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©2002 CRC Press LLC
In early phase II placebo controlled trials,
iloperidone at 8 mg per day was superior to
placebo in improving positive and negative
symptoms with EPS at placebo levels. The most
frequently described side-effects were dizziness,
postural hypotension and nausea
76
.
A large scale multicenter trial comparing
iloperidone 4mg, 8mg and 12mg with haloperidol
15 mg per day and placebo in a total of 621
patients over 42 days has recently been
completed
77
. Initial data indicates clinical respo-
nse similar to haloperidol but with significantly
lower rates of EPS (similar to placebo).
Aripiprazole
Aripiprazole is a quinolinone derivative and differs
from other novel antipsychotics in that rather than
being an antagonist at dopamine receptors, it
appears to be a high affinity partial agonist at
presynaptic D
2
receptors but exhibits antagonist
effects on postsynaptic D
2
receptors
78
. It has low
affinity for D
3
and D
4
receptors and no appre-
ciable affinity for D
1
-like receptors. Its affinity for
5-HT
2A
receptors is low and of a similar magni-
tude to that of clozapine.
In phase II clinical studies, aripiprazole is
significantly superior to placebo at improving the
total score of the PANSS
79
. A recently completed
phase III clinical trial compared aripiprazole 15mg
or 30 mg per day with haloperidol 10 mg per day
and placebo in a total of 414 patients for 28 days.
The preliminary results from this study show that
both doses of aripiprazole are significantly better
than placebo at improving PANSS total score and
equivalent to haloperidol. Aripiprazole at both
doses lead to placebo rates of EPS which is
significantly lower than the rate seen in the
patients treated with haloperidol
80
.
ADVERSE EVENTS OF ATYPICAL
ANTIPSYCHOTICS
The issue of side-effects or adverse events is
closely linked to tolerability and acceptability and
therefore to both compliance and relapse preven-
tion. Often the most debilitating and obvious side-
effects of conventional antipsychotics are motor.
As described above, all of the newer antipsych-
otics demonstrate a lower propensity to cause EPS
at clinically effective doses. There is increasing
evidence that these drugs may additionally
provide benefits for patients who suffer from
akathisia and tardive dyskinesia.
Indeed, it is in the area of tardive dyskinesias
that clozapine appears to have its most marked
effect. Lieberman and associates
81
reported a 50%
reduction of symptoms over 28 months of
treatment in 43% of patients, and Gerlach and
Peacock
82
reported a resolution of tardive
dyskinesia in 54% of patients after 5 years of
clozapine treatment. Furthermore, Tamminga and
colleagues
83
reported a significant difference in
reduction of tardive dyskinesia scores in a
clozapine group versus a haloperidol-treated
group and that this difference began after about 4
months of treatment. There have also been case
reports that switching to clozapine has been
effective in reducing tardive dystonia
84
.
Initial data from the studies quoted above on
the newer antipsychotics indicates that they too
produce very low rates of tardive dyskinesia. The
rate of other side-effects may vary between each of
the newer drugs, although fully adequate comparison
studies remain to be published (
Table 4.4
)
85
.
Negative symptoms
It is claimed that clozapine has an almost unique
action against the negative symptoms of schizo-
phrenia, out of proportion to its effect on positive
symptoms
86
, but the evidence for this is by no
means clear. Tandon and associates
87
found that
the improvement in negative symptoms covaried
with the improvement in positive symptoms, and
Hagger and co-workers
88
found no improvement
in negative symptoms. A more recent finding is
that in comparison with haloperidol, clozapine
had a significant effect on negative symptoms in
patients with non-deficit schizophrenia, but not in
those with deficit schizophrenia, i.e. those with
enduring negative symptoms
89,90
. It has therefore
been suggested that clozapine’s apparently benefi-
cial effect on negative symptoms may simply be a
reflection of its reduced tendency to cause EPS
91
.
The weight of current evidence suggests that
©2002 CRC Press LLC
clozapine has an excellent effect on the secondary,
but not primary, negative symptoms
92
. All of the
newer antipsychotics appear to have an effect on
secondary negative symptoms. Most of the
available trials have indicated a modest but
significant advantage for all of the newer
medications over conventional antipsychotics in
negative symptom improvement
54,58,87,93
.
Amisulpride at low doses (50–300 mg/day) is
claimed to have a unique effect in patients with
only negative symptoms. In comparison with
placebo, these low doses of amisulpride produced
significant reductions in negative symptom scores
with little change in positive symptom scores
94–96
.
However, in a study utilizing a different design but
similar patient population, low-dose amisulpride
was similar to low-dose haloperidol treatment in
terms of negative symptom improvement
97
.
Cognition
Neurocognitive deficits that are a core feature of
schizophrenia, are apparent at the onset of illness
and may deteriorate during the first few years of
illness. The older antipsychotics have limited
impact on these, although inconsistent long-term
improvements have been noted
98,99
. There has
been increasing interest in the possibility that the
newer antipsychotics may ameliorate these probl-
ems which are linked to poor outcome and future
unemployment. Clozapine may lead to improve-
ments in attention, memory and executive
function over 6–12 months
100
. Risperidone is
claimed to improve frontal function and spatial
working memory compared with halo-
peridol
101,102
. Olanzapine is claimed to improve a
variety of measures of function including psycho-
motor speed, verbal fluency and memory
103
. It has
recently been reported that quetiapine improves
attentional performance to the level of that seen
in a matched control group over 2 months of
treatment
104
. In a study comparing haloperidol
1 mg and 2 mg and amisulpride 50 mg and 100 mg
with placebo in healthy volunteers,
the
haloperidol-treated groups showed greater cogni-
tive impairment on tasks measuring problem-
solving abilites
105
.
