Schizophrenia is a mental health condition that affects the way a person processes their thoughts and emotions. Antipsychotic therapy can help with symptoms such as hallucinations and delusions.

Antipsychotic therapy is a cornerstone of schizophrenia treatment, both during episodes of psychosis and as long-term preventive care.

Schizophrenia is a chronic condition that can cause positive, negative, and cognitive symptoms.

Positive symptoms, historically called psychotic symptoms, are defined as delusions, hallucinations, and disorganized speech or behavior. Positive symptoms mainly occur from too much dopamine in the brain.

Negative symptoms are defined as diminished emotional expression, social withdrawal, and lack of motivation, among others.

Cognitive symptoms are defined as dysfunctions in attention, concentration, memory, language, and executive function.

There are three types of antipsychotic therapy: first-generation antipsychotics, second-generation antipsychotics, and third-generation antipsychotics.

This article explores antipsychotic treatment for schizophrenia and how these treatments have developed over time.

Doctors prescribe antipsychotic medications to prevent the positive symptoms associated with schizophrenia. People can use them for short-term symptom management as well as for long-term maintenance to prevent or reduce the severity of future episodes of psychosis.

According to the results of 75 clinical trials published since 1950, the long-term use of antipsychotics is associated with a nearly threefold lower risk of psychosis relapse. People undergoing antipsychotic therapy experienced a beneficial effect on their ability to participate in activities and engage in relationships.

However, schizophrenia is a complex condition involving changes in multiple neurotransmitter systems, said Dr. Ann Shinn, MPH, director of clinical research in the Schizophrenia and Bipolar Disorder Research Program at McLean’s Hospital in Belmont, Massachusetts.

As such, different antipsychotics can target different neurotransmitter systems. Research suggests that antipsychotic medications work at least in part by disrupting dopamine signaling, which is elevated in certain parts of the brain in people with schizophrenia. Some treatments also affect serotonin systems.

Antipsychotics improve the positive symptoms of schizophrenia, which include hallucinations and delusions.

Some antipsychotic medications, particularly first-generation, can affect negative symptoms, such as difficulty communicating and the inability to express emotions and feel pleasure.

First-generation antipsychotics are older medications that block dopamine receptors in the brain to prevent signaling. Some examples of first-generation antipsychotics include:

  • chlorpromazine (Thorazine)
  • fluphenazine (Modecate)
  • haloperidol (Haldol)
  • thiothixene (Navane)
  • trifluoperazine (Stelazine)

These medications have little to no effect on other neurotransmitter systems in the brain. As such, they may make negative and cognitive symptoms worse since they only work to decrease dopamine.

“Second-generation antipsychotics have offered greater treatment options to individuals with a variety of psychiatric conditions, including schizophrenia,” said Dr. Thomas Sedlak, PhD, director of the Schizophrenia and Psychosis Consult Clinic at Johns Hopkins Medicine in Baltimore, Maryland.

In addition to disrupting dopamine signaling, second-generation medications also affect serotonin levels.

Targeting serotonin levels was an intentional design to lessen the worsening of negative symptoms seen with first-generation antipsychotics due to the decrease in dopamine. As a result, second-generation medications are now the primary treatment for schizophrenia.

Examples of second-generation antipsychotics include:

  • asenapine (Saphris, Secuado)
  • clozapine (Clozaril)
  • iloperidone (Fanapt, Zomaril)
  • lurasidone (Latuda)
  • olanzapine (Zyprexa)
  • paliperidone (Invega)
  • quetiapine (Seroquel)
  • risperidone (Risperdal)
  • ziprasidone (Geodon, Zeldox)

Third-generation antipsychotics are dopamine partial agonists rather than dopamine antagonists (decreasing dopamine). They still decrease dopamine like first- and second-generation medications but allow for some dopamine to remain.

This, paired with the continued serotonin targets, is an intentional design to further lessen the worsening of negative and cognitive symptoms. In fact, it may partially improve these symptoms.

Examples of third-generation antipsychotics include:

Targeting the glutamate pathway

Antipsychotics are safe and effective at treating the positive symptoms of schizophrenia. They are less effective at addressing negative and cognitive symptoms, such as difficulty concentrating, thinking, and socializing. These symptoms can make it harder to hold a job, maintain a relationship, and live independently.

