Despite recent approval of the first new treatment for depression in years, most patients will still use one of the many generics on the market. As reported in Health Plan Weekly, step therapy and generics-first strategies will continue to prevail. Kellie Rademacher, Vice President, Experience and Access Team, Precision for Value, comments.

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Despite Drug Approvals, Generics Remain Depression Mainstay
by Jane Anderson
AIS Health

Nasal spray Spravato (esketamine) entered the market this spring as the first truly new product for major depressive disorder in years, but despite its potential to be a game-changer for those with treatment-resistant depression, most people with the condition will continue to be treated with tried-and-true generics, experts say.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are the predominant classes used to treat major depression, and both have multiple generic options, says Beckie Fenrick, Pharm.D., senior partner-consulting, RemedyOne. Meanwhile, Spravato’s impact on depression treatment costs is likely to be small, especially since plans will require prior authorization and its use is restricted to only certain prescribers.

Atypical antidepressants — for example Forfivo XL (bupropion), Trintellix (vortioxetine) and Wellbutrin (bupropion) — also may be used, Fenrick tells AIS Health. Second- and third-line agents include tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), she says, and other agents also may be added on, such as benzodiazepines and antipsychotics. Most of these agents are covered by plan sponsors and available as generics, so they fall to the first tier, Fenrick says.

“Selection of product is dependent on various patient-specific factors including presentation of depression and co-morbid conditions,” says Mesfin Tegenu, R.Ph., president of PerformRx. He agrees that SSRIs are generally considered to be first-line treatments, while others generally are reserved for treatment-resistant depression, especially since many offer the risk of drug-drug interactions with MAOIs.

It’s very common for someone to try more than one drug before finding one that works for them, Tegenu tells AIS Health. It’s also common to use more than one agent concurrently. “Some examples include: SSRIs with another antidepressant, such as trazodone, venlafaxine, dutoxetine or mirtazapine, SSRIs with buspirone, and antidepressants with atypical antipsychotics.”

Research on the various agents “shows similar efficacy amongst categories and even within categories,” says Kellie Rademacher, Pharm.D., vice president, access experience team, for payer insights and strategy firm Precision for Value.

Generics for major depressive disorder are covered on the lowest generic tier, Tegenu says. Brand products may be covered as preferred, or require use of a generic alternative first, he says. “Given that most of the products on the market have been available for many years, there are a lot of options, many of which are generic,” he says. “Therefore, driving use to generics is easier, given those drugs are the mainstay of treatment.”

Step therapy and generics-first strategies are common to keep costs low, Fenrick adds. However, “many plan sponsors limit the management of this class, since it is considered to be a protected class for some government programs.”

Branded agents are much more likely to be subjected to step therapy, Rademacher tells AIS Health. This is an effective tool that can be automated, minimizing disruption for providers and patients while increasing use of generic agents, she says. “Prior authorization is not as common, given the majority of agents are generic with limited off-label use and manageable safety considerations.”

According to Express Scripts’ 2018 Drug Trend Report, depression spending was $22.52 per member per year, with an average of 1.04 scripts per member per year. Utilization rose 4.5% in 2018 but unit cost fell by 8.3%, meaning overall spending in this category fell by 3.8% per member per year. About three-quarters of the annual drug spend was on generics.

Multiple clinical guidelines recommend a combination of pharmacotherapy and psychotherapy for more robust results in major depressive disorder, Rademacher says. And Tegenu notes that “for most patients, medications and psychotherapy give better results together than either alone.”

First-Month Cost Nears $7,000

Spravato represents almost the polar opposite of these inexpensive, generic depression treatments. The first month cost of twice-weekly treatment with the new nasal spray will range from $4,720 to $6,785, and a month of maintenance therapy will range from $2,360 to $3,540, according to manufacturer Johnson & Johnson’s Janssen Pharmaceuticals, Inc. (HPW 4/1/19, p. 3).

In addition, because Spravato is designated as a Schedule III controlled substance that may carry the risk of illicit use or diversion, patients must self-administer the nasal spray under the supervision of a health care provider in a doctor’s office or clinic certified by the drug’s manufacturer. That will raise the cost of administering the drug significantly. The FDA approved Spravato with a Risk Evaluation and Mitigation Strategy (REMS), making it available to patients through a restricted distribution program at certified health care facilities.

“This is the first new product in a long time, and there is a tremendous need,” Fenrick says. Still, she says, “the product restrictions are prohibitive: two-hour monitoring after administration, risk for sedation and difficulty with attention, judgment and thinking/dissociation, abuse and misuse, and suicidal thoughts and behaviors after administration.”

April Kunze, Pharm.D., senior director, clinical formulary development and trend management strategy at Prime Therapeutics LLC., says many of Prime’s health plan clients are planning to manage Spravato on the medical benefit. “Details on the current distribution system are being worked out now, but it will likely be through a hub and provider, but it won’t be direct to patient,” Kunze tells AIS Health.

Spravato Is for Niche Population

Spravato isn’t expected to increase major depression treatment costs significantly, Kunze says. “This is for a niche population — treatment-resistant depression — so overall impact to the category as a whole and majority of drug spend will be quite minimal. However, compared to using generic ketamine injection, it will increase costs.”

Fenrick also says Spravato is expected to be covered under the medical benefit, even though it’s self-administered. “If a plan sponsor constructs the benefit such that medical drugs are covered under the pharmacy benefit, Spravato will most likely be covered. The requirement to have it administered by a health care practitioner should theoretically cut down on abuse potential.” She says she anticipates plan sponsors requiring prior authorization for Spravato to ensure appropriate use.

Tegenu points out that Spravato is an option for major depressive disorder only when other pharmacologic and non-pharmacologic options have been exhausted.

“Coverage policies will likely be very conservative, using product labeling and REMS program requirements as a guide,” Tegenu tells AIS Health. “There are concerns with long-term safety of the product as well as risks around diversion of the product.”

Drug Could Be ‘Very Impactful’

The product could be “very impactful” for “the smaller, very refractory patient population,” Rademacher says. “Uptake of the new product by providers remains to be seen.”

There’s nothing of note in the drug development pipeline for major depressive disorder that could come out in the next year, Tegenu says. Zulresso (brexanolone) injection was just approved for postpartum depression, also under an FDA-mandated REMS strategy; it must be administered as a 60-hour continuous intravenous infusion, most likely in the hospital, because of the FDA’s concerns about serious risks, including loss of consciousness. Zulresso manufacturer Sage Therapeutics also is in advanced clinical trials with its oral agent SAGE-217 for major depression, which received breakthrough therapy designation from the FDA in February 2018 and also is being studied for postpartum depression.

“While we have made advancements with the treatment of anxiety and depression, suicide rates remain high,” Fenrick says. “Some experts indicate we are better at diagnosing depression. A significant number of people take these treatments, and mental health disorders are a major health issue worldwide.”

Contact Fenrick at, Tegenu at, Kunze via Prime Therapeutics spokesperson Denise Lecher at and Rademacher via spokesperson Tess Rollano at