50 (9.3)

12

16 6

(31.1)

mild

10

4

8

(9)

El-32 (16.1)

KJ”e

15

2

2-25

mild

moderate

m,ld

severe

moderately

22

32

6

6

11

22

(Ye.=)

NURTEPK TREATMENT

TARDIM DYSKINESLA

(7)

O-15

2.5

10

10

15

0

5

mgld

PRfXYUlDWE

with Risperidone

kksmrfff

Treated

DURATION Cf PRIOR

25

%FEWXNE TREATh4ENr (months)

DLR4TlCNOF

of Patients

6

12

2

Results

Table

8

44

40

6

6

44

F

B

6

30

51

UNITS mg/day

msPEFuxM DOSE mg/day

PRIOR H&CfERIKA

PGE

and Treatment

(Years)

F

sx

Characteristics

A

PATIENT

Patient

onw

900

30

100 ,,,h,um

900

brazepam 4 carbamazepine

Itthium

levothyroxine 0.05

,,urarepam

01

flurazepam 15 levothyroxine

None

0 075

levolhyroxine

MEDCAlKNS mglday

extremely

very much improved

very much improved

very much improved

improved

very much

MPKIVEMENT SCALE

w_cwL

CLINICAL

Risperidone

and clozapine in supersensitivity

I

I

1135

psychosis

I

LL

1136

G. Chouinard

31.1 (range: 6 - 50)

and the mean duration of prior neuroleptic

32) (Table 2). For the clozapine-treated mean haloperidol

el aL

equivalent

neuroleptic

treatment

risperidone

or clozapine,

treatment was 18.1 years (range 8 -

patients, the mean age was 38.6 years (range 33 - 46), the

mg per day was 37 (range: 10 - 70), and the mean duration of prior

was 17.4 years (range 13 - 27) (Table 3).

Of the 11 patients

treated with

10 patients were found to have TD. Three out of 11 are discussed

in the

following case reports.

Risueridone:

Case No. 1

Ms. A. is a 51-year old patient who has been treated for schizophrenia a psychiatric

outpatient at the age of 27. She was first hospitalized

since she was initially seen as

at the age of 29 and rehospitalized

at the age of 30. Except for an 11 -month period, at the age of 3 1, during which time she was placed in a foster home, Ms. A. has been continuously

hospitalized

in a psychiatric

hospital

(Louis-H.

Lafontaine Hospital) for 22 years up to the time she was treated with risperidone. Her family medical history reveals an admission

for major depression

(maternal

aunt) and two

brothers who are in good health. In her medical history, there is an episode of hypothyroidism is now well controlled smokes 20 cigarettes years.

with levothyroxine.

a day and has been going to occupational

Ms. A. thought

unspoken thoughts.

There is no evidence

that other people

of drug or alcohol intake.

other patients were controlled by her thought broadcasting.

She

therapy in the hospital for the last 2

were able to read her mind and could respond

She had the delusion that she controlled

which

radio and T.V. transmissions

to her and that

She heard the voices of the physician and

nurses every day as if they were talking in her head. She had the paranoid delusion that there were hired killers on the hospital delusions and hallucinations

ward and that organized

crime was present

levothyroxine

basis with risperidone

30 mg per day for 6 months.

She also received antiepileptics

for 3 consecutive

months.

2.5 mg bid, and

she had been treated with haloperidol such as carbamazepine

in order to treat her refractory condition.

mg per day of haloperidol

basis and continued to be

4 mg twice daily, with procyclidine

0.075 mg per day. Before starting risperidone,

in addition to halopetidol

These

were only partially controlled by standard anti-D2 neuroleptics.

Over 2 years ago, Ms. A. was first started on risperidone on a double-blind treated on a humanitarian

in the hospital.

and valproic acid

Prior to this, she received up to 60

She was also treated with low doses of

Rsperidone

and clozapine in supersensitivity

haloperidol

without

neuroleptics

which did not change her condition and likely induced a thyroid hypofunction.

treated with

much improvement.

1137

psychosis

up to 40 mg per day of fluphenazine

neuroleptics

received were chlorpromazine

a gradual decrease in her hallucinations and the hallucinations years.

For 2 years, she also received

and delusions

This led to her discharge

lithium

in addition

She was

by mouth without success for 9 months.

and thioproperazine.

to

Other

Once she was started on risperidone,

and delusions was noticed.

The voices stopped bothering her

became much less frequent than at any time in the previous 20

from the hospital to a foster home, an event which she had not

anticipated would ever be possible. At present,

the patient tries to be active but still has mild auditory hallucinations

broadcasting, However,

grandiosity,

and paranoid

these psychotic

symptoms

delusions

especially

are significantly

with thought

when she is under stress or anxious.

reduced and do not interfere

with her daily

functioning.

