What did chlorpromazine do? Understanding the First Antipsychotic

October 5, 2025 •

4 min read

Developed in the early 1950s, chlorpromazine was the first effective antipsychotic medication, with its introduction hailed as one of the great advances in the history of psychiatry. It fundamentally changed mental healthcare by offering a pharmacological treatment for severe psychotic symptoms, directly addressing the question: what did chlorpromazine do for patients previously facing long-term institutionalization?.

Quick Summary

Chlorpromazine is the first antipsychotic medication, acting primarily as a dopamine antagonist to treat psychotic disorders like schizophrenia and bipolar disorder. It produces calming effects but is associated with significant side effects, leading to the development of newer alternatives. Beyond mental health, it treats nausea, vomiting, and intractable hiccups.

Key Points

Pioneered a New Era: Chlorpromazine was the first antipsychotic drug, marking a paradigm shift in psychiatry from institutional confinement to pharmacological treatment of mental illness.
Influenced Deinstitutionalization: By effectively managing severe psychotic symptoms like delusions and hallucinations, it allowed many long-term institutionalized patients to leave asylums.
Blocked Dopamine Receptors: Its core mechanism involves blocking dopamine D2 receptors in the brain, which is the basis for its antipsychotic action and helped establish the dopamine hypothesis of schizophrenia.
Used for Diverse Conditions: Beyond mental health, chlorpromazine is used to treat nausea, vomiting, persistent hiccups, and to sedate patients before surgery.
Caused Significant Side Effects: The drug has numerous adverse effects, including sedation, anticholinergic effects, and notably, extrapyramidal symptoms like tardive dyskinesia, which led to the development of newer drugs.
Remains a Benchmark Drug: Despite being largely replaced by newer, better-tolerated agents, chlorpromazine's historical importance and efficacy mean it is still used as a reference drug in comparative studies.

A Revolution in Psychiatric Care

Before the 1950s, treatments for severe mental illnesses often involved invasive procedures or minimal symptom management through sedatives. The discovery of chlorpromazine marked a pivotal moment, shifting psychiatric practice from primarily custodial care to pharmacological intervention. For patients with severe psychosis characterized by hallucinations, delusions, and agitation, chlorpromazine provided a degree of relief previously unattainable. Its effectiveness allowed many patients to be discharged from institutions and reintegrate into society, fueling the deinstitutionalization movement. The drug, often marketed under the brand name Thorazine, became the benchmark against which all subsequent antipsychotics would be measured.

The Pharmacological Mechanism of Action

Chlorpromazine is classified as a first-generation, or 'typical,' antipsychotic. Its therapeutic effects are attributed to its activity as an antagonist at several neurotransmitter receptors. The most crucial action for its antipsychotic properties is the blockade of dopamine D2 receptors. By blocking these receptors in specific brain pathways, chlorpromazine helps to reduce the overactivity of dopamine believed to cause the 'positive' symptoms of psychosis, such as hallucinations and delusions. However, chlorpromazine's effects are not limited to dopamine. It also acts on other receptors, which explains its wide range of effects and side effects:

Histamine H1 receptor blockade: Leads to significant sedation and drowsiness.
Muscarinic M1 receptor blockade: Causes anticholinergic side effects like dry mouth, blurred vision, constipation, and urine retention.
Alpha-1 adrenergic receptor blockade: Can cause orthostatic hypotension, which is a drop in blood pressure when standing up.

The Dopamine Hypothesis

Chlorpromazine's mechanism was instrumental in forming the original dopamine hypothesis of schizophrenia. The theory, developed in the 1960s, proposed that psychosis, particularly the positive symptoms, is caused by hyperdopaminergic activity in the brain. The fact that chlorpromazine effectively treated these symptoms by blocking dopamine receptors strongly supported this idea. Furthermore, researchers noticed that side effects of chlorpromazine resembled Parkinson's disease, which is known to involve dopamine deficiency, further solidifying the connection. While the dopamine hypothesis has since evolved to be more nuanced, chlorpromazine's action was the foundational evidence.

Diverse Clinical Applications

While chlorpromazine is best known for its role in psychiatry, its broad pharmacological profile means it has several other approved indications.

Controlling nausea and vomiting: It blocks dopamine receptors in the chemoreceptor trigger zone of the brain, effectively suppressing nausea and vomiting, including during surgical procedures or in terminal illness.
Relieving persistent hiccups: For intractable hiccups (singultus) that have not responded to other treatments, chlorpromazine can be an effective remedy.
Pre-operative sedation: Its powerful sedative effects can be used to manage anxiety and produce relaxation before surgery.
Managing behavioral problems: It has been used to treat severe behavioral problems, such as agitation or hyperexcitability, in both adults and children.
Adjunctive therapy: It can be used as an adjunct to treat tetanus and acute intermittent porphyria.

