Antipsychotic Pharmacology: Clozapine Mechanism and Side Effects

Antipsychotic Development and Clozapine History

In the search for new antipsychotics, several points have been targeted: atypical antipsychotics should be more efficacious on positive, negative, depressive, and cognitive symptoms, not inducing EPS or hyperprolactinemia, increase psychomotor and cognitive performance, and compliance of the patient.

Clozapine has been very important in the development of new antipsychotic agents; it was discovered in 1958 by Sandoz Wander, who started to synthesize compounds similar to imipramine, an antidepressant. It was patented in 1960, but around 1975 the first cases of a very dangerous side effect, agranulocytosis, were first described. This was the reason why it was withdrawn from the market at that point. In 1989, it was demonstrated that the risk of agranulocytosis was very low, and patients just required leukocyte monitoring. Moreover, efficacy of clozapine was demonstrated to be very high.

Since the advantages outnumbered the risks, it was reintroduced in the market at first for hospitalized selected patients, and then psychiatrists were allowed to administer it.

Clozapine Receptor Blockade

Clozapine It blocks 9 receptors:

• Dopamine receptors
  • D1
  • D2: it is antagonized in basal ganglia not more than 40-60% (lower affinity)- this is another difference between clozapine and neuroleptics
  • D3
• Serotonergic receptors
  • 5HT2A: almost all blocked in the cerebral cortex
  • 5HT2C
  • 5HT3
• Muscarinic receptor
  • M1
• Histaminergic receptor
  • H1
• Adrenergic receptor
  • a1

Clozapine Pharmacological Properties

Clozapine is efficacious on positive and negative symptoms. It is also efficacious on 30-40% of patients who are resistant to typical neuroleptics. It has a low risk of EPS, the risk of agranulocytosis is 0.5-1%, and it does not induce hyperprolactinemia.

Leukocyte Monitoring for Clozapine

Leukocytes monitoring every week for 18 weeks from the beginning of the treatment, and then every month is required. If leukopenia is present (leukocytes are less than 3000/mmc) the treatment must be stopped, and leukocytes must be daily monitored until the number is higher than 3000/mmc.

Clozapine Side Effects

Among other side effects, there is a very high incidence of side effects due to the block of the H1 receptor, so sedation and body weight increase (34% approximately). Even if it is an antagonist of M1, instead of dry mouth, sialorrhea is present in 23% of patients. Blocking of a1 receptor causes hypotension in 11% of the patients. There can also be tachycardia due to the block of the M1 receptor. Fever can be present, together with convulsions (5%), ECG alterations (4%), leukopenia (1%), and agranulocytosis (0.6%).

The most important side effects besides agranulocytosis are the significant body weight increase, significant hypotension, cardiac dysrhythmia, and convulsions. These side effects are important for pharmacological interactions; it cannot be administered with anticholinergics, antihistamine drugs, antihypertensive drugs, since all of them potentiate its effect. Because of the risk of agranulocytosis, it cannot be administered together with myelosuppressors.

Since it also inhibits H1 receptors causing sedation and CNS depression, it cannot be administered with CNS depressors, in particular with long half-life benzodiazepines (it can cause hypotension, sedation, delirium, and respiratory block). When given together with lithium salts, it can induce malignant neuroleptic syndrome.

Clozapine Pharmacokinetics

Regarding pharmacokinetics, it is a well absorbed drug after oral administration, with a variable bioavailability. The halflife is 5-15 h.

Dopaminergic Pathways and Clozapine Action

Regarding the effects, remember that there are 4 main dopaminergic pathways:

• tubero-infundibular: inhibition of prolactin release
• nigrostriatal: control automatic and involuntary movements
• mesolimbic: its increase in activity causes positive symptom of schizophrenia
• mesocortical: its hypoactivity induces negative symptoms of schizophrenia.

Clozapine blocks dopamine receptors only by 40-60%. In the striatum there is a high concentration of dopamine released by dopaminergic neurons. This means that in the striatum endogenous dopamine is able to displace clozapine from its receptor, since the latter has a low affinity for dopamine receptors. Clozapine, thus, does not_induce EPS and tardive dyskinesia, because of the lack of blockage of the dopaminergic system in the nigrostriatal pathway.

On the contrary, in the limbic system there is a lower concentration of endogenous dopamine, therefore clozapine is not displaced from the D2 receptor, and it blocks mesolimbic dopaminergic neurons; through this mechanism, clozapine controls the positive symptoms of schizophrenia.

Clozapine has also a high affinity for muscarinic receptors. Antimuscarinics are used for the treatment of Parkinson's disease, and in this case the strong cholinergic block in the striatum overcomes the effects of the dopaminergic blockade (decrease in EPS side effects).

