Antipsychotic drugs

A classification of the antipsychotic drugs is given in Table 20.5; as with antide-pressant drugs, in recent years there have been several newer agents introduced into clinical practice. These essentially, with some exceptions, fall into the class of atypical antipsychotics. Table 20.6 gives a review of the receptor-binding profiles of a number of these agents.

The classical neuroleptic drugs, such as chlorpromazine and haloperidol, antagonize dopamine D2 receptors. Essentially their clinical efficiency has been shown to correlate with inhibitory activity at these receptor subtypes. However, these drugs block dopamine receptors in the striatum leading to catalepsy in animal models, and unwanted extrapyramidal side effects in clinical practice.

The new generation of antipsychotic drugs essentially fall into two categories; those that are clozapine related, which includes olanzapine and quetiapine, and others such as risperidone.

Table 20.6. Receptor binding profiles of antipsychotics

Affinity for receptor (K in nmol/l)

Table 20.6. Receptor binding profiles of antipsychotics

Affinity for receptor (K in nmol/l)

Drug

D1

D2

D4

a1

a2

H1

5HT2a

5hHT2c

M

Haloperidol

25

1

5

46

360

>1000

78

>1000

570

Clozapine

85

126

9

7

8

6

12

8

1.0

Risperidone

75

3

7

2

3

155

0.6

26

>1000

Olanzapine

31

112

27

19

228

7

4

11

2.1

Quetiapine

455

160

NA

7

87

11

220

615

56

Notes:

Receptors: D1, D2, D4, dopamine; al, a2, adrenergic; M, muscarinergic; 5HT2a, 5HT2c, Serotonine; H, histamine; NA, not available.

Source: Information from premarketing trials and product monographs.

Receptors: D1, D2, D4, dopamine; al, a2, adrenergic; M, muscarinergic; 5HT2a, 5HT2c, Serotonine; H, histamine; NA, not available.

Source: Information from premarketing trials and product monographs.

Although clozapine has been available for many years, it was initially removed from clinical practice (except in some selected countries) on account of its potential to produce agranulocytosis. However, it was reintroduced as a model of an atypical antipsychotic. The term relates to the low potential of these compounds to cause extrapyramidal problems, and they also have minimal effects on serum prolactin levels. The mechanism of atypicality seems to relate to different receptor profiles.

In general, the atypical antipsychotics occupy lower levels of D2 receptors than the classical antipsychotics (20-60% as opposed to 80-90%) (Kapur et al., 1999). One reason for their profile may be due to the rapid displacement of these agents from receptors by endogenous dopamine, on account of their being more loosely bound.

The newer antipsychotic agents also have a lower relative affinity for striatal D2 receptors as opposed to limbic D2 receptors (dorsal vs. ventral striatum). Further, of all the newer agents, clozapine is the one that seems not to bind to the core of the nucleus accumbens.

Since their introduction, antipsychotic drugs have been shown to be proconvul-sant. Early animal models, using the photosensitive baboon Papio papio, suggested that there may be differences between the phenothiazine-derived agents, such as chlorpromazine, and the butyrophenones, represented for example by haloperidol and pimozide. Pimozide in particular seemed to have less of an effect on the seizure threshold. In clinical practice it has recently been problematic to prescribe because of the need to carry out ECG investigations before prescription. It is one of a growing number of drugs associated with prolonging the Q-T interval, with the possibility of being associated with cardiac complications.

In general, the use of intramuscular preparations, such as fluphenazine deca-noate, was not associated with any change in the frequency of reporting of seizures in patients with epilepsy who also had psychosis.

As with the newer antidepressants, there is much less information about the effect of the atypical neuroleptics on the seizure threshold, with the single exception of clozapine. The latter was known to be proconvulsant from early studies, the seizures being a dose-related effect. The incidence of seizures rises to about 5% at doses of 600 mg, although EEG changes may be recorded at lower doses. The seizures are often myoclonic, but can be generalized tonic-clonic, or partial, depending on the individual patient.

It is perhaps no coincidence that the drug which appears to be the most effective antipsychotic, namely clozapine, is also associated with a high frequency of seizures. The relationship of convulsive seizures to the relief of psychopathology is an integral part of psychiatric therapy, through ECT. It is often forgotten that the latter was introduced for the treatment of dementia praecox, and has clinically and theoretically important antipsychotic effects.

There are some patients with epilepsy who are nonresponsive to neuroleptic drugs, and need clozapine. In particular there is a group of patients whose seizure frequency decreases or who become seizure-free, whose psychosis deteriorates in this setting. For them clozapine may be the drug of choice.

CASE REPORT

A 30-year-old patient, diagnosed as having leucine-sensitive hypoglycaemia at 10 months of age developed epilepsy at the age of four. This typically presented with clusters of several episodes daily, lasting 3 or 4 days, recurring at monthly intervals. During her seizure she would have a typical aura with a feeling of fear and butterflies in her stomach lasting about 30 seconds. This was followed by a scream, and a generalized seizure, which would last about a minute. Prior to these seizures she would often have a prodrome of 2-3 days with a build-up of verbal and physical aggression.

She had been treated with various medications, but at the age of 26 she was changed to sodium valproate, and her seizure frequency improved, indeed she became seizure-free. She had gradually developed a psychotic illness, but this dramatically deteriorated with resolution of the seizures and she was admitted twice to psychiatric hospitals under the Mental Health Act, aged 26 and 27.

An EEG had revealed left anterior temporal abnormalities, and an MRI showed prominent ventricles.

She had been prescribed several antipsychotic drugs, including the atypical antipsychotics risperidone and olanzapine. None of these were of any help in resolving her psychosis.

She was therefore started on clozapine, in gradually increasing doses. Her EEG was initially monitored.

On clozapine, her EEG revealed more frequent sharp waves over the left temporal region, and she began to develop auras again, although had no complex partial or generalized seizures. The auras were simple partial attacks, and were of little concern to her.

A dramatic improvement in her psychosis was noted, such that she is once again living independently in the community, with stable mood, infrequent auditory hallucinations, and with more insight into her paranoia. She remains on sodium valproate and clozapine (400 mg a day).

Figures for the incidence of seizures with the other atypical antipsychotics vary from a reporting of 0.1% of seizures in double-blind clinical trials of rispiridone, to 0.2-0.9% for olanzapine, and 9 out of 1710 cases for quetiapine. These latter figures come from the reporting of seizures in clinical trials, and do not necessarily reflect a direct cause-effect relationship between prescription of the drug and the seizure event.

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