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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
©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
©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
©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
©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
1
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
2
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