Risneridone:

Case No. 2

Ms. B. is a 44-year old patient who has a B.Sc. in electronic engineering. that a brother,

a sister, and an aunt all have had a psychotic

Her family history reveals

episode.

Her medical

history

is

unremarkable. She was fit psychotic

admitted for 2 weeks on a psychiatric ward of a general hospital for an episode of acute

reaction at the age of 35. During this period, she had the sensation of bugs crawling over

her hands and thought that an evil spirit was following her. She did not see the spirit but felt it around her because of the crackling treated with haloperidol psychotic

episodes

amitriptyline haloperidol diazepam restless

noises which followed her wherever she went.

and responded

well.

At the age of 36, she was twice rehospitalized

and was given haloperidol

50 mg per day.

She developed

4 mg per day, benztropine severe extrapyramidal

which was therefore discontinued. up to 10 mg per day and procyclidine

and thioridazine

discontinued

was discontinued

for

2 mg per day , and

side effects

to small doses of

She was then given chlorpromazine

100 mg per day,

20 mg per day.

75 mg per day was added.

and amitriptyline

At that time, she was

After a few weeks, she became

Later, chlorpromazine

and thioridazine

were

was restarted up to 150 mg per day. After a few months, amimptyline

and methotrimeprazine

up to 50 mg per day was initiated.

At the age of 37, she

G. Chouinard

1138

was again hospitalized ideation,

mystical

in a psychiatric

delusions,

paranoia,

pimozide 4 mg per day, benztropine years, she has been followed treated with pimozide procyclidine

with a diagnosis

and auditory

of schizophrenia

hallucinations.

with suicidal

She was then treated with

2 mg per day, and oxazepam up to 45 mg per day. For the last 5

at the Special Follow-up

Clinic of the Allan Memorial

up to 10 mg per day, then fluspirilene

with a return of disturbing

8 mg per day and her condition,

Institute and

up to 6 mg I.M. every week, and

5 mg per day. She became gradually unresponsive

therapy (i.m. fluspirilene) risperidone

hospital

et aL

to her dosage of anti-D2 neuroleptic

positive symptoms.

She was then started on

over the last 6 months, is considered

as much improved.

She hears noises less frequently and has fewer intrusive thoughts about the evil spirit. There are now days when she is not preoccupied

by these symptoms.

and her insight and judgment have improved.

There is also a decrease in somatic concerns

She feels so much better that she recently registered to

take some university courses.

Mr. G. is a 40-year old single man who was first seen on a psychiatry because of persecutory

feelings for which he was treated without medication.

became acutely psychotic and was hospitalized with auditory hallucinations During

his 4-month

discharged

hospitalization,

without psychotic

paranoid schizophrenia.

Mr. Cl. improved

symptoms

slowly

on trifluoperazine

fluphenazine

and persecutory delusions.

with oral neuroleptics.

of

Institute

6.25 mg I.M. every 2 weeks.

Later, the patient was referred to the

where his medication

with an increase in parkinsonian

symptoms of schizophrenia

was changed

to

The patient then reported that his persecutory

feelings were under better control, except for the last 4 days before his injection. not associated

He was

He had a small relapse when the dose was reduced to 10 mg per day h.s. and

Clinic at the Allan Memorial

enanthate,

At the age of 21, he

15 mg per day with the diagnosis

he developed paranoid symptoms that occurred in the afternoon. Special Follow-up

service at the age of 19

signs or symptoms.

Moreover,

These feelings were his mild negative

actually improved toward the end of the injection interval.

He was able to

continue his occupation and normal way of life, but paranoid ideation occurred a few days before each injection.

This continued

for 6 months and necessitated

the following

dosage increases:

12.5 mg

every 2 weeks; 6 months later, 25 mg every 2 weeks; 2 months later, 37.5 mg every week; 6 months

Rispertdone later, 50 mg every week. hallucinations

increased

Over the next year, the pre-injection

injection

He received

20 mg q.i.d.

persecutory

of procyclidine.

and dyskinetic

and auditory

enanthate,

movements

(1978) call “medical” withdrawal

375 mg

One week after his

Symptom Rating Scale (ESRS) (Chouinard

indicated constant tremor of both legs, mild akathisia, occasional dyskinetic

associates

delusions

At this point, he was still able to work as a computer

no other drugs with the exception

his ratings on the Extrapyramidal

partial protrusion,

1139

psychosis

to such an extent that the patient was given fluphenazine

every week, and haloperidol, programmer.

and clozapine in supersensitivity

et al 1980)

lingual movements

with

of one hand. There were no signs of what Gardos and symptoms such as nausea, vomiting, and sweating.