It is still not clear how relevant the modest
improvements or impairments reported in these
studies are to long-term outcome.
Table 4.4 Qualitative comparison of the relative side-effects of the newer medications.
These will be subject to change
over time, as new tolerability data are published and report forms returned. Adapted from reference 85
Typicals
Clozapine
Risperidone
Olanzapine
Quetiapine
Amisulpride
Ziprasidone
Anticholinergic
±
+++
±
+
±
±
±
Orthostatic
hypotension
± to +++
+++
+
±
+
±
±
Prolactin
elevation
++ to +++
0
++
±
±
++
±
QT prolongation
± to +
+
± to +
± to +
± to +
±
± to +
Sedation
+ to +++
+++
+
++
++
±
+
Seizures
±
++ to +++
±
±
±
±
±
Weight gain
± to ++
+++
+ to ++
+++
+ to ++
± to +
±
©2002 CRC Press LLC
Affective symptoms
Patients with schizophrenia are significantly more
likely than the general population to suffer from
other psychiatric disorders such as depression,
and conventional antipsychotics are used to treat
other psychotic disorders outside of schizo-
phrenia
Clozapine has been reported to be effective in
patients with treatment-resistant schizoaffective
or manic illnesses
106
(see reference 107 for
review). In one study, clozapine reduced baseline
mania ratings by more than 50% in 72% of a
group of patients suffering from either mania or
schizoaffective disorder and 32% had a significant
improvement in BPRS scores. The latter finding
was more frequent in the patients with bipolar
disorder and the non-rapid cycling patients
108
. In
depressive disorders, clozapine had a more
equivocal response. Although it was seemingly
effective against depressive symptoms occurring
comorbidly with schizophrenia
109
, there has been
little work showing a particular use for clozapine
in treatment-refractory depression
110,111
.
Conventional antipsychotics may both
improve and contribute towards depressive symp-
toms. Clozapine reduces both depressive features
and suicidality
109
. Risperidone produces signifi-
cantly greater reduction in anxiety/depression
subscales in comparison with haloperidol
52
.
Olanzapine has significant antidepressant effects
in comparison with haloperidol
112
. Amisulpride
(50 mg/day) has been compared with imipramine
(100 mg/day) and placebo in patients with
dysthymia and major depressive disorder. In this
study (
n = 219), both imipramine and amisulpride
produced similar and significant improvements on
all rating scales
113
. The implications of this in
patients with schizophrenia have yet to be
elucidated.
THE FUTURE
Despite the advances in schizophrenia pharmaco-
therapy since the early 1950s there are still many
limitations. EPS make use of high doses of the
older typical antipsychotics problematic and often
–0.5
–0.3
–0.1
0
–0.4
–0.2
0.1
<
12 mg
haloperidol
>
12 mg
haloperidol
Favors
atypical
Favors
haloperidol
COMPARISON OF ATYPICAL AND TYPICAL ANTIPSYCHOTICS
-0.5
-0.3
-0.1
0
-0.4
-0.2
0.1
<
12 mg
haloperidol
>
12 mg
haloperidol
Favors
atypical
Favors
haloperidol
−
<
<
−
Figure 4.19
Results from a meta-analysis of trials comparing newer atypical antipsychotics and typical antipsychotics (mainly
haloperidol). The left graph suggests that the clinical superiority of atypical antipsychotics over typical antipsychotics is lost
if lower doses of typical antipsychotics are used (less than 12 mg per day of haloperidol equivalents). The right-hand graph,
suggests that any superiority in tolerability for the atypical antipsychotics is similarly lost if patients receive lower doses of
typical antipsychotics. These findings and interpretations have been criticized on a number of counts including selection bias
in the trials chosen for the meta-analysis, no similar control for the doses of atypicals used and using the drop-out rates from
clinical trials as a measure of medication tolerability. Figure reproduced with permission from Geddes J, Freemantle N,
Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression
analysis.
Br Med J
2000;321:1371–6
©2002 CRC Press LLC
unpleasant for those taking them. Lower doses of
‘typicals’ and the newer ‘atypical’ antipsychotics
offer benefits in terms of reductions in EPS, but
the latter medications are not without their own
unpleasant side-effects. In a recent meta-analysis,
Geddes and colleagues
114
described that in their
analysis of all of the trials of atypical anti-
psychotics versus typical antipsychotics there was
no treatment advantage for the newer medications
over doses of haloperidol below 12 mg/day and no
significant difference in total side-effect load
(
Figure 4.19
). Such meta-analyses have, however,
come under criticism for obscuring real treatment
effects by being overinclusive of available
trials
115,116
. Furthermore, a recent critical review
of treatment trials with low-dose typical anti-
psychotics could find no convincing evidence that
there is a low dose of typical antipsychotics which
is effective but does not produce EPS
117
.
Another failing in the pharmacotherapy of
schizophrenia is that there are still 40–50% of
patients with schizophrenia who do not have an
optimal response to medication, and some 20%
who are resistant to all forms of treatment,
including clozapine.
Future developments may include a new
generation of antipsychotic drugs which are
partial agonists (rather than antagonists) at D
2
and
D
2
-like receptors, such as aripiprazole
78
. As
described above, early clinical trials with this
medication show good efficacy with placebo rates
of EPS
80
.
In conjunction with developments in trial
methodology, combinations of neurochemical and
functional imaging may help to elucidate the
neural correlates of treatment response and
resistance and allow more rationale therapeutic
decisions.
Pharmacogenetics may further help to define
the parameters which predict response or non-
response to particular medications by analyzing
the allelic variations for individual receptors
which correlate with response
118
.
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