P2

Psychotic disorders and antipsychotics

Tolerability and cardiovascular safety of

risperidone

P. Lemmens 1, M. Brecher 2, Bart Van Baelen. 1janssen Research

Foundation, Beerse, Belgium, 2janssen Research Foundation, Titusville,

NJ, USA
Combined data on severity of extrapyramidal symptoms (EPS) from 12
double-blind trials, in which 2,074 patients with chronic schizophrenia
received risperidone, were analyzed. Factors associated with increased
severity of EPS were increasing dose, lower baseline ESRS scores, and
longer duration of psychotic symptoms. EPS severity was greater in
patients receiving haloperidol or other antipsychotics than those receiving
risperidone (4-8 mg/day) or placebo. Only four cases of tardive dyskinesia were reported in 3,298 patients participating in 27 trials of risperidone
(probability, 0.0034 per treatment year). Data from three short-term
double-blind studies (N = 1,885) and seven long-term studies (N = 1,156)
indicate that mean QTc changes in patients receiving risperidone were
negative or minimally positive. QT~ changes were similar in patients
receiving risperidone, placebo, and haloperidol.

Clotiapine: Another forgotten treasure in

psychiatry?

Pavel Lokshin, Moshe Kotler, R.H. Belmaker. Ministry of Health Mental

Health Center, Faculty of Health Sciences, Ben Gurion UniversiO, of the
Negev, Beersheva, Israel
Clotiapine is a neuroleptic with chemical structure similar to clozapine, and has been in use in several European countries and Israel for
twenty seven years. It is often said that patients unresponsive to other
neuroleptics respond to clotiapine. The history of clozapine's discovery
as an atypical neuroleptic suggests that not only new drugs may have
unique properties. Some old compounds whose patents have expired and
on whom little research is being done may have unique properties. Forty
patients in our 400 bed hospital were being treated with clotiapine and the
treating physicians felt that this drug has unique antipsychotic properties
in neuroleptic non responsive patients. The use of clotiapine persisted
despite its high cost and repeated administrative requests to reduce use.
We decided to survey clotiapine use in our hospital.
All patients receiving clotiapine were identified and their charts reviewed and their physicians and nurses interviewed. Clotiapine was
administered for hospital inpatients by oral route only (tablets of 40 mg).
There were 40 patients, 20 males and 20 females with a mean age of
46.45 (4- 15) (range 20 to 86) with a mean length of schizophrenic illness
of 22.6 ( 11) (range 2 to 42). Mean dose of clotiapine was 162.94 mg
(range 80 to 360) mg. Eighteen patients had received 5 or more other
neuroleptic drugs in the past; 14 had received 3-4 other neuroleptics;
twelve patients had received clozapine in the past but stopped for non
response, drug induced leukopenia or non compliance, two had received
risperidone, seroquel and one olanzepine.
Improvement with Clotiapine among schizophrenic
non responder patients
Partial only
Significant with residual signs
Length of remission
Month to year
More than a year with residual symptoms

12
21

(35.3)
(61.8)

12
22

(35.3)
(64.7)

These results are far from the conclusive study of Kane et al (1988)
that proved the efficacy of clozapine in neuroleptic nonresponders and
thereby broke the rule that all neuroleptics are equivalent. However, the
Kane et al (1998) study would not have been done if not for persistent
and irrepressible clinical opinion that clozapine had unique properties.
Clotiapine affects multiple receptors like clozapine or olanzepine. It
blocks 5HT3-receptors and downregulates cortical 5HTe-receptors like
clozapine. The ratio of De to 5HT2 blockade by clotiapine is very similar
to that of clozapine. Clotiapine and clozapine share high affinity for
the 5HT-6 receptor. Clotiapine shows little blockade of D-2 receptors
either biochemically or behaviorally and in the rat retinal model seems to
possess D-4 blockade like clozapine, although D-4 blockade by clotiapine
has not to our knowledge been evaluated directly. Clotiapine has been

$217

reported to exacerbate OCD as does clozapine. The uripatented status

of clotiapine should not lead to the neglect of this possibly unique
;mtipsychotic.

