By Jeffrey Rado, MD, MPH, With Keri Wiginton
Jeffrey Rado is an associate professor in the Department of Psychiatry and Behavioral Sciences at Northwestern University Feinberg School of Medicine. The information here represents his knowledge and experience as a medical professional. Rado was not involved in the development of or clinical trials for lumateperone (Caplyta).
Major depressive disorder (MDD) is a common and often long-lasting mental health condition. It can trigger low mood, fatigue, poor focus, and loss of interest in things you once enjoyed.
Antidepressants like SSRIs and SNRIs are usually the first step in treatment, and they work well for some people. But not everyone sees relief. Some improve only partly, while others don't respond at all. That's where add-on treatments come in.
One option on the horizon is lumateperone, the active ingredient in Caplyta. Research shows it can ease depression symptoms when combined with a standard antidepressant. The FDA is expected to approve it in late 2025 as an adjunctive, or add-on, treatment for adults with MDD who aren't benefiting from their current medication.
To learn more about how this drug works and who it might help, we spoke with Jeffrey Rado, MD, a psychiatrist at Northwestern Medicine in Chicago with expertise in depression treatment and clinical research.
Who Is This Treatment For?
Lumateperone is meant for adults with major depression who are already taking an antidepressant but still don't feel all the way better. That's actually fairly common. The first antidepressant often helps some, but not enough to get you into remission. That means few to no symptoms.
When that happens, your doctor may suggest adding a second medication instead of switching right away. If approved by the FDA, lumateperone could be considered in that situation.
What's Different About This Drug?
Lumateperone is unique among second-generation antipsychotics because it acts on multiple chemical messengers at the same time but with a more selective approach. It regulates both serotonin and dopamine, with downstream effects on glutamate, another chemical tied to mood and thinking.
Since these all play a role in depression, the idea is that lumateperone may give you another path to feeling better because it targets several chemical messengers. And because it's already been used safely as a treatment for schizophrenia and bipolar depression, doctors see it as a logical option for major depression too.
How Effective Is It? How Fast Does It Work?
Clear improvements were seen after about six weeks in two large studies that included nearly 1,000 people total. That's the main time frame researchers looked at, and lumateperone did better than a placebo. But there are hints it may start working sooner.
Some people showed changes within the first week or two. Overall, lumateperone seems to kick in faster than standard antidepressants, which can take a month or more to show results, and that's something we often see with other antipsychotics used as add-on treatments.
How Do You Take It?
Lumateperone is a pill you take once a day along with an antidepressant. You can take it with food or on an empty stomach. If it makes you feel sleepy, your doctor may suggest taking it at night. Otherwise, you can take it at whatever time of day works best for you as long as you're consistent.
Are There Any Side Effects? How Do You Manage Them?
Like all medications, lumateperone can cause side effects. But the ones doctors usually worry about with antipsychotics – weight gain, high blood sugar, or cholesterol changes – don't seem to be a big issue here. Overall, most people seem to tolerate it better than many other antipsychotics.
Weight and lab results stayed pretty steady for people in the studies. Lumateperone also didn't cause much in the way of movement problems, like tremors or restlessness, which can happen with other drugs in this class.
The most common side effects are feeling tired, sleepy, or having a dry mouth. These usually improve within a couple of weeks as your body gets used to the medication.
Of course, everyone responds differently. Some people simply may not tolerate a particular drug. If side effects don't let up after a few weeks or they start to interfere with daily life, it's a good idea to ask your doctor about other options.
Is This Treatment Safe?
"Safe" can mean a lot of different things. But lumateperone has already been on the market for several years for other conditions, and nothing new or concerning has popped up in real-world use.
Like I said before, one of the biggest worries with antipsychotics is weight gain, high blood sugar, or cholesterol changes, all of which can raise your risk of diabetes or heart disease. In studies, those numbers stayed steady with lumateperone, which is reassuring.
Of course, no medication is completely free of side effects. But looking at the big picture, including the fact that no serious safety issues came up in the depression trials, doctors see its safety profile as encouraging, compared to many other drugs in this class.
And if the FDA approves it, that means experts have decided the benefits outweigh the risks.
How Long Do You Take It?
If lumateperone helps, your doctor may suggest staying on it for the long haul, especially if you've had more than one episode of depression. But that doesn't mean you'll be on it forever. It really depends on your situation.
Needing long-term treatment for depression is very common, and it's nothing to feel discouraged about. You and your doctor can decide what makes the most sense for you.
How Often Will You Need Follow-Ups?
When you start a new depression treatment, your doctor will usually want to check in after two to three weeks. That's to make sure the medication is working as expected, you're tolerating it, and that things aren't getting worse.
If it's helping and side effects are manageable, those visits can be spaced out over time. Because lumateperone is an antipsychotic, there are also standard health checks your doctor will likely follow.
At the start, you'll usually get your weight, blood pressure, cholesterol, and blood sugar tested. Those are checked again around 12 weeks, then once a year after that to make sure everything stays on track.
Will Insurance Cover It?
It's hard to know for sure right at the start. Once a drug is FDA approved for a specific condition, like depression, insurance plans usually do cover it. But in the beginning, you might run into a few extra hurdles, like prior authorizations or other restrictions.
Over time, though, coverage tends to get easier as insurance companies update their policies.
How Can You Find Out if It's Right for You?
Start by talking to the doctor who prescribes your antidepressant. That could be your primary care doctor or a psychiatrist. Bring it up directly. You can ask, "Would Caplyta be a good option for me?" That conversation helps you and your provider decide together if it's the right fit.
It's important to note that lumateperone, like all antipsychotics, carries a boxed warning against use in older adults with dementia-related psychosis. It's not approved for people in this group. It's also not approved for children or teens.
How Carefully Was This Drug Studied?
Researchers tested lumateperone in two large clinical trials for depression. Each one followed about 500 people. That's nearly 1,000 patients in total, which is a strong number for this kind of research.
Studies 501 and 502 lasted six weeks and were "double-blind." That means neither the people being studied nor the researchers knew who was getting the real drug versus a placebo. That helps make the results more reliable.
People were closely monitored for both symptom changes and side effects, and the trials followed the strict standards the FDA requires to prove a drug works. The results were clear: Compared to a placebo, more people taking lumateperone saw their depression symptoms improve, and more reached remission.
Remission doesn't mean just feeling better, but having few to no symptoms, which is the goal of treatment. And with large, well-designed trials like these, it's less likely the benefits happened by chance.
There was also a six-month extension study that looked at longer-term use. That trial added extra reassurance that the medication would work well over time, with no new safety issues emerging during extended treatment.