Significant Adverse Effects

Chlorpromazine's effectiveness came with a trade-off of notable side effects, many resulting from its broad-spectrum receptor antagonism. While some, like sedation, were tolerable or even desired in agitated patients, others proved to be severe and debilitating.

Common Adverse Effects:

Drowsiness
Dry mouth
Blurred vision
Constipation
Weight gain
Dizziness, especially when standing (orthostatic hypotension)

Serious Adverse Effects:

Extrapyramidal Symptoms (EPS): This group of movement-related side effects, caused by D2 receptor blockade, includes pseudoparkinsonism (tremors, shuffling gait), dystonia (muscle spasms), and akathisia (restlessness).
Tardive Dyskinesia (TD): A potentially irreversible movement disorder characterized by involuntary, repetitive body movements, such as grimacing and tongue movements, that can occur with long-term use.
Neuroleptic Malignant Syndrome (NMS): A rare but life-threatening reaction that causes fever, muscle rigidity, and altered mental status.

Chlorpromazine vs. Newer Antipsychotics

The high incidence of extrapyramidal symptoms and tardive dyskinesia associated with typical antipsychotics like chlorpromazine prompted the development of newer, 'atypical' antipsychotics. These newer agents typically have a different receptor profile, with a lower affinity for D2 receptors compared to serotonin receptors, leading to a reduced risk of movement-related side effects.


Feature	Chlorpromazine (Typical/First-Gen)	Newer Antipsychotics (Atypical/Second-Gen)
Antipsychotic Class	First-Generation (Typical)	Second-Generation (Atypical)
Primary Mechanism	High D2 dopamine receptor antagonism	Lower D2 affinity, higher serotonin 5-HT2A affinity
Risk of EPS/TD	High, especially at higher doses	Lower risk compared to chlorpromazine
Side Effect Profile	More anticholinergic effects, sedation, orthostatic hypotension	Metabolic side effects (weight gain, high blood sugar) are common
Dosage Frequency	May be required multiple times daily	Often taken once or twice daily

The Lasting Legacy of Chlorpromazine

Although newer antipsychotics are often preferred today due to their improved side effect profiles, chlorpromazine's legacy in medicine is profound and enduring. It is still recognized as a valuable and cost-effective medication, particularly in settings with limited resources. Its discovery not only transformed the practical treatment of severe mental illness but also laid the groundwork for modern psychopharmacology, paving the way for a deeper understanding of the chemical basis of mental disorders. The clinical observations and side effects from its use directly spurred research into brain chemistry, forever altering the course of psychiatric research and treatment. The story of chlorpromazine is a compelling reminder of the scientific breakthroughs that have shaped the field of medicine.

Further Reading: For more on the history of this drug and its clinical development, see "Fifty years chlorpromazine: a historical perspective" in PMC.

Frequently Asked Questions

Chlorpromazine's introduction in the 1950s revolutionized mental healthcare by providing the first effective drug treatment for psychosis. It enabled the shift from lengthy institutionalization and invasive therapies like lobotomies to pharmacological management, contributing to the deinstitutionalization movement.

Yes, chlorpromazine is still available and used for a number of conditions, although it is less common than newer antipsychotic medications due to its significant side effects. It remains a benchmark drug and is valued for its low cost and effectiveness.

The main mechanism for chlorpromazine's antipsychotic effects is the blockade of dopamine D2 receptors in the brain. This action helps to normalize the overactive dopamine signaling associated with the positive symptoms of psychosis, such as hallucinations and delusions.

Common side effects include drowsiness, sedation, dry mouth, blurred vision, constipation, weight gain, and orthostatic hypotension. Its low-potency nature means non-neurologic side effects are prevalent.

Tardive dyskinesia is a potentially permanent movement disorder characterized by involuntary, repetitive movements of the face, mouth, and extremities, which can be caused by long-term use of chlorpromazine and other typical antipsychotics.

While the generic form of chlorpromazine is still available, the brand name Thorazine was discontinued in the United States. The exact reason is not publicly clear, but it is likely related to the availability and preference for lower-cost generic versions and newer antipsychotics with different side effect profiles.

Chlorpromazine is a first-generation ('typical') antipsychotic with a higher risk of extrapyramidal side effects compared to most newer, second-generation ('atypical') antipsychotics. Atypical antipsychotics often have a better side-effect profile but may carry different risks, like metabolic changes.