One theory asserts that the negative and cognitive symptoms of schizophrenia arise when the neurotransmitter glutamate becomes overactive. According to this theory, glutamate imbalances also stimulate dopamine receptors to cause positive symptoms.

Researchers have been exploring how to target the glutamate pathway to treat negative symptoms. Some drugs, such as lumateperone, target or otherwise affect this pathway.

These treatments are safe and effective at improving overall schizophrenia symptoms. However, so far, research has not shown these treatments to be more effective at addressing negative schizophrenia symptoms.


Second-generation antipsychotics are as effective as the first generation for the treatment of positive symptoms. Some claim they are more effective than the first generation in treating negative symptoms.

The second-generation drug clozapine is also particularly effective in treatment-resistant cases. It is unclear what about clozapine’s action mechanism makes it much more effective, but it is the gold standard for individuals who have treatment-resistant schizophrenia.

People take most antipsychotics orally as a pill. However, for some people with schizophrenia, it may be difficult to take medication daily.

For people who have trouble remembering to take their medications, long-acting injectables are often an effective alternative to oral medication.

Long-acting injectable versions are now available for both first- and second-generation antipsychotics, including:

  • aripiprazole or aripiprazole lauroxil (Abilify, Aristada)
  • fluphenazine decanoate (Prolixin, Permitil)
  • haloperidol decanoate (Haldol)
  • olanzapine pamoate (Zyprexa, Relprevv)
  • paliperidone palmitate (Invega)
  • risperidone (Risperdal, Perseris)

Most long-acting injectables require an injection once per month. Some require less frequent dosing.

One of the major benefits of second-generation antipsychotics is that they are associated with a lower risk of neurological side effects than first-generation antipsychotics.

People taking first-generation antipsychotic medications, especially at high doses, sometimes experience abnormal muscle movements. These may include:

  • tremors
  • rigidity
  • shuffling gait
  • reduced facial expressions

“Recall that the loss of dopamine neurons causes Parkinson’s disease,” said Shinn. “First-generation antipsychotics can essentially produce a similar effect, not by causing loss of dopamine neurons, but with a molecular block of dopamine activity.”

Experts told MNT that second-generation antipsychotics generally cause fewer neurological symptoms than first-generation medications. However, this does not mean that they are not without side effects.

Second- and third-generation antipsychotics are more likely to cause metabolic side effects, such as:

  • weight gain
  • high cholesterol
  • high blood pressure
  • high blood sugar

It is also important for people to practice healthy behaviors, including:

  • staying active
  • eating a well-balanced diet
  • avoiding alcohol and recreational drugs
  • quitting or reducing tobacco use, if applicable

A person’s choice of antipsychotic should be based on a discussion with a doctor about their goals, disease history, and concerns. Choosing the right medication is a balance of managing symptoms without experiencing problematic side effects.

“Unfortunately, where psychiatry is today, prescribing is very much about trial and error,” said Shinn. “The person tries a prescription and they and the doctor together see how well it is working, as well as whether it is causing any side effects that are not tolerable.”

“It is best to be frank and upfront with [a] doctor about your feelings on a medication,” added Sedlak. “If someone is having side effects and does not want to continue a medication, it is important to let the doctor know immediately, rather than stopping it abruptly and risking symptom relapse.”

A psychiatrist may also prescribe an antidepressant alongside antipsychotic therapy. This may help with the negative symptoms of schizophrenia, such as social withdrawal or a lack of motivation.

A doctor may also recommend psychotherapy with a trained mental health practitioner. Techniques such as cognitive behavioral therapy can be helpful in addressing the negative and cognitive symptoms of schizophrenia.

First-, second-, and third-generation antipsychotic medications can effectively reduce psychosis symptoms associated with schizophrenia and improve overall quality of life.

Second- and third-generation antipsychotics are associated with a lower risk of neurological symptoms, such as tremors, than first-generation drugs. They can also affect blood pressure, blood sugar, and cholesterol. Doctors should carefully monitor these measures of metabolic health.

Choosing the right treatment option involves a collaborative discussion between a person and a doctor.

Long-acting injectable options are available for people who have trouble taking their oral medications daily.