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©2002 CRC Press LLC

specifically associated with QT

C 

interval prolong-

ation bind specifically to the I(kr)

42

.

Although there is little consensus as to what

represents a ‘normal’ QT

C 

it is generally accepted

that a QT

C 

of over 500 ms increases the likelihood

of an arrhythmia. When interpreting data on
medication-related QT

C 

prlongation it is impor-

tant to note that the mean daily QT

C 

intrasubject

variability is 76ms

43

.

Other risks factors which increase the

likelihood of QT

C 

prolongation include age over

65 years and co-administration of other drugs
associated with cardiac arrythmias, such as tricyc-
lic antidepressants. Safety studies are ongoing with
both the newer and the older medications, prelim-
inary data suggests that the newer medications do
not differ significantly in their likelihood to
prolong the QT

C 

interval.

THE NEWER ‘ATYPICAL’ ANTIPSYCHOTICS

The reintroduction of clozapine in the early 1990s
and the subsequent release of several new,
‘atypical’ antipsychotics has increased optimism in
the treatment of schizophrenia. As these are likely
to be the mainstay of treatment for schizophrenia
in the future, it is worthwhile considering them
individually (

Figure 4.17

 and 

Table 4.3

)

44,45

.

Clozapine

Clozapine,

the prototypical third-generation

antipsychotic, has been used since the 1960s for
treatment of schizophrenia. However, after
reports of several deaths from neutropenia, in
most countries clozapine can be used only in
patients unresponsive to two other antipsychotics
given at an adequate dose for an adequate dura-
tion, or those with tardive dyskinesia or severe
extrapyramidal symptoms, and only with blood
monitoring. Each patient has to be registered and
the drug is dispensed only after a normal white
cell count. In the UK, a blood count is performed
every week for 18 weeks, then every 2 weeks for
the next year, and thereafter monthly. In the USA,
blood monitoring is weekly throughout treatment.
Clozapine is contraindicated for those with
previous neutropenia.

Important aspects of clozapine’s pharmacology

include its low affinity for the D

2

receptor, in

comparison with older antipsychotics. Clozapine
has higher affinity at the D

1

and D

4

receptors than

at the D

2

receptor and also binds to the extra-

striatal D

2

-like receptor, the D

3

receptor. It is

thought that the low incidence of extrapyramidal
side-effects is due to the low activity at the D

2

receptor. Clozapine also has antagonistic activity
at the 5HT

1A

, 5HT

2A

, 5HT

2C

and 5HT

3

Table 4.3  Amisulpride 

vs.

reference antipsychotics – selectivity for recombinant human D

2

/D

3

receptor subtypes.

Amisulpride only has appreciable affinity for D

2

and D

3

receptors in contrast to the other antipsychotics in this table.

It has relatively high affinity for both receptors. The implications of this for amisulpride’s mechanism of action and
atypicality are hypothesized to involve an increased tendency to bind to presynaptic D

2

and D

2

-like receptors. Table

reproduced with permission from Schoemaker H, Claustre Y. Fage D, 

et al.

Neurochemical characteristics of

amisulpride, an atypical dopamine D

2

/D

3

receptor antagonist with both presynaptic and limbic selectivity. 

J

Pharmacol Exp Ther

1997;280:83–97

Positively coupled with

adenyl cyclase 

Negatively coupled with adenyl cyclase

Compound

D

1

D

5

D

2

D

3

D

4

Amisulpride

>10000

>10000

2.8

3.2

>1000

Haloperidol

27

48

0.6

3.8

3.8

Clozapine

141

250

80

230

89

Olanzapine

250

–

17

44

–

Risperidone

620

–

3.3

13

–

©2002 CRC Press LLC

Figure 4.17 

A representation of the absolute receptor affinity of haloperidol in comparison with some of the newer ‘atypical’

antipsychotics drawn from data in reference 112. Each line represents a single receptor, the further along the bar on a given line the
higher the affinity of that medication for that receptor. Each of the gradations on the lines represents 10 times greater affinity for that
receptor. What can be seen from this is that clozapine, quetiapine and to a lesser extent olanzapine have much lower affinities for the
dopamine D