Serotonin-Dopamine Antagonists (SDA)

fig.5 5HT2/DA2 ANTAGONISTS (SDA) 5HT2A QUETIAPINE OLANZAPINE RISPERIDONE ZIPRASIDONE SDA DA2 The mechanism by which clozapine improves negative symptoms is described in [fig.5]. In the mesocortical system, there are dopaminergic neurons (grey) that are under the control of serotonin; there is indeed a negative 8 control of dopaminergic neurons induced by serotonin. When serotonin binds a presynaptic EFFECTS OF SDA IN BASAL GANGLIAA heteroreceptor for serotonin (5HT2A), dopamine release is inhibited. Clozapine has a very high affinity for the 5HT2A receptor and a very low affinity for D2; it blocks the 5HT2A receptor and in this way it blocks the inhibition by serotonin causing an increased release of dopamine in the mesocortical system. On the other hand, the postsynaptic blockade is very weak, so the endogenous dopamine released by the mesocortical system displaces the postsynaptic binding of clozapine to D2 receptors. The final effect is that by this mechanism, clozapine is able to increase the activity of the mesocortical system. It was said before that a hypoactivity of the mesocortical system causes the negative symptoms of psychosis, so by increasing the activity of mesocortical dopaminergic neurons, clozapine has an effect on these latter.

The hypothesis regarding the improvement of negative symptoms is based on the 5HT2A receptor antagonism. 5HT reduces the release of dopamine in the brain nuclei which produce EPS and affective flattening (mesocortical system). If 5HT2 receptors are blocked, dopamine release increases.

This mechanism of action was the basis of the development of new atypical antipsychotics.

Receptor Binding Comparison

Typical neuroleptic Clozapine Risperidone D2 receptors fig.6 5-HT2 receptors In [fig.6], a PET scan showing the binding of typical neuroleptics, clozapine, and risperidone (one of the drugs belonging to the SDA class of new antipsychotics) to D2 and 5HT2 receptors can be appreciated. Typical neuroleptics bind - with high affinity - dopamine receptors in the basal ganglia, possibly causing extrapyramidal symptoms and not improving negative symptoms.

Clozapine has low affinity for dopamine receptors in the basal ganglia, thus not causing EPS. As said, it binds 5HT2 receptors in the cerebral cortex, causing activation of the mesocortical dopaminergic system. Risperidone, the first drug discovered in the class of SDA (serotonin- dopamine antagonist) antipsychotics, mimics the mechanism of clozapine by binding and inhibiting both D2 receptors in the basal ganglia and 5HT2 receptors in the cerebral cortex.

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin-dopamine antagonists (SDAs) are quetiapine, olanzapine, risperidone, ziprasidone.

Risperidone

It is the first SDA synthesized and it is an antagonist of 5HT2 and D2 receptors; it blocks 60% of 5HT2 and 50% of D2, as well as a1 and H1 receptors. It is more effective towards negative symptoms compared to neuroleptics; compared to them, it is less likely to cause EPS.

Risperidone has an antiemetic effect, it can cause hyperprolactinemia, hypotension (due to the block of a1 receptors) and sedation (due to the block of H1 receptors). It is metabolized by cytochrome P450 (2D6 form) in 9-OH-risperidone, which is an active metabolite, able to prolong its action. Half-life is short (3h).

Olanzapine

It is effective towards positive symptoms during acute presentation, though it may also be employed in maintenance therapy. It has increased efficacy towards negative symptoms, depressive episodes and cognitive impairment compared to typical antipsychotics.

It blocks 5HT2A, M1, D2, H1, and a2 receptors.

Side effects are mainly due to blockade of H1 (sedation and body weight increase) and M1 (dry mouth and constipation). However, olanzapine is a very well-tolerated drug, with a low risk of overdose.

Compared to neuroleptics and clozapine, olanzapine has a lower risk of EPS, hyperprolactinemia, agranulocytosis, convulsions and cardiovascular side effects.

It improves the quality of life of the schizophrenic patients and their adherence to treatment, prevents psychotic exacerbations and guarantees more active participation in the implementation of rehabilitation and reintegration projects.

Concerning pharmacokinetics, it has a long half-life, so it is administered once a day, from the first day at the desired dose. It passes into breast milk, but at low percentages with low risk of side effects for the baby. Depot preparations are available and they are administered every 2- 4 weeks.

Quetiapine

Good efficacy on positive symptoms, acutely and during maintenance.

It is used both in the treatment of schizophrenia and acute bipolar disorder, particularly in adolescents.

There is a risk of abuse concerning quetiapine, since it has a sedative and anxiolytic effect. The active metabolite is 7-OH-quetiapine. Depot formulations are available.

Ziprasidone

It blocks D2 and 5HT2 receptors; it also has a partial agonist effect on 5HT1A receptors, and causes the inhibition of serotonin effect, with anxiolytic and antidepressant effects.

It is effective in the treatment of positive symptoms, and generally it does not induce EPS. The main advantage compared to all the other neuroleptics and atypical neuroleptics is that it induces negligible weight gain.

Because of its anxiolytic and antidepressant effect, it has therapeutic indication to treat schizoaffective disorder. The main side effect is QT prolongation.

Substituted Benzamides (Amisulpride)