Файл: An.Atlas.of.Schizophrenia.eBook-EEn.pdf

©2002 CRC Press LLC

Table 4.2 Results of four studies comparing continuous medication treatment with ‘targeted’ or ‘crisis’ medication
treatment. 

In the latter condition the patients only received medication when psychotic symptoms appeared and medication

was stopped when these symptoms had resolved. Treatment was 24 months in all studies. As can be seen, although the
targeted/crisis groups received lower total doses of medication they were significantly more likely to have a relapse of their
psychotic illness than patients receiving continuous medication. Table adapted with permission from reference 33

Study Herz 

et al

. Carpenter 

et al

. Jolley 

et al

. Gaebel 

et al.

characteristics (1991)

35 

(1990)

36 

(1990)

37 

(1993)

38

Number 

101 116 54 365

Patient population 

outpatients recently discharged outpatients recently

hospitalized

Stabilization 

3 months 8 weeks 6 months 3 months post-

discharge

Psychosocial 

weekly support individual case monthly RN/MD special outpatient

support 

groups managers visits clinics

Control features 

random/double- random/non-blind random/fluphenazinerandom/non-blind

blind decanoate

double-blind

Dosage

Continued 

290

* 

1.7

** 

1616

=

208

= =

Targeted early 

150 1.0 298 91

Targeted crisis 

–

–

–

118

12-month relapse (%)

Continued 

10 33 9 15

Targeted early 

29 55 22 35

24-month relapse (%)

Continued 

17 39 14 23

Targeted early 

36 62 54 49

*

mg/day expressed in chlorpromazine (CPZ) eqivalents; 

**

1=low, e.g. <300 mg CPZ; 2=moderate, e.g. 301–600 mg/day; 

=

mean

total dose expressed in haloperidol equivalents; 

= =

cumulative dosage over 2 years in 1000 g CPZ equivalents

stopped gradually, the relapse rate at 6 months
was halved. Fifty percent of in-patients had relap-
sed by 5 months after cessation of medication,
whilst in their out-patient group relapse rates
remained less than 50% to 4 years’ follow-up
(

Figure 4.13

).

Thus, findings from medication discontin-

uation studies have conclusively shown that, as a

group patients with schizophrenia fare better if
they receive antipsychotic medication. However,
prolonged use of antipsychotic medication, parti-
cularly the older typical antipsychotics, carries a
high risk of adverse effects, particularly tardive
dyskinesia. In order to minimize the risk of these
events, much recent work has focused on the use
of low-dose medication regimes.

©2002 CRC Press LLC

Low-dose antipsychotics

The rationale underlying the use of low-dose
strategies is that significantly lower doses of
medication are required for the maintenance, as
opposed to the acute treatment, of schizophrenia.
This assumes that all major treatment goals have
been met for the patients by the time of dose
reduction. The two major aims are to ensure that
the stability of symptomatic improvement is at
least maintained and to minimize the risk of
neurological side-effects and secondary negative
symptoms caused by higher doses of anti-
psychotics, particularly typical antipsychotics.

A number of trials have investigated the use of

standard doses of depot antipsychotics (between
250–500 mg chlorpromazine equivalents) in com-
parison with continuous ‘low dose’ regimes,
usually at least 50% less (reviewed in references
33 and 34). On the whole, these studies have
indicated that the patients treated with the lower
doses of antipsychotics have a higher rate of
exacerbations of their psychotic symptoms and

higher rates of relapse. Barbui and colleagues

34

quoted a relative risk of relapse of 45–65% in the
low-dose groups at 12 months’ follow-up; with
the relapse rate highest in the group with the low-
est dose (50 mg chlorpromazine equivalents/day).

Intermittent or targeted medication

This treatment strategy is based on the
assumption that patients can be maintained with
intermittently administered low doses of
antipsychotics. To summarize the results from the
main published studies

35–38

, it appears that

patients receiving intermittent targeted therapy
while receiving less medication than those on
continuous therapy, have a higher rate of relapse
and may have a higher rate of re-hospitalization.
At 2 years there is little difference in social
functioning or psychopathology between the two
groups. However, because of the increased risk of
relapse and hospitalization, intermittent targeted
treatment is no longer generally recommended
(

Table 4.2

).