2 

receptor than haloperidol. This may be why they are ‘atypical’ in terms of producing fewer extrapyrimidal side-effects

than antipsychotics such as haloperidol. Risperidone and ziprasidone have similar D

2 

receptor affinities to haloperidol and yet they

too are ‘atypical’. It has been hypothesized that very high affinity for the serotonin-2A receptor, (5-HT

2A

), may underlie the atypicality

of ziprasidone and risperidone. Indeed this may be important for ‘atypicality’ 

per se

, as all of the newer medications have a higher

affinity for the 5-HT

2A 

than for the D

2 

receptor. Amisulpride, by contrast to the medications in this figure, only has appreciable affinity

for D

2 

and D

3 

receptors and has high equipotent affinity for both receptors, as can be seen in 

Table 4.3

. Data from reference 45

©2002 CRC Press LLC

receptors. It is postulated that it is the balance
between the blockade of these receptors that
underlies clozapine’s clinical efficacy in improving
positive and negative symptomatology. Clozapine
is an antagonist at the 

α

1 

receptor but less so at the

α

2 

receptor, resulting in sedation and hypotension.

Clozapine’s antagonism at the histamine H

1

receptor adds to the sedative effects and may be,
in part, responsible for weight gain. Other side-
effects include hypersalivation, tachycardia, seda-
tion and hypotension. More rarely, clozapine can
produce seizures (approximately 1%) and blood
dyscrasias (< 1–2%). The risk of neutropenia is
1–2%, and in most cases is reversible. The majority
of cases (83%) occur within the first 20 weeks of
treatment. Risk of agranulocytosis decreases to
0.07% after the first year of treatment. Agranulo-
cytosis probably results from toxic and immuno-
logical factors (reviewed in reference 46). It is this
last potentially fatal side-effect that has led to the
limits on the use of clozapine and the requirement
for blood monitoring in patients receiving cloza-
pine. Interestingly, clozapine does not increase
serum prolactin.

Clozapine is the most effective treatment for

schizophrenic patients refractory to other therapies,

and improves both positive and negative
symptoms. In non-comparative studies, clozapine
has led to > 15% improvement in baseline ratings
in 30–70% of previously treatment-refractory
patients after 2–6 months of treatment (reviewed
in reference 46). In comparison to chlorprom-
azine

47–49 

(

Figure 4.18

), haloperidol

50 

or fluphen-

azine

51

, clozapine shows a 30–100% response rate,

versus a 4–17% rate for the comparator, when
administered to patients resistant to previous
treatment with classical antipsychotics.

Clozapine has been investigated in few

randomized controlled trials of maintenance
therapy. This is due to the restrictions imposed on
its use. In one of the few studies published, Essock
and co-workers

52 

followed up a sample of 227

patients randomized to either clozapine or treat-
ment as usual. They reported that those treated
with clozapine had significantly greater reductions
in side-effects, disruptiveness, hospitalization and
readmission after discharge. Furthermore, the
clinical efficacy of clozapine in relapse prevention
is well established, naturalistically, at 1–2 years of
treatment and there have been reports of good
maintenance efficacy for up to 17 years of
treatment (for review see reference 46).

30%

25%

5%

10%

15%

20%

0%

CLOZAPINE vs. CHLORPROMAZINE IN

TREATMENT-RESISTANT SCHIZOPHRENIA

Clozapine Chlorpromazine

P

roportion of Patients Responding

Figure 4.18 

Comparison of efficacy of

clozapine versus chlorpromazine in
treatment-resistant schizophrenia.
Figure reproduced with permission from
Kane J, Honigfeld G, Singer J, Meltzer
H. Clozapine for the treatment-resistant
schizophrenic: a double blind
comparison with chlorpromazine. 

