Should Psychotherapy Be Approved and Prescribed Like a Drug?

Should psychotherapy be approved and prescribed like a drug? The U.S. Food and Drug Administration (FDA) seems to think so. On March 30, 2024, the FDA’s Center for Devices and Radiological Health approved a cognitive-behavioral therapy (CBT)–based digital treatment for major depressive disorder called Rejoyn. Approved for use in combination with medication, Rejoyn is owned and marketed by Otsuka America Pharmaceutical, Inc. It is available only by prescription.

Rejoyn is a 6-week, app-based intervention that combines elements of CBT with an N-back working memory training task (Emotional Faces Memory Task; EFMT) designed to engage regions of the brain that are linked to depression-related deficits in cognitive control and emotion regulation. Specifically, EFMT targets the activation of cognitive control and emotion-processing networks, including the dorsolateral prefrontal cortex (DLPFC) and the amygdala (1). CBT targets maladaptive cognitions and behaviors that contribute to depression (2).

CBT is a well-established treatment for depression with robust evidence of efficacy and effectiveness in multiple clinical trials (3), including adaptations for computerized or app-based formats (4). EFMT is an experimental intervention tested previously in two small pilot studies. In the first pilot study of EFMT, unmedicated individuals with major depressive disorder (N=21) were randomly assigned to eight sessions of EFMT over 4 weeks or to a control condition. Investigators found a greater reduction in depression symptoms in the EFMT group compared with the control group at week 4, although there were no changes in scores on cognitive measures (5). The second trial of EFMT, also conducted with unmedicated individuals with major depressive disorder (N=51), involved 18 training sessions over 6 weeks. Similar to the findings of the first study, the EFMT group had a significantly greater reduction in depression symptoms compared with the control group (6). A follow-up study of unmedicated EFMT completers (N=14) showed significant posttreatment changes in brain activation patterns (increased connectivity from the right DLPFC to the right amygdala), which were associated with depression reduction (1).

When medications are vetted by the FDA, requirements for approval typically include at least two pivotal clinical trials that provide sufficient evidence showing that the benefits of the drug outweigh its risks. These two pivotal studies are usually large, phase 3 randomized controlled trials (RCTs) demonstrating that the effect of the investigational drug can be distinguished from that of the placebo with regard to prespecified outcomes and that the investigational drug is not associated with excessive harms (7). However, when medical devices are approved (Rejoyn is designated as a device), the standards are much different (8). For approval of class II low- to medium-risk medical devices such as Rejoyn, the FDA requires proof only that a device is safe and “substantially equivalent” to a “predicate” device, which is typically another approved or legally marketed device. Thus, there are no published pivotal trials of Rejoyn, as would be required if Rejoyn were a medication. Instead, at the time of product launch, Otsuka provided unpublished—and therefore not peer-reviewed—data from one clinical trial in which individuals with major depressive disorder (N=386) were randomly assigned to receive Rejoyn or a sham treatment plus antidepressant pharmacotherapy and were followed up for 6 weeks (9). Of note, the company did not find a statistically significant difference in its primary outcome (change in observer-rated depression scores from baseline to week 6) between Rejoyn and the comparator. Rejoyn was found to be significantly more efficacious than the comparator for several secondary outcomes, including self-reported measures of anxiety and depression. If it were a drug, Rejoyn would not meet FDA criteria for approval. However, Otsuka’s filing satisfies regulatory requirements for approval as a low- to medium-risk medical device.

Seeking FDA device approval for Rejoyn was a bold decision that may have some benefits to the field. Psychosocial interventions are sometimes considered as lower-value treatments in the therapeutic armamentarium; being able to prescribe digital therapy underscores the legitimacy of psychosocial interventions and may help to level the playing field with pharmacotherapy. The psychological impact of prescribing a treatment can be tremendous (10), adding to the likelihood that some patients will engage meaningfully with this behavioral intervention. Prescription of such interventions may also encourage pharmaceutical and health care companies to invest in psychotherapy research, a field that has been largely abandoned by NIMH (11). As a relatively low-risk intervention, Rejoyn may help some patients with their depressive symptoms without causing harm.

We have many concerns, however, about the FDA’s decision to approve Rejoyn as an adjunctive treatment for major depressive disorder. As discussed above, the bar for approving low- to medium-risk devices is quite low, raising questions about the efficacy of this approach. With Rejoyn being a fully self-guided intervention, whether patients will use this app appropriately is unclear. In meta-analyses, self-guided online therapy interventions have been found to have poor adherence rates and are typically inferior to interventions that incorporate some human contact, underscoring the importance of human support (4, 12). Although adherence rates were quite high (>80%) in the trial results reported by Otsuka, the company enrolled a nonrepresentative sample of participants with depression that excluded people with posttraumatic stress disorder, panic disorder, and substance use disorders. Less than 10% of the sample reported cannabis use, which is lower than typical samples of individuals with depression (13). These common comorbid conditions interfere with attention, motivation, and focus, all of which are likely to affect the use of a self-guided program. Thus, high rates of adherence in a clinical trial may not predict uptake in a general population, thereby contributing to decreased effectiveness.

In addition, N-back tasks are often used in basic research as a tool to assess cognitive functioning in the setting of behavioral challenges rather than as a depression treatment. Although two small pilot studies with unmedicated patients and unpublished data from Otsuka suggest that the EFMT N-back variant, with emotional faces as stimuli, may be beneficial for symptom relief as a monotherapy, no large trials have shown that this intervention is better than a comparator for the primary outcome of reduction in observer-rated depression symptoms, and no published trials that use it as an adjunct to antidepressant medications exist. Other cognitive training protocols have been examined in RCTs for depression and show more promise than the EFMT task (14). Despite FDA approval, Rejoyn remains an experimental intervention that requires further testing.

Information from Otsuka states that patients who want to access its app will have to go to a “designated pharmacy for fulfillment” (9). It is hard to imagine patients traveling to a pharmacy to obtain access to an app, especially when there are many app-based psychotherapies available either for free or at minimum cost in online app stores (15). Because Rejoyn has not been compared with these existing interventions, many of which are also based on CBT or other forms of cognitive training, it is unclear whether this product is superior to those more accessible alternatives. There are risks that the public will be misled to think that this particular app has robust empirical support for its efficacy and that other evidence-supported behavioral therapies that do not have FDA approval will no longer be eligible for reimbursement or will be downgraded in the court of public perception. Further, given that any substantial changes to a device may require a lengthy and expensive FDA reapplication process, the ability to adapt the CBT protocol to an individual’s needs or further enhance the app (as is typical in other CBT approaches) will be impeded.

Approval of Rejoyn by the FDA as a medical device ushers in a new era for psychotherapy and other behavioral interventions—for better and for worse. Prescription of and reimbursement for psychotherapies may help give patients access to much-needed behavioral health support. Companies may be more willing to fund studies testing psychosocial interventions for other diseases if they know that these interventions may become commercial products. Rejoyn itself, however, is approved as a device, not a drug. We should therefore think of Rejoyn in the same way we do about other noninvasive, FDA-approved medical devices such as stethoscopes or pulse oximeters: we can feel confident that the intervention is safe for consumers but should keep in mind that rigorous demonstration of efficacy was not required for approval. In other words, Rejoyn should not be mistaken for a well-tested treatment for depression. Without conclusive evidence of efficacy or effectiveness, both patients and prescribers should proceed with caution.