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Second-Generation (Atypical) Antipsychotics

Reviewed by: HU Medical Review Board | Last reviewed: August 2023

Second-generation antipsychotic drugs are used in the long-term treatment of schizophrenia. They are also called atypical antipsychotics.1

More than 90 percent of all antipsychotic drugs prescribed in the United States belong to the second-generation class. These drugs have mostly replaced older, first-generation drugs (typical antipsychotics). This is because experts think they target a wider range of schizophrenia symptoms and are better tolerated.1,2

How do second-generation antipsychotics work?

Many symptoms of schizophrenia are related to an imbalance of neurotransmitters. Neurotransmitters are chemicals the brain uses to send messages. Dopamine and serotonin are examples of neurotransmitters.3

Like first-generation drugs, second-generation drugs affect dopamine receptors. But they target these receptors better. This leads to fewer movement-related side effects called extrapyramidal symptoms (EPS).1-4

Another difference is that while second-generation drugs block dopamine in some areas of the brain, they actually boost it in other areas. Second-generation drugs affect serotonin, too. Having different targets allows second-generation drugs to work differently than first-generation drugs.1,2,4

Some scientists believe there are added benefits of second-generation antipsychotics by reducing severity of negative and cognitive symptoms of schizophrenia. Negative symptoms include lack of motivation, decreased desire for socialization, and inability to feel pleasure. Cognitive symptoms are issues with thinking and memory.5

First-generation drugs do not usually improve these issues. However, second-generation drugs may help with them. This can make a big difference in the lives of people living with schizophrenia. Negative and cognitive symptoms are common, and they can greatly affect quality of life.1,2,6

Examples of second-generation antipsychotics

There are many second-generation antipsychotic drug, including:1

  • Aripiprazole
  • Asenapine
  • Brexpiprazole
  • Cariprazine
  • Clozapine
  • Lumateperone
  • Iloperidone
  • Lurasidone
  • Olanzapine
  • Paliperidone
  • Pimavanserin
  • Quetiapine

Like first-generation drugs, second-generation antipsychotics come in different forms. Some are taken as daily pills. Longer-acting options are given through an injection into the muscle. Many of these drugs are also used to treat other health issues such as obsessive-compulsive disorder (OCD), bipolar disorder, Parkinson’s disease, and Huntington’s disease.1,2

The choice of what drug to use depends on other health issues you may have and past treatments you may have tried. It also depends on your access to follow-up care, ability to pick up your drugs, and personal preference. You and your doctor will work together to find the best plan for you.

Clozapine for treatment-resistant schizophrenia

One second-generation drug, clozapine, has a special use. When a person does not respond to antipsychotics, they are said to have treatment-resistant schizophrenia. In the past, other options like electroconvulsive therapy (ECT) or hospitalization were needed to try to control symptoms in these cases.1,4,5

But clozapine seems to help as many as half of those with treatment-resistant schizophrenia. It can improve their quality of life and help them avoid more intense treatment options.1,4,5

What are the possible side effects?

Side effects can vary depending on the specific drug you are taking. Common side effects of second-generation antipsychotics include:1,2,4

  • Weight gain
  • Sleepiness
  • Dizziness when standing up
  • Fast or irregular heartbeat
  • Blurry vision
  • Dry mouth
  • Constipation

These are not all the possible side effects of second-generation antipsychotics. Talk to your doctor about what to expect when taking these drugs. You also should call your doctor if you have any changes that concern you when taking antipsychotics.

Other things to know

One of the benefits of second-generation drugs is that they are less likely to cause EPS. These side effects can be severe and permanent. But second-generation drugs do increase the risk of metabolic problems. This means that the way your body processes hormones, fats, and sugars can change when taking one of these drugs. This can lead to weight gain and high blood pressure. It can also increase your risk of diabetes or heart disease.1,2,4

If you are pregnant, planning to become pregnant, breastfeeding, or planning to breastfeed, talk with your doctor. Some antipsychotic drugs may not be safe to take while pregnant or breastfeeding.3

Second-generation drugs can interact with other drugs. Before beginning treatment, tell your doctor about all your health conditions and any other drugs, vitamins, or supplements you take. This includes over-the-counter drugs.1,4

Following your treatment plan closely is important in managing the symptoms of schizophrenia. Take all drugs as prescribed by your doctor. Do not skip doses or stop taking drugs on your own. If you do, symptoms of psychosis could return. If you are having trouble, ask your healthcare team for help.4

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