0

10 20

Percentage point prevalance

30

40

50 60

One or more movement disorders Parkinsonism

Tardive dyskinesia Akathisia/pseudoakathisia

SIDE-EFFECTS OF CONVENTIONAL ANTIPSYCHOTICS

Figure 4.14

Graphical representation of

the point prevalence of extrapyramidal
side-effects in 88% of all known schizo-
phrenics living in Nithsdale, Southwest
Scotland (n = 146), treated with conven-
tional antipsychotics. There was no
relationship between antipsychotic
plasma levels and akathisia,
parkinsonism or tardive dyskinesia.
Figure reproduced with permission from
McCreadie RG. Robertson LJ. Wiles DH.
The Nithsdale schizophrenia surveys.
IX: Akathisia, parkinsonism, tardive
dyskinesia and plasma neuroleptic
levels. 

Br J Psychiatry 

1992;160:793–9

©2002 CRC Press LLC

SIDE-EFFECTS OF TYPICAL
ANTIPSYCHOTICS

Acute neurological side-effects

Acute neurological side-effects secondary to
dopamine D

2

receptor blockade with typical

antipsychotics include acute dystonia. This is
characterized by fixed muscle postures with
spasm, e.g. clenched jaw muscles, protruding
tongue, opisthotonos, torticollis, oculogyric crisis
(mouth open, head back, eyes staring upwards). It
appears within hours to days and young males are
most at risk. It should be treated immediately with
anticholinergic drugs (procyclidine 5–10 mg or
benztropine 50–100 mg) intramuscularly or intra-
venously. The response is dramatic.

Medium-term neurological side-effects

Medium-term neurological side-effects due to D

2

blockade include akathisia and parkinsonism
(

Figure 4.14

)

39

. Akathisia is an inner and motor,

generally lower limb, restlessness. It is usually
experienced as very distressing by the patient, and
can lead to increased disturbance. Treatment is by
reducing the neuroleptic dose and/or propranolol,
not with anticholinergics. Akathisia usually
appears within hours to days. Parkinsonism is due
to blockade of D

2 

receptors in the basal ganglia.

The classical features are a mask-like facies,
tremor, rigidity, festinant gait and bradykinesia. It
appears after a few days to weeks and treatment
involves use of anticholinergic drugs (procycli-
dine, orphenadrine), reduction in antipsychotic
dose, or switching to an ‘atypical’ antipsychotic
which is less likely to produce such extra-
pyramidal symptoms (

Figure 4.15

).

Chronic neurological side-effects

The chronic neurological side-effects due to D

2

blockade are tardive dyskinesia and tardive
dystonia. Tardive dyskinesia is usually manifested
as orofacial dyskinesia and the patient exhibits lip
smacking and tongue rotating. Tardive dystonia
appears as choreoathetoid movements of the
head, neck and trunk. It appears after months to
years. There is an increased risk of tardive 

dyskinesia in older patients, females, the edent-
ulous and patients with organic brain damage.
With chronic use of antipsychotics, 20% or more
of patients will develop tardive dyskinesia.
Although there is no clear relationship with dura-
tion or total dose of treatment, or class of anti-
psychotic used there is a cumulatively increased
risk with length of exposure (

Figure 4.16

)

40

.

Increasing the dose may temporarily alleviate
symptoms, and reducing the dose may exacerbate
them. Clozapine, olanzapine and quetiapine have
been shown to improve symptoms, and with
risperidone and amisulpride, have a lower propen-
sity to cause tardive dyskinesia.

Neuroendocrine effects

The effect of D

2

blockade on the neuroendocrine

system produces hyperprolactinemia by reducing
the negative feedback on the anterior pituitary.
High serum levels of prolactin produce galactorr-
hea, amenorrhea and infertility.

Idiosyncratic effects

The most life-threatening side-effect of
neuroleptic use is neuroleptic malignant syndrome
(NMS). This is thought to be due to derangement
of dopaminergic function, but the precise patho-
physiology is unknown.

Symptoms include

hyperthermia, muscle rigidity, autonomic instabi-
lity and fluctuating consciousness. It is an idiosyn-
cratic reaction. The diagnosis is often missed in the
early stages, but a raised level of creatine phospho-
kinase is often seen. It can occur at any time. The
untreated mortality rate is 20% and therefore
immediate medical treatment is required. Bromo-
criptine (a D

1

/D

2

agonist) and dantrolene (a

skeletal muscle relaxant) are used to reverse
dopamine blockade and for muscular rigidity,
respectively. The management includes supportive
treatment for dehydration and high temperature.
Renal failure from rhabdomyolysis is the major
complication and cause of mortality. NMS can
recur on reintroduction of antipsychotics; it is
therefore recommended to wait at least 2 months
and introduce a drug of a different class at the
lowest effective dose.