Arch

Gen Psychiatry

1988; 45:789–96

©2002 CRC Press LLC

Risperidone

This drug has high affinity for the 5-HT

2A

receptor, with a similar affinity at the D

2

receptor

to most typical antipsychotics. In the acute phase
of treatment, risperidone appears as effective as
haloperidol in terms of improvement in positive
and secondary negative symptom scores

53

.

The optimal dose of risperidone appears to be

between 4 and 6 mg/day. At doses higher than
8–12mg/day risperidone can cause extrapyramidal
side-effects of tremor, rigidity and restlessness,
with a similar frequency to typical antipsychotics.
Risperidone can increase serum prolactin which
may lead to sexual dysfunction.

Risperidone has been assessed for long-term

efficacy and safety in a number of long-term open-
label studies. Earlier data suggested that long-term
therapy with risperidone was associated with a
meaningful reduction in psychopathology, amelio-
ration of extrapyrimidal side-effects (EPS) and
improved social functioning from baseline
measures or against placebo.

More recently a meta-analysis of eleven of the

risperidone/conventional antipsychotic compara-
tor randomized controlled trials was performed

54

.

The author reported that slightly but significantly
more patients on risperidone showed clinical
improvement than with comparison antipsych-
otics (57% vs. 52%) and used significantly less
medication for EPS (29.1% vs. 33.9%).

Olanzapine

A more broad-spectrum atypical antipsychotic,
olanzapine has a side-effect profile similar to that
of clozapine but with a higher incidence of extra-
pyrimidal side-effects at doses above 20 mg/day.
Olanzapine also demonstrates antagonistic effects
at a wide range of receptors, but has a higher
affinity for D

2

and 5-HT

2A

receptors than

clozapine and a lower affinity at the D

1

receptor

subtype. In acute-phase studies, olanzapine is effi-
cacious for positive and secondary negative symp-
toms and was superior to haloperidol on overall

improvement according to the Brief Psychiatric
Rating Scale (BPRS)

55 

and every other secondary

measure.

Standard-dose olanzapine (5–15 mg/day) has

been shown to be an effective maintenance treat-
ment for schizophrenia in comparison with
placebo

56

. The estimated 1-year risk of relapse

with olanzapine was 19.6–28.6% for standard-
dose olanzapine in comparison with a 69.9% risk
of relapse with placebo. Initial data from a meta-
analysis of three studies using haloperidol-treated
patients as a test group, indicated that 80.3% of
patients receiving olanzapine maintained their
response at 1 year in comparison with 72% for
haloperidol-treated patients

57

.

Quetiapine

Another broader-spectrum atypical, quetiapine
has a similar receptor binding profile to clozapine,
but with relatively lower affinity for all receptors
and virtually no affinity for muscarinic receptors.
Quetiapine is effective in acute phase studies for
the treatment of positive and secondary negative
symptoms. Initial randomized controlled trials
indicated that quetiapine (250–750mg, n=96) was
more effective than placebo (n = 96) and that this
efficacy was not seen at doses of less than 250
mg/day of quetiapine

58

. In comparison with chlor-

promazine, response rates to quetiapine were
similar across all symptom domains

59

. Response

rates between haloperidol- and quetiapine-treated
groups are also similar

60

.

In all of these studies, the rates of EPS with

quetiapine were similar to those seen in placebo-
treated groups and significantly lower than in conv-
entional antipsychotic comparator groups. Most
common side-effects are somnolence and dry
mouth. Quetiapine demonstrates a lower potential
to cause weight gain than clozapine and olanzapine,
and does not increase serum prolactin

61

.

In long-term studies, quetiapine was well

tolerated with up to 75% of respondents to a
questionnaire denying any side-effects from
quetiapine

62

.

©2002 CRC Press LLC

Amisulpride

In contrast to all the other newer antipsychotics,
amisulpride only has effects on the dopamine D

2

and D

3

receptors, where it is a potent antagonist.

