Caplyta (lumateperone) was just approved by the FDA as an adjunct therapy for adults with major depression disorder (MDD). This atypical antipsychotic was originally approved to treat adults with schizophrenia and bipolar I and II as a monotherapy; or as an adjunct to lithium or valproate (Depakote). The approval of Caplyta was based on the positive results from two phase 3 clinical trials. Medscape quoted a professor of psychiatry and pharmacology at the University of Toronto as saying for people with lingering depressive symptoms, “adding Caplyta to a patient’s treatment regimen may offer early improvement, with the potential for remission.”
The Johnson & Johnson (J&J) press release on the FDA approval of Caplyta said it offered a new option for 2 in 3 people who experience residual depression symptoms despite their current antidepressant treatment. Side effects from Caplyta such as weight gain and metabolic changes (lipid and glucose levels), akathisia and restlessness were similar to placebo. The most common side effects included sleepiness, dizziness, nausea, dry mouth, feeling tired and diarrhea. It does not need dose titration, allowing individuals to start treatment at the effective dose. “Caplyta also demonstrated the potential to help patients achieve remission. During this 26-week safety study, 80% of patients responded to treatment and 65% of patients experienced remission.”
J&J said although the exact mechanism of action for Caplyta was unknown, “it is characterized by high serotonin 5-HT2A receptor occupancy and moderate amounts of dopamine D2 receptor occupancy at therapeutic doses.” The company said the FDA approval was a testament to its commitment of bringing “innovative and differentiated therapies that redefine treatment expectations … to patients living with some of today’s most prevalent and debilitating mental health conditions.”
Fierce Pharma added further nuance to Johnson & Johnson’s glowing announcement of the FDA’s approval of Caplyta as an add-on, stating the company supersized its treatment reach. It noted that Johnson & Johnson’s purchase of Intra-Cellular Therapies for $14.6 billion earlier this year was largely because the acquired company was close to bringing Caplyta to market. Now J&J will reap the financial benefits of the potential blockbuster drug, anticipating it will eventually bring in $5 billion in annual sales.
Caplyta, with $680 million in 2024 sales, has been a commercial and clinical success since its 2019 approval, but MDD represents a much larger market opportunity. At least triple the size of the bipolar space, analysts say, the MDD field is teeming with competition from treatment agents new and old.
With the new approval as an add-on for MDD, Caplyta is expected to help patients achieve greater symptom relief than with their antidepressant alone. This adds 22 million more patients who can potentially use Caplyta. Paired with an oral antidepressant, Caplyta had statistically meaningful improvements in depression symptoms compared to an antidepressant and placebo. However, the cross pollination of antidepressants with atypical antipsychotics is not simply the result of scientific innovation. Marketing played a major role in developing the use of atypical antipsychotics to treat MDD.
How Atypical Antipsychotics Became a Billion-Dollar Industry
Lydia Green, a former medical advertising writer, wrote about how she helped to market Risperdal, “and how that effort helped turn atypical antipsychotics into a multi-billion-dollar industry.” She said it wasn’t just a story about how her agency promoted Risperdal (the first widely prescribed atypical antipsychotic) as a medication, but also about a revolution in psychiatric care. It is a story about how schizophrenia was redefined, how the safety narrative of antipsychotics was rewritten, and how this helped make Risperdal “one of the most successful (and concerning) pharmaceutical launches in history.”
She was a copywriter in pharmaceutical advertising and worked for an agency whose client was Janssen, which originally brought Risperdal to market. The agency faced an ultimate challenge—convince psychiatrists to substitute a drug that cost ten times more (Risperdal) than a widely accepted and effective drug (Haldol). They needed to justify Risperdal’s price “by positioning it as the next generation option for schizophrenia.” This meant a complete reframing of what schizophrenia was—”and a redefinition of Risperdal’s role in treating it.”
Many people don’t realize that a drug’s marketing story begins long before FDA approval. Today, drug and device business strategy and planning is backed by an army of researchers, communication companies, and consultants. Often, these strategies are covert and secretive, so much so that those involved at different stages of the drug’s life cycle may be unaware of the corporation’s ultimate marketing intent.
In an aside, note this happened in the mid-1990s, at the same time Purdue Pharma was doing something similar with OxyContin for the treatment of pain. For more information on Purdue Pharma, the Sacklers and OxyContin, see: “The Tale of the OxyContin Lie,” “Doublespeak in the Opioid Crisis, Part 2,” and “Giving an Opioid Devil Its Due,” among other articles on Purdue Pharma and the Sackler family on the Faith Seeking Understanding website.
