Drug Therapy for Schizophrenia

Drug therapy (pharmacotherapy) is the most common treatment for schizophrenia and typically forms the first line of intervention. There are two main classes of antipsychotic medication: typical (first-generation) antipsychotics and atypical (second-generation) antipsychotics. This lesson examines their mechanisms, effectiveness, and the ethical and practical issues surrounding their use.

Key Definition: Antipsychotic drugs are medications used to manage psychotic symptoms such as hallucinations and delusions. They work primarily by altering neurotransmitter activity in the brain, particularly dopamine.

---

Typical Antipsychotics

Typical antipsychotics were the first class of antipsychotic drugs developed and have been in use since the 1950s. The most well-known is chlorpromazine (brand name: Largactil/Thorazine).

Mechanism of Action

Typical antipsychotics are dopamine D2 receptor antagonists — they bind to D2 receptors in the brain and block them, preventing dopamine from exerting its effects. By reducing dopamine activity in the mesolimbic pathway, they alleviate positive symptoms such as hallucinations and delusions.

The process can be summarised as follows:

1. Dopamine is released into the synapse from the pre-synaptic neuron
2. Chlorpromazine binds to post-synaptic D2 receptors, occupying the receptor site
3. Dopamine cannot bind to the receptor and therefore cannot generate a post-synaptic response
4. The result is reduced dopaminergic transmission in the mesolimbic pathway
5. Positive symptoms are reduced as a consequence

Typical antipsychotics also have sedative effects due to their action on histamine receptors, which can help manage agitation and aggressive behaviour in acute episodes.

Side Effects of Typical Antipsychotics

Typical antipsychotics are associated with a range of significant side effects:

Side Effect	Description
Extrapyramidal symptoms (EPS)	Movement disorders including tremors, rigidity, and involuntary muscle contractions — caused by D2 blockade in the nigrostriatal pathway (which controls voluntary movement)
Tardive dyskinesia	Involuntary, repetitive movements of the face, tongue, and jaw — develops in approximately 20–30% of patients after prolonged use and may be irreversible
Sedation	Drowsiness and lethargy due to antihistamine effects
Weight gain	Common with many antipsychotics
Neuroleptic malignant syndrome (NMS)	A rare but potentially fatal reaction involving fever, muscle rigidity, and altered consciousness
Raised prolactin levels	Due to D2 blockade in the tuberoinfundibular pathway, leading to breast enlargement, menstrual irregularities, and sexual dysfunction

Key Definition: Tardive dyskinesia is a potentially irreversible movement disorder caused by long-term use of typical antipsychotics, characterised by involuntary movements of the face, tongue, and limbs. It results from chronic D2 receptor blockade in the nigrostriatal pathway.

Exam Tip: When evaluating typical antipsychotics, always mention tardive dyskinesia. It is one of the most important reasons why atypical antipsychotics were developed — the need for equally effective drugs with fewer motor side effects.

---

Atypical Antipsychotics

Atypical antipsychotics were developed from the 1990s onwards to address the limitations of typical antipsychotics, particularly the high incidence of extrapyramidal symptoms and tardive dyskinesia. The two most commonly discussed at A-Level are clozapine and risperidone.

Clozapine

Clozapine is widely regarded as the most effective antipsychotic drug, particularly for treatment-resistant schizophrenia — patients who have not responded to at least two other antipsychotics.

Mechanism of action:

• Clozapine is a serotonin-dopamine antagonist — it blocks both D2 dopamine receptors and 5-HT2A serotonin receptors
• It has a lower affinity for D2 receptors than typical antipsychotics and binds more loosely, which is thought to explain the reduced risk of extrapyramidal symptoms
• By blocking serotonin receptors in the mesocortical pathway, clozapine may increase dopamine release in the prefrontal cortex, helping to alleviate negative symptoms and cognitive deficits
• It also acts on noradrenergic, histaminergic, and cholinergic receptors

Effectiveness:

• Kane et al. (1988) conducted a landmark study comparing clozapine with chlorpromazine in 268 treatment-resistant patients. After six weeks, 30% of clozapine patients showed significant improvement compared with only 4% of chlorpromazine patients
• Meltzer (2012) reviewed evidence showing that clozapine reduces suicidality in schizophrenia patients — it is the only antipsychotic with an evidence base specifically for anti-suicidal effects
• Clozapine has been shown to improve quality of life, social functioning, and cognitive performance

Risks:

• The most serious side effect is agranulocytosis — a dangerous drop in white blood cell count that can be fatal. This occurs in approximately 1–2% of patients
• Because of this risk, patients taking clozapine must undergo regular blood monitoring (weekly for the first 18 weeks, then fortnightly, then monthly)
• Other side effects include weight gain, metabolic syndrome, diabetes, sedation, and hypersalivation

Risperidone