The

patient did complain of loss of libido. His prolactin level 7 days after the injection was 64 ng/mL, at which time he showed positive and negative symptoms, no positive

symptoms

or dyskinetic

movements.

whereas 5 days after the injection there were

In contrast,

however,

his negative

symptoms

remained unchanged and his prolactin level was 94 ng/mL. Mr. G. became increasingly He did not respond drug-resistant

psychotic,

to antiepileptic

schizophrenic

treated with haloperidol30

drugs which have been found to be efficacious

mg per day and procyclidine

refractory

to several

fluphenazine

enanthate,

fluphenazine

in 50% cases of

classical

30 mg per day for 5 years.

neuroleptics

decanoate),

(fluspirilene,

He experienced

ideation and auditory hallucinations

As he became

haloperidol

decanoate,

clozapine was initiated at a dose of 75 mg per day

over several months to 200 mg per day. The antiparkinsonian

was gradually discontinued.

pension.

patients (Chouinard and Sultan 1990). Before starting clozapine, he was

increasingly

and gradually increased

had to stop working, and was put on a disability

not only progressive

but also marked improvement

procyclidine

decrease of his paranoid delusional of akathisia and tardive dyskinesia

to the point that they disappeared.

After 9 months of treatment with 200 mg per day of clozapine, he

was rated as very much improved

on the Clinical Global

clozapine

dose has now been decreased

Impression

Scale of Improvement.

to 150 mg per day and, although

positive symptoms

His still

persist, they have been much reduced by clozapine.

Discussion

Of the six schizophrenic

women treated with risperidone

8 to 12 mg of per day (mean 9.3) for a

period of 2 to 25 months (mean: 9), 2 were rated as extremely improved by the treating physician and 4 as very much improved on the Clinical Global Impression

Improvement

Scale (Table 2). Of the 5

patients (4 men and 1 women) treated with clozapine 50 to 250 mg per day (mean: 170) for a period of 7 to 16 months (mean: 13 months), all four men were found to have a marked response

to clozapine

1140

G. Chouinard

and the woman to be minimally noting that schizophrenic to be efficacious

improved

In the present sample of patients, it is worth

(Table 3).

men were good responders

in schizophrenic

et aL

to clozapine.

In contrast, risperidone

was found

women.

Conclusion

The authors have presented

evidence

risperidone

is beneficial

haloperidol

are no longer effective.

due to the destruction

that therapy with atypical

in drug-resistant

schizophrenic

patients

neuroleptics when classical

like clozapine neuroleptics

These patients were thought to have developed

of cholinergic

interneurons

or like

drug resistance

in the striatum as a consequence

of prolonged

neuroleptic administration. Drug resistance remains a major problem in the treatment of schizophrenia. 20% of long-term

treated patients have a good outcome to neuroleptic

It is estimated that only

(Breier et al, 1991), even though 75% of

patients showed a significant

response

drug treatment during the acute phase of their

illness (NIMH Collaborative

Study, 1964). The atypical neuroleptic

risperidone

(Chouinard

1993) was found to raise to 50% the percentage of responders among chronic schizophrenic

et al,

patients.

References

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(1987). Diagnostic and Statistical Manual of Mental

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L. (1978). Neuroleptic-induced

CHOUINARD, G. and JONES, B.D. (1980). Neuroleptic-induced supersensitivity Clinical and pharmacological characteristics. Am. J. Psychiatry 137:16-21. -

supersensitivity

psychosis:

CHOUINARD, G., ROSS-CHOUINARD, A., ANNABLE, L. and JONES, B.D. (1980). Extrapyramidal Symptom Rating Scale. Can J. Neurol Sci 2233. CHOUINARD, G., ANNABLE, L. and ROSS-CHOUINARD, A. (1986). Supersensitivity psychosis and tardive dyskinesia: a survey in schizophrenic outpatients. Psychopharmacol 22:891-6. CHOUINARD, G. (1990). Severe cases of neuroleptic-induced supersensitivity psychosis: Diagnostic criteria for the disorder and its treatment. Schizophrenia Research 521-33.

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Risperidone

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KANE, J., HONIGFELD, G., SINGER, J., MELTZER, H. AND THE CLOZARIL COLLABORATIVE STUDY GROUP (1988). Clozapine for the treatment-resistant schizophrenic: A double-blind comparison with chlorpromazine. Arch Gen Psychiatry g:789-96. LIEBERMAN, J., JOHNS, C., COOPER, T., POLLACK, S. and KANE, J . (1989). pharmacology and tardive dyskinesia. Psychophrumacologyg:S54-S59. MILLER, R. and CHOUINARD, tardive and L-dopa-induce Biol Psychiatry (in press).

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Inquires and reprints requests should be addressed to: Dr. Guy Chouinard Allan Memorial Institute Clinical Psychoph~acology 1025 Pine Avenue West Montreal, Quebec, Canada H3A 1Al

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