Medical Pharmacology Topics   

Antipsychotics

Schizophrenia is the most common psychotic illness, affecting 1% of the population, mostly young adults. The characteristic symptoms may be "positive" or "negative". Positive symptoms include dilussions, hallucinations, paranoia and illogical speech. Negative symptoms include withdrawal and lack of motivation.

There are two theories for the cause of schizophrenia. According to the dopamine hypothesis, there is excessive dopamine activity in the mesolimbic system (leading to positive symtoms) and decreased dopamin activity in the mesocortical system (negative symptoms). According to another theory, schizophrenia is due to developmental abnormalities of the CNS.

Antipsychotics, also known as neuroleptics, were first used in the early 1930's. They ae classified as either "typical" or "atypical".

Typical Antipsychotics

All the typical antipsychotics are antagonists at D2 receptors, and to variying extents at D1, D3 and D4 receptors. They block D2 in all major dopamine pathways: mesolimbic, nigrostrial and tuberoinfandibular. Their block of D2 receptors in the mesolimbic pathway leads to the antipsychotic effects, while adverse effects come from their block of D2 at the nigrostrial (extrapyramidal, movement) and tuberoinfandibular (prolactenia) pathways.

The antipsychotic effects of D2 blockade in the mesolimbic pathway ameliorate only the positive symptoms of psychosis (as well as relapse prevention). They are not effective in improving the negative or cognitive symptoms, thought to be due to a lack of dopamine in the mesocortical pathway.

The typical antipsychotics are classified as phenothiazines (chlorpromazine, thioridazine, fluphenazine), butyrophenones (haloperidol), thioxanthenes (thiothixene) and heterocyclics (molindone, loxapine).

Antipsychotic drugs have many other effects. All exept molindone decrease seizure threshold. All except thioridazine are antiemetics (inhibit the chemoreceptor trigger zone). Most have sedative effects: haloperidol/fluphenazine < thiothixene < chlorpromazine/thioridazine. Some have anticholinergic effects: haloperidol/fluphenazine < thiothixene < chlorpromazine/thioridazine. Haloperidol and chlorpromazine are a-adrenergic blockers.

Extrapyramidal symptoms of antipsychotics due to their blockade of D2 in the nigrostrial pathway include acute dystonias, parkinsonism, akathesia and tardive diskinesia/dystonia. Other adverse effects include neuroleptic malignant syndrome, weigth gain, photosensitivity, jaundice and blood dyacrasias (rare).

Atypical Antipsychotics

The atypical antipsychotics include clozapine, olanzapine, quetiapine, risperidone, ziprasidone and aripiprazole.

Clozapine is a significant D1 and D4 antagonist, and to a lesser extent a D2 antagonist. It is also a potent antagonist at some seratonin receptors. Clozapine improves both positive and negtive symptoms, while having a lower risk of tardive dyskinesia and minimal acute extrapyramidal symptoms. Adverse effects include bone marrow suppression (1-2% in the first month), weight gain, sedation, decreased seizure threshold and anticholinergic effects. Olazapine is similar to clozapine but does not induce bone marrow suppression, thus is becoming the leading antipsychotic.

Risperidone has a higher D2 blockade and extrapyramidal effects than other atypical agents. Quetiapine has potent dopamine and seratonin receptor blockade properties. Ziprasidone has modest selective seratonin reuptake inhibtitionr (SSRI) ativity in addition to its antipsychotic properties. Aripiprazole has partial agonist properties at D2 and 5-HT1A receptors, and is an antagonist at 5-HT2A receptors.

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