Second-generation antipsychotics, also called atypical antipsychotics, are a class of medications used to treat psychosis and to stabilize mood, generally with a lower risk of the movement side effects seen with older antipsychotics. They are among the most useful tools in psychiatry, and this page explains the medications in this class, why we use them, the conditions they treat, how they are dosed, and the side effects we watch for.

What second-generation antipsychotics are

Antipsychotics work mainly by adjusting dopamine signaling in the brain, and the second-generation agents also act on serotonin, which is part of why they tend to cause fewer movement-related side effects than the older, first-generation drugs. A newer subgroup, sometimes called dopamine partial agonists, fine-tunes dopamine rather than simply blocking it. As the largest comparative analysis of these medications has shown, they differ meaningfully from one another in their effects and side effects, so the choice is individualized to each person (Huhn et al., 2019).

The medications in this class

The second-generation antipsychotics include clozapine, risperidone, paliperidone, olanzapine, quetiapine, ziprasidone, asenapine, iloperidone, lurasidone, and lumateperone. A related subgroup that works as dopamine partial agonists includes aripiprazole, brexpiprazole, and cariprazine. Pimavanserin, used specifically for the hallucinations and delusions of Parkinson’s disease psychosis, is another atypical agent. Several of these — including risperidone, paliperidone, aripiprazole, and olanzapine — are also available as long-acting injectables given every few weeks to a few months.

Why we use them

These medications can quiet the hallucinations, delusions, and disorganized thinking of psychosis, steady the highs and lows of bipolar disorder, and add benefit when depression has not responded to an antidepressant alone. Compared with first-generation antipsychotics, they generally carry a lower risk of stiffness, tremor, and the long-term movement disorder called tardive dyskinesia, though that risk is not zero. For people who struggle to take a daily pill, long-acting injectable forms can make staying well much easier (American Psychiatric Association, 2020).

Conditions they help with

Second-generation antipsychotics are used to treat schizophrenia and schizoaffective disorder, the manic and depressive phases of bipolar disorder and its long-term maintenance, and, as add-on treatment, major depression that has not fully responded to an antidepressant. Specific agents are also used for irritability and aggression in autism, for Parkinson’s disease psychosis, and in other situations your clinician will discuss with you. For treatment-resistant schizophrenia, clozapine is uniquely effective and is also recommended when the risk of suicide remains high despite other treatments (American Psychiatric Association, 2020).

How they are dosed

Dosing is always individualized. We generally start at a low dose and increase gradually to find the lowest dose that controls symptoms with the fewest side effects, and most of these medications are taken once daily. Long-acting injectables are an option when a steady, convenient routine helps. Clozapine is reserved for specific situations and requires regular blood-count monitoring for safety. We never recommend starting, stopping, or changing the dose on your own — stopping suddenly can trigger a relapse, so we always adjust together.

Side effects and monitoring

The most important long-term concern with this class is metabolic: weight gain and rises in blood sugar and cholesterol, which are more pronounced with some agents (such as olanzapine and clozapine) and minimal with others. Because of this, we follow the American Diabetes Association and American Psychiatric Association monitoring plan, checking weight, blood pressure, blood sugar, and lipids before starting and at regular intervals (American Diabetes Association et al., 2004). Other possible effects include drowsiness, restlessness or an inner sense of needing to move (akathisia), tremor or stiffness, dizziness on standing, elevated prolactin (which can affect periods or cause breast changes), and, with certain agents, effects on the heart’s rhythm. Tardive dyskinesia, a movement side effect, is less common than with older drugs but still possible, so we screen for it. Clozapine carries specific risks — including a drop in infection-fighting white blood cells — which is why it requires scheduled blood tests.

When to seek help right away

Call us or seek urgent care for high fever with muscle stiffness, confusion, and a racing heart (which can signal a rare but serious reaction called neuroleptic malignant syndrome), for fainting or an irregular heartbeat, or for signs of infection such as fever and sore throat while taking clozapine. In an emergency, call 911.

Culturally grounded care

We care for the whole person, in the spirit of lōkahi — balance and harmony among the body, mind and emotions, spirit, ʻohana (family), and our connection to the ʻāina (land) and community. To mālama (care for and protect) you and to support living pono (in balance), we explain your medication clearly, weigh benefits and side effects with you, welcome your ʻohana, and honor the values that ground you. Offering kōkua (help given freely, with aloha) is at the heart of how we practice.

Common questions about second-generation antipsychotics

What are the second-generation (atypical) antipsychotics?

They include clozapine, risperidone, paliperidone, olanzapine, quetiapine, ziprasidone, asenapine, iloperidone, lurasidone, and lumateperone, plus the dopamine partial agonists aripiprazole, brexpiprazole, and cariprazine, and pimavanserin for Parkinson’s disease psychosis.

What conditions do they treat?

Schizophrenia and schizoaffective disorder, the manic and depressive phases of bipolar disorder, add-on treatment of depression, irritability in autism, and Parkinson’s disease psychosis, among others.

What are the main side effects to watch for?

The most important are metabolic — weight gain and rises in blood sugar and cholesterol — which is why we monitor these regularly. Others include drowsiness, restlessness (akathisia), tremor or stiffness, dizziness on standing, and elevated prolactin. Clozapine requires regular blood-count monitoring.

Why might my provider recommend a long-acting injection?

Long-acting injectable forms, given every few weeks to a few months, can make treatment simpler and more reliable, especially when remembering a daily pill is difficult, and they are recommended when adherence is a concern.

This page is general health education from OhanaPsych. It is not a substitute for a personal evaluation by a qualified clinician who knows your situation, and reading it does not create a provider–patient relationship. Do not start, stop, or change any medication without talking with your clinician. In an emergency, call 911.

George Mackel, MSN, APRN, NP-C, PMHNP-BC, CARN-AP — President & Owner

References

American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, & North American Association for the Study of Obesity. (2004). Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care, 27(2), 596–601. https://diabetesjournals.org/care/article/27/2/596

American Psychiatric Association. (2020). The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. American Journal of Psychiatry. https://psychiatryonline.org/doi/10.1176/appi.ajp.2020.177901

Huhn, M., Nikolakopoulou, A., Schneider-Thoma, J., Krause, M., Samara, M., Peter, N., et al. (2019). Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: A systematic review and network meta-analysis. The Lancet, 394(10202), 939–951. https://www.thelancet.com/article/S0140-6736(19)31135-3/fulltext