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©2002 CRC Press LLC

Figure 3.19 

Profile of neuro-

psychological performance of
patients with schizophrenia.
The deficits seen in
schizophrenia are not uniform,
but they encompass both
executive function and
memory. The zero line is the
score of normal controls. Figure
reproduced with permission
from Bilder RM, Goldman RS,
Robinson D, 

et al

.

Neuropsychology of first-
episode schizophrenia: initial
characterization and clinical
correlates. 

Am J Psychiatry

2

0

0

0

;

1

5

7

:

549–59

0.0

–1.5

–1.0

–0.5

–2.0

Z sco

re

Language

Memory

Attention

Executive

Motor

V

isuospatial Pr

emorbid

NEUROPSYCHOLOGICAL PERFORMANCE IN SCHIZOPHRENIA

Figure 3.18

Deficits in

premorbid IQ (as measured by
the National Adult Reading Test)
are seen in people with
schizophrenia, but not in their
first-degree relatives, or patients
or relatives of patients with
affective psychoses. The zero
line is that of normal controls.
Figure reproduced with permis-
sion from Gilvarry C, Takei N,
Russell A, 

et al. 

Premorbid IQ in

patients with functional
psychosis and their first-degree
relatives. 

Schizophr Res

2000;41:417–29

6

–2

4

2

0

–6

–8

–4

–10

–12

Patients with

schizophrenia

Relatives of

patients with

schizophrenia

Patients with

affective

psychoses

Relatives of

patients with

affective

psychoses

P

remorbid IQ

PREMORBID IQ IN PATIENTS WITH  

PSYCHOSIS AND THEIR RELATIVES


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©2002 CRC Press LLC

The cognitive deficits seen in schizophrenia

include lower premorbid IQ (

Figure 3.18

)

13

, as

well as more circumscribed deficits, for example
in memory and executive function (

Figures 3.19

14

and 

3.20

15

). These are almost certainly a primary

feature of the disorder.

Some neuropsychological deficits are present

long before the onset of schizophrenia. Two large
cohort studies from the UK have supported the
idea that the deficits of schizophrenia may be
apparent early in life, with evidence of impaired
educational test performance and avoidant social
behavior (

Figure 3.21

)

16

. Childhood ‘schizoid’

personality traits may reflect deficits in cognition
and in social behavior that are part of the disease
process itself. Abnormalities of social behavior,
movement and posture have also been reported
(for example, in studies based on old home movies
of affected and unaffected siblings). The antece-
dents of schizophrenia may therefore become
identifiable long before the clinical onset of the
illness.

Figure 3.20 

Wisconsin card sort test (WCST) in

monozygotic twins discordant for schizophrenia. The
WCST is a measure of executive function. In twins
discordant for schizophrenia, performance on the WCST is
uniformly impaired in the affected twin. Data from
Goldberg TE, Torrey EF, Bigelow LB, 

et al.

Genetic risk of

neuropsychological impairment in schizophrenia: a study
of monozygotic twins discordant and concordant for the
disorder. 

Schizophr Res

1995:17:77–84

10

5

4

3

2

1

6

7

8

9

0

Sco

re 

Unaffected

twin

Affected

twin

SCORE ON WISCONSIN CARD SORT TEST

Figure 3.21 

The study of large birth

cohorts provides a powerful tool
for investigating risk factors in
schizophrenia. In the 1946 UK
birth cohort

16

, risk factors for later

schizophrenia included problems
at play, few friends, inappropriate
emotional expression, anxiety,
impaired intellectual function and
odd movements. Figure
reproduced with permission from
Jones P, Rodgers B, Murray R,
Marmot M. Child development risk
factors for adult schizophrenia in
the British 1946 birth cohort.

Lancet

1994;344:1398–402

2

–3

–4

–2

–1

0

1

–5

20

–6

Deviance f

rom cont

rols

Age in years

15

10

5

0

Mean deviance

95% Confidence interval

TRAJECTORY OF PREMORBID IMPAIRMENT


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©2002 CRC Press LLC

9.