©2002 CRC Press LLC

Figure 4.15

Side-effects with antipsychotics. Side-effects will vary between drugs depending on their receptor profile. In

general as all antipsychotics produce some degree of dopamine D

2

receptor blockade they are all likely to produce

neurological side-effects above a certain dose, with the exception of clozapine and quetiapine

Acute neurological side-effects

Acute dystonia

Idiosyncratic side-effects

Neuroleptic malignant

syndrome

Neuroendocrine effects

Amenorrhea

Galactorrhea

Infertility

Acute/medium term neurological side-effects

Akathisia and Parkinsonism

Chronic neurological side-effects

Tardive dyskinesia

Tardive dystonia

D

2

D

2

Dry mouth

Photosensitivity

Heat sensitivity

Sedation

Retinal pigmentation

α

1

H

1

Cholestatic

jaundice

Hypotension

Arrhythmia

Blurred vision

Ejaculatory failure

Constipation

Urinary retention

Antidopaminergic side-effects due to D

2 

receptor blockade

Anticholinergic side-effects due to muscarinic  

acetyl choline receptor blockade

Idiosyncratic side-effects due to histaminergic 

(H

1

) and adrenergic (

Ȋ

1) receptor blockade

Anticholinergic side-effects

include a dry

mouth (hypersalivation with clozapine), difficulty
urinating or retention, constipation, blurred vision
and ejaculatory failure. Profound muscarinic
blockade may produce a toxic confusional state.

The  sedative effects of antipsychotics are

primarily produced by the blockade of histamine-1
receptors.

Side-effects due to 

a

-adrenergic

blockade 

include postural hypotension, cardiac

arrhythmias and impotence.

Some side-effects may be due to autoimmune

reactions

such as urticaria, dermatitis and rashes.

Dermal photosensitivity and a gray/blue/purple
skin tinge are more commonly seen with the
phenothiazines, as are the conjunctival, corneo-
lenticular and retinal pigmentation sometimes
reported. Cholestatic jaundice due to a hyper-
sensitivity reaction is now rarely seen with chlor-
promazine and was possibly due to an impurity.

Weight gain is also frequently seen with a wide

variety of antipsychotics. This may be due to
increased appetite, and although the mechanism is
unclear, it may be due to a combination of
histamine-1 and 5-HT

2C

receptor blockade.

Cardiac conduction effects of antipsychotics

Recently, concern has grown over the ability of
antipsychotic medications to produce changes in

cardiac conduction. QT

C

interval prolongation is

the most widely reported conduction deficit. This
first came to attention after sudden deaths
secondary to arrhythmias with pimozide. The UK
Committee for the Safety of Medicines’ (CSM)
advice about pimozide is that all patients should
have an electrocardiogram (ECG) prior to starting
treatment and patients with a known arrhythmia
or prolonged QT interval should not receive the
drug. Sertindole, an atypical antipsychotic, was
voluntarily suspended from sale by its manufact-
urers in 1997 after similar concerns. Most recently
the CSM has advised on restrictions to the use of
thioridazine and droperidol as these medications
produce the most profound QT

C

prolongations

41

.

The QT interval on the standard ECG

represents the interval between the end of
ventricular depolarization and the end of cardiac
repolarization. The ‘c’ in QT

C 

indicates that the

QT value quoted has been corrected for cardiac
rate. It is thought that prolongation of this interval
increases the risk of a potentially fatal ventricular
arrhythmia known as torsade-de-pointes.

The mechanism of this is becoming clearer and

implicates the blockade of the delayed rectifier
potassium channel (I(kr)). Blockade of this recep-
tor in the heart prolongs cardiac repolarizaton and
thus the QT

C

interval. It is known that drugs most

©2002 CRC Press LLC

RISK OF TARDIVE DYSKINESIA

30

0

6

1

2

3

4

5

20

10 

0

Pe

rcentage of patients

with ta

rdive dyskinesia

Years on medication

Figure 4.16

With prolonged expo-

sure to conventional antipsychotics
there is a cumulative risk of tardive
dyskinesia with time. Figure reprod-
uced with permission from Glazer
WM, Morgenstern H, Doucette JT.
Predicting the long-term risk of
tardive dyskinesia in out-patients
maintained on neuroleptic medica-
tions. 

J Clin Psychiatry

1993;54:133–9