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 psychosis episodes and as long-term preventive care.

There are two types of antipsychotic therapy: first-generation antipsychotics and second-generation antipsychotics.

MNT spoke with experts in the field to understand the differences and similarities between antipsychotic therapies. Here is what people with schizophrenia should know about their treatment options.

Doctors prescribe antipsychotic medications to prevent the psychotic symptoms associated with schizophrenia. People can use them for immediate relief 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 psychotic relapse. People undergoing antipsychotic therapy experienced a positive effect on their ability to participate in activities and engage in relationships.

How these medications work is not exactly straightforward.

“Schizophrenia is a complex […] condition involving [changes] in multiple neurotransmitter systems,” explained Dr. Ann Shinn, MPH, a psychiatrist in McLean Hospital’s Schizophrenia and Bipolar Disorder Program in Belmont, MA.

Experts believe 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.

Both first-generation and second-generation antipsychotics improve the “positive” symptoms of schizophrenia, which include hallucinations and delusions. They do not seem to have a major effect on “negative” and cognitive 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)
  • trifluoperazine (Stelazine)
  • thiothixene (Navane)

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

Drs. Sedlak and Shinn explained that in addition to disrupting dopamine signaling, second-generation medications also affect serotonin levels. They can help treat schizophrenia in people whose bodies do not respond to or cannot tolerate first-generation antipsychotics.

Examples of second-generation antipsychotics include:

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

Some second-generation antipsychotics actually work by increasing dopamine signaling in certain parts of the brain. Examples of these include:

  • aripiprazole (Abilify)
  • brexpiprazole (Rxulti, Rexulti)
  • cariprazine (Vraylar)

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 for a person to hold a job, maintain a relationship, and live independently.

A newer theory of schizophrenia asserts that negative and cognitive symptoms 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.

Efficacy

“With one notable exception, the efficacy of second-generation antipsychotics as a group are not measurably better than the first-generation antipsychotics,” explained Dr. L. Fredrik Jarskog, research director at North Carolina’s Psychiatric Research Center.

The exception to this is the second-generation drug clozapine. One 2013 analysis of studies found this drug to be more effective than other antipsychotics for the treatment of schizophrenia.

“It is unclear what about clozapine’s mechanism of action makes it so much more efficacious,” added Dr. Shinn. “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 can sometimes be difficult to take medication daily.

“For people who have trouble remembering to take their medications, long-acting injectables are an excellent alternative to oral medication,” said Dr. Jarskog.

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)
  • paliperidone palmitate (Invega)
  • risperidone (Risperdal, Perseris)

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

“If there are barriers to remembering to take medications regularly enough, then long-acting injectable medications really can help individuals stay well and out of the hospital,” noted Dr. Sedlak.

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

“A lot of the motivation for coming up with second-generation antipsychotics was [people’s] dissatisfaction with the [neurological symptoms] caused by many first-generation antipsychotics,” noted Dr. Shinn.

People taking first-generation antipsychotic medications, especially at high doses, sometimes experience Parkinson-like symptoms. These may include:

  • tremors
  • rigidity
  • shuffling gait
  • reduced facial expressions

“Recall that Parkinson’s disease is caused by the loss of dopamine neurons,” explained Dr. 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. However, this does not mean that they are not without side effects.

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

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

As Dr. Shinn explained, these factors combine with a higher prevalence of tobacco use and sedentary behavior among people with schizophrenia to increase the risk of diabetes and heart disease.

If a person is taking an antipsychotic, particularly a second-generation one, a psychiatrist should monitor these measures regularly. Dr. Shinn emphasized that it is also important for people to practice healthy behaviors, including:

  • staying active
  • eating healthily
  • avoiding alcohol and recreational drugs
  • quitting or reducing tobacco use, if applicable

Although many experts consider clozapine the most effective antipsychotic option, it is generally reserved for people whose bodies do not respond well to two or three other antipsychotics. This is because this medication can reduce the body’s ability to fight off infections.

Experts told MNT that 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 should be a balance of controlling the symptoms without experiencing problematic side effects.

“Unfortunately, where psychiatry is today, prescribing is very much about trial and error,” explained Dr. 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 Dr. 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 medication 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 for addressing the negative and cognitive symptoms of schizophrenia.

Dr. Jarskog also noted that the decision to start clozapine is sometimes delayed for longer than necessary.

If a person has already tried two or three antipsychotics and these treatments have not controlled their psychotic symptoms, they should talk with a psychiatrist about using clozapine.

Both first- and second-generation antipsychotic medications can effectively reduce psychotic symptoms associated with schizophrenia and improve overall quality of life.

Second-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 should be based on 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.