Treatment of positive symptoms of schizophrenia:

A meta-anaiysis comparing risperidone with other
antipsychotics

P. Lemmens, B. Van Baelen, M. Brecber. Janssen Pharmaceutica,

Beerse, Belgium, Janssen-Cilag, USA

Data from the twelve double-blind comparative trials in schizophrenic
patients were pooled. In meta-analysis, efficacy results from 1056 risperidone-treated patients (from fixed dose studies, patients treated with 4-8
mg were included) were compared with those of 703 patients treated with
other antipsychotics (OA), i.e. haloperidol (n = 473), levomepromazine,
zuclopenthixol, remoxipride, and thioridazine. The duration of treatment
was 8 weeks in most trials. Patients" psychopathology was assessed by
means of the Positive and Negative Symptoms Scale (PANSS) in all the
trials.
The mean total PANNS score at baseline was 94.7 (PalS), 93.9 (OA)
and 92.2 (HAL). At endpoint, the mean shift from baseline was significantly higher in the risperidone-treated patients at --20.9, compared
with - 1 6 . 2 the other antipsychotics group (p < 0.001)or - 1 4 . 3 in the
haloperidol-treated patients (p < 0.01).
The superiority of risperidone was very evident on the positive subscale
of the PANSS: the mean score at baseline was 21.8 (RIS), 21.1 (HAL)
and 21.8 (OA). At endpoint, the mean shift from baseline was - 5 . 9 in the
risperidone group, compared with --4.7 in the patients treated with other
psychotics (p < 0.001), and - 4 . 3 in the patients treated with haloperidol
Ip < 0.01).
In 7 of the l 2 trials, there were patients diagnosed with acute exacerbalion (DSM-III-R) at the time of recruitment into the trial. A subanalysis
was done on these, i.e. 372 risperidone-treated patients and 285 patients
treated with other antipsychotics, namely haloperidol (n = 120), levomepromazine, thioridazine, zuclopenthixol, and remox~pride. The mean
lotal PANSS score at baseline was between 99 and 100 in the 3 groups.
At endpoint, the total PANSS score had decreased with :24.7 under RIS,
compared with 19.8 under HAL (p < 00.5) and 19.8 under OA (p <
0.01).
On the positive subscale of the PANSS of the patients with acute
exacerbation, the mean score at baseline was 24.1 (RIS), 24.4 (HAL) and
24.1 (OA). At endpoint, the mean shift from baseline was - 7 . 8 in the
risperidone group, compared with - 6 . 3 in the patients treated with other
psychotics (p < 0.01), and - ? . 1 in the patients treated with haloperidol
!p < 0.1).
The results of this meta-anatysis conform that risperidone is a very
effective antiphychotic agent, corttrolling the positive symptoms of
schizophrenia more effectively than halopendol or other antipsychotic
drugs.

[ i ~

Effect of calcium channel blockers on stimulant Induced hyperactivity

A. Do~rul, O. Y%ilyurt, A. I~imer. Faculty qfMedieine, Department of

Pharmacology, Giilhane Militam' Medical Academy Anlalra, Turkey

C'alcium channel blockers (CaCBs) are drug used in the treatment
of neurological and cardiovascular disorders and occasionally produce
parkinsonism and movement disorders as a side effect. Several CaCBs
have been found to antagonise or supress physiological and behavioral
responses elicited dopaminergic agonist. Bromocriptine (BRC) elicits
iLocomotor stimulation. But, BRC can not be considered directly acting
agonist like apomorphine, since reserpine and alpha methyl-p-tyrosine
inhibit or completely abolish most of the behavioral effects induced by
BRC. In order to examine the functional significance between L-type
voltage dependent calcium channel and CNS dopamine systems, we have
~tudied L-type voltage dependent calcium channel blockers amlodipine,
alcardipine, diltiazem and verapamil on bromocriptine, morphine and
~pomorphine-induced hyperlocomotion where dopamine release or its
modulation is though to play a majcw role.