The ad agency and Janssen realized they didn’t simply need to market a new drug, they needed to “aggressively differentiate Risperdal from older agents by promoting a new framework for thinking about schizophrenia.” They began with their selection of the rating scale used to assess whether the drug is working in the clinical trials. Companies choose the scale most likely to portray their product in a favorable light. “That choice shapes trial results, positioning, marketing claims, and how the product is perceived compared to its competitors.”
Janssen chose the PANSS for many of Risperdal’s Phase 3 trials. PANSS broke schizophrenia symptoms into two categories: positive (hallucinations, delusions) and negative (emotional withdrawal, apathy). While older drugs like Haldol primarily treated positive symptoms, we said that Risperdal could also target the harder-to-treat negative symptoms. That positioning didn’t just help Risperdal—it helped usher in the entire atypical antipsychotic era by shifting psychiatry’s focus toward chronic, cognitively framed symptoms as targets for pharmaceutical treatment.
In addition to its efficacy with negative symptoms, they pointed to how Risperdal seemed to cause less extrapyramidal symptoms (EPS) when compared to Haldol. But in those clinical studies Haldol was dosed at very high levels, “almost ensuring worse side effects.” The FDA restricted them from claiming Risperdal was safer or more effective than Haldol, so they emphasized how Risperdal balanced the blockade of dopamine D₂ and serotonin 5-HT₂A receptors. Then they contrasted this with Haldol’s high-potency and nearly exclusive blockade of D₂ receptors. “We linked strong D₂ blockade to movement-related side effects, such as EPS, while suggesting that serotonin-D₂ balance might reduce these risks.”
This allowed us to tell a compelling, science-based story without stepping over regulatory lines. Risperdal thought leaders, however, could link the receptor narrative to clinical advantages in abstracts, journal articles, and sponsored CME programs.
There was more involved in their marketing strategy, but you get the point. For a while, the strategy worked. They had the talking points, the scientific language, the educational tools and the belief that Risperdal was more effective than Haldol and caused fewer side effects—particularly tremors and stiffness with older antipsychotics. “Sales representatives echoed this—as did medical conferences, educational materials, and journal reprints that positioned Risperdal as psychiatry’s future: modern, safer, and better.” Risperdal was ranked the 21st best brand-name drug by retail sales in 2000 by Drug Topics, with total retail sales of $959,707. Haldol (haloperidol) was 160th on the top 200 generic list with $25,865 total retail sales.
Cracks Begin to show in the Claims with Risperdal
Then larger scale, independent studies suggested the efficacy differences between atypicals and traditional antipsychotics were not as dramatic as claimed. The studies of Risperdal that showed fewer EPS were noted to have used Haldol doses that guaranteed worse outcomes. Then, five years after it was launched in 1993, metabolic side effects surfaced. “Risperdal was increasingly associated with significant weight gain, diabetes, and in adolescent boys, gynecomastia—breast development linked to elevated prolactin levels.” For more on Janssen, Risperdal and gynecomastia, see: “Liar, Liar Pants on Fire.”
We didn’t just promote Risperdal. We helped launch a new era of medical marketing—one where disease education, clinical research, and sales strategy blurred into a single message. And we convinced ourselves it was all in the name of better care.
This marketing approach transformed mental health. Atypical antipsychotics—initially approved for adult schizophrenia—eventually came to dominate the market, accounting for nearly 93.2% of all Medicaid antipsychotic prescriptions by 2021. Much of that use was off-label. In some states, psychiatrists prescribed so many atypicals for children in foster care that state legislators had to intervene.
If we genuinely want to rebuild trust in medicine, we can’t just blame one bad actor or a single scandal. We need comprehensive reform, including transparency in science, independent oversight, stricter control of marketing claims, and government funding for clinical trials. As long as those with financial interests control the design of studies, influence the narratives, and manage the messaging, no one—whether it’s doctors, patients, or the public—can truly know what to believe.
Perhaps Caplyta needs further scrutiny before we start singing its praises. Notice it was brought to market by the same parent company as Risperdal. The Janssen name was retired by J&J in 2023 and the subsidiary was renamed as Johnson & Johnson Innovative Medicine. The language about Caplyta and Risperdal and their action on serotonin 5-HT2A receptors and dopamine D₂ deserves further clarification. Hopefully, they’re not reusing the same rhetorical playbook they did with Risperdal. Also, look closely at the Caplyta clinical trials to be sure something like the unfair comparison of Risperdal and Haldol wasn’t done.
Let’s at least see if the results noted by J&J with Caplyta can be replicated before we accept what a Global Therapeutic Area Head for Johnson & Johnson Innovative Medicine said when Caplyta was approved as an adjunct therapy for adults with MDD: “Caplyta has the potential to become a new standard of care across multiple mental health disorders, including major depressive disorder.”
