cp11_contents

Clear Perspectives - Volume 1 Issue 1

EPS and the new antipsychotic drugs

by Professor Jes Gerlach

In general, extrapyramidal symptoms (EPS) may be categorized according to the following criteria:

Acute, tardive, or mixed
Side-effects of treatment, or independent of antipsychotic drugs
Single syndromes, such as akathisia, or a mixture of syndromes
Reversible or irreversible
Recognized or not recognized by the patient.

Key factors that help to minimize the occurrence of EPS include:

More knowledge of EPS among doctors and medical staff
More awareness of the discrete signs of EPS (strange finger positions and other mild dystonic features)
The introduction of specific EPS examination procedures, and
More knowledge of alternative treatments.

The crucial tests that can aid the identification of EPS are listed in Table 11. Many psychiatrists do not carry out these simple, but extremely valuable observations. Rating scales such as the St Hans rating scale for extrapyramidal syndromes may encourage a systematic approach and prevent parkinsonism being overlooked.

Sit in front of the patient, focus on facial expression, oral and leg dyskinesia, akathisia and
dyskinesia in legs.

Perform activation tasks – focus on bradykinesia and oral dyskinesia.

While the patient is standing and distracted, watch for akathisia (shifting weight
foot-to-foot), dyskinesia, dystonia or finger tremor.

While walking – look for arm swing and gait, finger tremor and finger dystonia/dyskinesia.

Table 11. Simple EPS observation principles.

The prevention of EPS
A number of principles emerge for preventing the occurrence of EPS:

Closely observe particularly vulnerable patients such as the elderly, and patients with a previous history of EPS.
Restrict the use of D₂-blocking antipsychotics. The use of antipsychotics in negative symptoms may well increase with the advent of new antipsychotics which avoid EPS.
Minimize D₂-receptor blockade by using the lowest effective dose, antipsychotics with low D₂ blockade (such as clozapine or other new agents), and potential non-dopamine antipsychotics.
Anticholinergics have only symptomatic effect: they reduce akathisia, dystonia/acute dyskinesia, parkinsonism, but aggravate tardive dyskinesia and tardive akathisia.

The new antipsychotics are as different from each other as they are from standard agents. They include the D₂ antagonists, sulpiride and amisulpride; the D₂-5HT₂-a₁ antagonists, risperidone, ziprasidone, and sertindole; and the multireceptor antagonists clozapine, quetiapine and olanzapine (Table 12).

New antipsychotics

Receptor binding

Side-effects

D₁

D₂

5HT₂

a₁

Chol

Hist

Seda

Auto

EPS

D2 antagonists
Sulpiride
Amisulpride

D2-5HT2-a1 antagonists
Risperidone
Ziprasidone
Sertindole

Multireceptor antagonists
Clozapine
Olanzapine
Quetiapine

–
–

–
+
–

++
++
(+)

+++
+++

+++
+++
+++

+++
++
+

–
–

+++
+++
+++

+++
++
+

–
–

+++
++
++

+++
++
+++

–
–

–
–
–

+++
+++
–

–
–

–
–
–

++
++
++

+
+

++
++
+

+++
+
++

+
+

++
++
++

+++
+ (+)
++

++
++

    ++
    ++
    +

    (+)
     +
    (+)

Table 12. Receptor binding and side-effect profiles of new antipsychotics. Abbreviations: Chol, cholinergic; Hist, histamine; Seda, sedative; Auto, autonomic. Symbols: the plus signs represent semi-quantitative estimations of the degree of receptor binding and side-effects, based on available literature.

Risperidone and ziprasidone show a classical D₂-receptor blockade, and in high doses they will cause traditional EPS and also some autonomic side-effects due to a₁ blockade. Sertindole, clozapine, olanzapine, and quetiapine are all interesting drugs because they produce a relatively low D₂ receptor blockade, in contrast to all other antipsychotics. In vitro studies show that sertindole provides strong D₂ blockade, but studies in vivo show only mild D₂ antagonism. Clozapine is a multireceptor antagonist. Olanzapine closely resembles clozapine, but does not block as many receptors. Quetiapine is interesting because of its atypical receptor profile.

Studies have confirmed that clozapine produces much less EPS than the classical drugs, such as haloperidol. Tardive dyskinesia may disappear when patients are prescribed clozapine.
Aside from EPS, other side-effects must also be considered. Depression and emotional indifference are clearly lower on clozapine compared with haloperidol. Sexual problems, caused by effects on prolactin levels, are also less pronounced with clozapine.

In conclusion
EPS are disabling and distressing, and in some patients are painful and irreversible. EPS are often not recognized by the physician or patient and may become accepted as ‘unavoidable’. People working in psychiatry should be taught more about EPS and be trained in simple EPS examination techniques.

Prevention and treatment strategies should focus on reducing D₂-receptor blockade. Clozapine produces less EPS but has other side-effects. The new antipsychotic drugs under development should offer this facility. Drugs under development such as quetiapine, olanzapine and sertindole offer low D₂-receptor antagonism, which promises a good EPS profile.

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