McGuire PK, Silbersweig DA, Wright I. Speech: a
physiological basis for auditory hallucinations. Lancet
1995;346:596–600

10.

Spence SA, Brookes DJ, Hirsch SR, et al. A  PET
study of voluntary movement in schizophrenic
patients experiencing passivity phenomena (delu-
sions of alien control). Brain 1997;120:1997–2011

11.

McGuire PK, Quested DJ, Spence SA, et al.
Pathophysiology of ‘positive’ thought disorder in
schizophrenia. Br J Psychiatry 1998;173:231–5J

12.

Frangou S, Sharma T, Alarcon G, et al. The Maudsley
Family Study, II: Endogenous event-related poten-
tials in familial schizophrenia. Schizophr Res 1997;
23:45–53

13.

Gilvarry C, Takei N, Russell A, et al

Premorbid IQ in

patients with functional psychosis and their first-
degree relatives. Schizophr Res 2000;41:417–29

14.

Bilder RM, Goldman RS, Robinson D, et al.
Neuropsychology of first-episode schizophrenia:
initial characterization and clinical correlates. Am J
Psychiatry 
2000;157:549–59

15.

Goldberg TE, Torrey EF, Bigelow LB, et al. Genetic
risk of neuropsychological impairment in schizo-
phrenia: a study of monozygotic twins discordant
and concordant for the disorder. Schizophr Res 1995:
17:77–84

16.

Jones P, Rodgers B, Murray R, Marmot M. Child
development risk factors for adult schizophrenia in
the British 1946 birth cohort. Lancet 1994;344:
1398–402

REFERENCES

1.

Van Horn JD, McManus IC. Ventricular enlargement
in schizophrenia. A meta-analysis of studies of the
ventricle : brain ration (VBR). Br J Psychiatry
1992;160:687–97

2.

Suddath RL, Christison GW, Torrey EF, et al.
Anatomical abnormalities in the brains of mono-
zygotic twins discordant for schizophrenia. N Engl J
Med 
1990;322:789–34

3.

Wright IC, Rabe-Hesketh S, Woodruff PW, et al.
Meta-analysis of regional brain volumes in
schizophrenia. Am J Psychiatry 2000;157:16–25

4.

Akbarian S, Bunney WE, Jr, Potkin SG, et al. Altered
distribution of nicotinamide-adenine dinucleotide
phosphate-diaphorase cells in frontal lobe of schizo-
phrenics implies disturbances of cortical develop-
ment. Arch Gen Psychiatry 1993:50:169–77

5.

Longworth C, Honey G, Sharma T. Science,
medicine, and the future. Functional magnetic
resonance imaging in neuropsychiatry. Br Med J
1999;319:1551–4

6.

Curtis VA, Bullmore ET, Brammer MJ, et al.
Attenuated frontal activation during a verbal fluency
task in patients with schizophrenia. Am J Psychiatry
1998;155:1056–63

7.

Spence SA, Hirsch SR, Brooks DJ, Grasby PM.
Prefrontal cortext activity in people with schizo-
phrenia and control subjects. Evidence from positron
emission tomography for remission of ‘hypofronta-
lity’ with recovery from acute schizophrenia. Br J
Psychiatry 
1998;172:316–23

8.

Liddle PF, Friston KJ, Frith CD, et al. Patterns of
cerebral blood flow in schizophrenia. Br J Psychiatry
1992;160:179–86


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©2002 CRC Press LLC

Table 4.1  The classification of antipsychotic drugs.

The relevance of classifying antipsychotics according to their chemical

class is seen when switching antipsychotics. Patients who do not respond to a medication coming from a particular
chemical class should be switched to a medication of a different chemical class. The emphasis is now changing to
pharmacological rather than chemical classes, as all of the newer medications belong to different chemical classes, but
some share similar pharmacological properties

efficacy of typical antipsychotic (neuroleptic)
medication for acute schizophrenia, and for
maintenance in chronic schizophrenia.

