Second generation antipsychotics, also called atypical antipsychotics, are a class of psychiatric medications that work by blocking both dopamine and serotonin receptors in the brain. They were developed starting in the 1990s as an alternative to older (first generation) antipsychotics, with the goal of treating psychosis effectively while causing fewer movement-related side effects. Today they are among the most widely prescribed psychiatric medications, used not only for schizophrenia but also for bipolar disorder, treatment-resistant depression, and as add-on therapy for major depressive disorder.
How They Work in the Brain
First generation antipsychotics work almost entirely by blocking dopamine D2 receptors. They’re effective when they block roughly 72% of those receptors, but that heavy dopamine blockade comes with a cost: stiffness, tremors, and other movement problems collectively known as extrapyramidal symptoms.
Second generation antipsychotics also block D2 dopamine receptors, but they add a second action: blocking serotonin receptors, primarily the 5-HT2A subtype. This dual mechanism is thought to be the reason they cause fewer movement side effects. The serotonin blockade essentially loosens the grip on dopamine pathways that control motor function, while the dopamine blockade in other brain regions still addresses psychotic symptoms like hallucinations and delusions.
A newer subgroup, sometimes called third generation antipsychotics, takes a different approach. Medications like aripiprazole and cariprazine act as partial agonists at dopamine receptors rather than fully blocking them. Instead of shutting down dopamine signaling, they dial it down where activity is too high and boost it slightly where activity is too low. Cariprazine in particular has a strong preference for the D3 dopamine receptor, which may help with the motivational and cognitive symptoms of schizophrenia that older drugs struggle to treat. Despite this distinction, these newer agents are still commonly grouped under the second generation umbrella in clinical practice.
Medications in This Class
The FDA has approved a number of second generation antipsychotics, each with a somewhat different side effect profile and set of approved uses:
- Aripiprazole (Abilify)
- Asenapine (Saphris)
- Clozapine (Clozaril)
- Iloperidone (Fanapt)
- Lurasidone (Latuda)
- Olanzapine (Zyprexa)
- Paliperidone (Invega)
- Quetiapine (Seroquel)
- Risperidone (Risperdal)
- Ziprasidone (Geodon)
An olanzapine/fluoxetine combination (Symbyax) is also available specifically for treatment-resistant depression and bipolar depression. These medications are not interchangeable. Choosing between them depends on the condition being treated, individual response, and which side effects are most important to avoid.
What They’re Prescribed For
Schizophrenia is the most well-known use, but several second generation antipsychotics carry FDA approvals that extend well beyond it. Quetiapine, for instance, is approved for acute bipolar mania, bipolar depression, bipolar maintenance therapy, and as an add-on treatment for major depressive disorder. Aripiprazole is approved for bipolar mania and as adjunctive therapy for major depression in adults. Olanzapine is approved for bipolar mania, bipolar maintenance, treatment-resistant depression (in combination with fluoxetine), and acute agitation in schizophrenia and bipolar disorder.
Paliperidone has a specific approval for schizoaffective disorder. Clozapine occupies a unique role: it is reserved for treatment-resistant schizophrenia and is the only antipsychotic shown to reduce suicidal behavior in people with the condition. Because of a rare but serious risk of dangerously low white blood cell counts, clozapine requires regular blood monitoring, with weekly draws for the first six months, every two weeks from six to twelve months, and monthly thereafter.
Movement Side Effects: A Real Improvement
One of the main reasons second generation antipsychotics were developed was to reduce the risk of tardive dyskinesia, a condition involving involuntary, repetitive movements of the face and body that can become permanent. A large meta-analysis of randomized trials found the annualized incidence of tardive dyskinesia was 2.6% per year with second generation agents compared to 6.5% per year with first generation drugs. That translates to roughly half the risk. The difference held up even when researchers controlled for the dose of the older drugs, ruling out the possibility that it was simply a matter of first generation medications being given at unnecessarily high doses.
This is a meaningful improvement, but 2.6% per year is not zero. Over several years of treatment, the cumulative risk adds up, which is why movement side effects still need monitoring even with newer medications.
Metabolic Side Effects
The tradeoff for fewer movement problems is a higher risk of metabolic complications, particularly weight gain, elevated blood sugar, and changes in cholesterol and triglycerides. Not all second generation antipsychotics carry equal metabolic risk, and the differences between individual drugs are substantial.
Olanzapine consistently ranks as the highest-risk option for weight gain. A meta-analysis found that at equivalent doses, olanzapine increased the probability of clinically significant weight gain by about 12.6% compared to placebo, with an estimated 16.1% added risk at standard dosing. Quetiapine and risperidone fall in the middle range. Aripiprazole, lurasidone, and ziprasidone tend to be more weight-neutral, making them preferable options when metabolic risk is a concern.
Clinical guidelines recommend metabolic monitoring before starting any second generation antipsychotic, again at three months, and then annually for as long as treatment continues. This typically includes blood sugar (fasting glucose or A1c), a lipid panel (cholesterol, triglycerides, HDL), liver function tests, and a complete blood count. Weight and waist circumference should also be tracked. In practice, these monitoring guidelines are often followed inconsistently, so it’s worth being proactive about keeping up with lab work.
Prolactin Elevation
Some second generation antipsychotics raise levels of prolactin, a hormone normally involved in milk production. Because dopamine normally keeps prolactin in check, blocking dopamine receptors can cause prolactin to rise. Risperidone has the highest prevalence of this effect, with studies showing elevated prolactin in 70% to 100% of people taking it.
High prolactin can cause missed or irregular periods, breast tenderness or milk production in people who aren’t nursing, sexual dysfunction, and fertility problems in both men and women. Over time, it can also reduce bone density. Aripiprazole sits at the opposite end of the spectrum: because it partially activates rather than fully blocks dopamine receptors, it is considered prolactin-sparing and is sometimes used specifically to counteract prolactin elevation caused by other antipsychotics.
Long-Acting Injectable Formulations
For people who have difficulty taking daily pills or who prefer less frequent dosing, several second generation antipsychotics are available as long-acting injectables. Nine FDA-approved injectable formulations currently exist, covering four medications: aripiprazole, olanzapine, paliperidone, and risperidone.
Dosing intervals vary widely. Risperidone injections are given every two to four weeks depending on the formulation. Aripiprazole injectables range from every four weeks to every eight weeks. Paliperidone offers the broadest range, with formulations given monthly, every three months, or every six months. The six-month paliperidone injection represents the longest interval currently available for any antipsychotic, requiring only two injections per year.
These injectables are particularly useful for maintaining steady medication levels and avoiding the relapses that can happen when daily doses are missed. Transitioning to an injectable typically involves a period of overlap with oral medication to ensure adequate drug levels are established.
How They Differ From First Generation Drugs
The distinction between first and second generation antipsychotics is sometimes overstated. Both classes are effective for psychosis, and both carry significant side effects. The real difference is in which side effects predominate. First generation drugs are more likely to cause stiffness, restlessness, tremors, and tardive dyskinesia. Second generation drugs are more likely to cause weight gain, blood sugar elevation, and cholesterol changes. Prolactin effects vary by individual drug rather than by generation.
In terms of effectiveness for the core symptoms of schizophrenia, most head-to-head comparisons show similar results between the two classes, with one notable exception: clozapine remains the most effective antipsychotic available for people who haven’t responded to other treatments. For bipolar disorder and depression, second generation agents have a much broader evidence base, with multiple drugs carrying specific FDA approvals that first generation drugs lack.