In animal models at lower doses, amisulpride
appears to bind preferentially to presynaptic D

2

receptors

64

, and at projected therapeutic levels it

also appears to be selective, in a neurochemical
imaging study in humans, for limbic D

2

and D

3

receptors

63

. It has a similar efficacy to haloperidol

for positive symptoms in acute exacerbations of
schizophrenia

64–67

, with a projected optimum

dose in this group of between 400 and 800
mg/day

66

. Some studies at this dose range have

reported a significantly greater efficacy for amisul-
pride in comparison with placebo for treating the
negative symptoms of schizophrenia

65,66

.

In all of the studies above, amisulpride has a

significantly lower incidence of extrapyrimidal
side-effects, at doses below 1200 mg/day, than
haloperidol. Amisulpride may cause less weight
gain than other atypical antipsychotics but it does
increase plasma prolactin

68,69

.

In a 12-month trial of amisulpride 

200–800 mg/day versus haloperidol 5–20 mg/day,
amisulpride showed enhanced efficacy for positive
and negative symptoms in comparison with halo-
peridol. Those treated with amisulpride had
significantly greater improvement in quality of life
and significantly fewer extrapyrimidal side-effects.
Long-term efficacy and relapse prevention were
similar in the amisulpride- and haloperidol-treated
groups

70

.

Ziprasidone

Ziprasidone has a high 5HT

2A

/D

2

receptor

blockade ratio and a similarly high affinity for the
5HT

2A

receptor to risperidone and sertindole. It is

an agonist at the 5HT

1A

receptor. Ziprasidone also

has potent affinity for D

3

and moderate affinity

for D

4

receptors. It exhibits weak serotonin and

noradrenergic reuptake inhibition.

Ziprasidone appears to have relatively low

levels of side-effects. These may include somno-
lence and headache, but results of full clinical
studies remain to be published.

An initial clinical trial of ziprasidone versus

haloperidol 15 mg/day over 4 weeks suggested
that ziprasidone 160 mg/day was as effective as
haloperidol at reducing positive symptom scores,
but produced fewer side-effects

71

. In two placebo-

controlled trials lasting 4 and 6 weeks,
respectively

72,73

, the pooled data indicated that

ziprasidone 80–160 mg was consistently signi-
ficantly more effective than placebo and lower
doses of ziprasidone. Improvements in positive
and negative symptoms were similar in magnitude
to those seen in patients treated with risperidone,
olanzapine or quetiapine. Interestingly, 160 mg of
ziprasidone was associated with a greater than
30% decrease in depressive symptoms in the sub-
group of patients with significant depression at the
outset of the trials.

Ziprasidone has also been used in a 1-year

placebo-controlled trial in order to assess its utility
for relapse prevention. A total of 294 patients
were studied and randomized to placebo treat-
ment or ziprasidone 40–160 mg/day. At 6 months
into the study, 117 patients remained on
ziprasidone and 23 on placebo. Of these, only 6%
of the ziprasidone-treated patients had experien-
ced an exacerbation of their symptoms over the
subsequent 6 months, in comparison with 35% in
the placebo-treated group

74

.

NEW ANTIPSYCHOTICS CURRENTLY IN
PHASE III CLINICAL TRIALS

Iloperidone

Iloperidone is a benzisoxazole derivative and is
therefore from the same chemical class as
risperidone. As for risperidone, iloperidone has a
high affinity for the 5-HT

2A

receptor and a lower

affinity for the D

2

receptor, although in absolute

terms its affinity for the D

2

receptor is of a similar

order of magnitude to haloperidol and risperidone.
Relative to other newer antipsychotics iloperidone
has a higher affinity for 5-HT

1A

receptors and

lower affinity for 5-HT

2C

receptors

75

. It also has

high affinity for 

a

1

receptors but no affinity for

acetylcholine muscarinic M

1

receptors.