Antipsychotics are therefore the mainstay of

treatment in schizophrenia and knowledge of the
chemistry and pharmacology of these medications
has led to a greater understanding of the neuro-
chemical basis of schizophrenia.

C

HAPTER

4

Neurochemistry and pharmacotherapy 

INTRODUCTION

The discovery of the antipsychotic effects of
chlorpromazine in the early 1950s heralded an era
of effective pharmacological treatment for
schizophrenia. Since the initial 1952 report of
reduction in agitation, aggression and delusional
states in schizophrenic patients, a wealth of
placebo-controlled trials have established the

Type

Class

Examples

Typical antipsychotics

phenothiazines

chloropromazine, thioridazine

trifluoperazine, fluphenazine

butyrophenones

haloperidol, droperidol

thioxanthenes

flupenthixol, zuclopenthixol

diphenylbutylpiperidines

pimozide, fluspiraline

Atypical antipsychotics

dibenzodiazepines

clozapine

benzixasoles

risperidone, iloperidone

thienobenzodiazepines

olanzapine

dibenzothiazepines

quetiapine

imidazolidinones

sertindole

benzothiazolylpiperazines

ziprasidone

substituted benzamides

amisulpride, sulpiride
(NB. sulpiride is considered by 
some to be a typical atipsychotic)

quinolinones

aripiprazole


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©2002 CRC Press LLC

CLASSIFICATION OF ANTIPSYCHOTICS

Antipsychotic drugs are not a homogeneous
group, and there are various classes. The pheno-
thiazines include chlorpromazine, trifluoperazine
and fluphenazine. Other classes include the thio-
xanthenes (e.g. flupenthixol and zuclopenthixol)
and the butyrophenones (e.g. haloperidol) (

Table

4.1

). The newer ‘atypical’ antipsychotics are

mostly in different chemical classes, although they
may share pharmacological characteristics.

NEUROCHEMISTRY OF SCHIZOPHRENIA
AND MECHANISMS OF ACTION OF
ANTIPSYCHOTICS

Dopamine

The observation from the early use of chlor-
promazine that clinical improvement was often
accompanied by a parkinsonism-like syndrome led

to a focus on dopaminergic mechanisms of action
for antipsychotics. In 1963 Carlsson and
Lindqvist

reported that antipsychotics increased

turnover of brain dopamine, and suggested that
this was in response to a functional ‘blockade’ of
the dopaminergic system. Creese and colleagues

2

demonstrated that the affinity of a wide range of
antipsychotics to dopamine D

2

receptors was

proportionate to their clinical potency (

Figure

4.1

). Further evidence for the dopamine hypo-

thesis is that amphetamines, which increase
dopamine release, can induce a paranoid psychosis
and exacerbate schizophrenia and that disulfiram
inhibits dopamine hydroxylase and exacerbates
schizophrenia

3,4

.

Initial positron emission tomography (PET)

studies of D

receptor densities in drug-naive and

drug-free patients with schizophrenia, using
different tracers, were equivocal, with one group
showing a marked increase in receptor density and

Figure 4.1 

Plot of the affinity of a wide variety of antipsychotic medications for the dopamine D

2

receptor (y-axis), plotted

against the average clinical daily dose used for controlling schizophrenia (x-axis), an estimate of clinical potency. As can be
seen, there is a direct relationship between these two indices. This replicated finding contributed to the use of high-dose
antipsychotics on the assumption that giving higher doses would make an antipsychotic more potent by ‘blocking’ more
receptors

AFFINITY FOR DOPAMINE RECEPTORS AND CLINICAL POTENCY

10-7

10-8

10-9

10-10

0.1

IC

50 

(mol/l)

1

10

100

Range and average clinical dose

for controlling schizophrenia (mg/day)

1000

Spiroperidol

Benperidol

Trifluperidol

Pimozide Fluphenazine

Droperidol

Moperone

Molindone

Clozapine

Chlorpromazine

Promazine

Haloperidol

Thiothixene

Trifluperazine

Prochlorperazine

Thioridazine

Trazodone