Effects of Adjunctive Cariprazine Formulary Restrictions in Major Depressive Disorder

ABSTRACT

Objectives: To evaluate the effects of formulary-related rejections of initial adjunctive cariprazine (Vraylar) claims on health care resource utilization (HCRU) among patients with major depressive disorder (MDD).

Study Design: Retrospective claims-based analysis.

Methods: Using data from Symphony Health Integrated Dataverse from March 2015 through October 2020, we identified adults with MDD who were being treated with antidepressants and had an initial cariprazine claim that was either rejected for a formulary-related reason (eg, noncoverage, prior authorization requirement, step therapy requirement) or approved; rejected patients were required to receive a subsequent atypical antipsychotic (which helps balance the health status across cohorts but may induce bias and affect generalizability). Rejected and approved cohorts were matched (1:2) using propensity scores. Outcomes included all-cause and mental health (MH)–related HCRU (hospitalizations, emergency department [ED] visits, outpatient visits) and treatment patterns. HCRU was compared between cohorts using rate ratios (RRs), with 95% CIs and P values. Treatment patterns were analyzed using descriptive statistics.

Results: The rejected cohort comprised 566 patients, with 1132 matched patients in the approved cohort. All-cause and MH-related hospitalization rates were 61% and 89% higher, respectively, for the rejected vs approved cohort (all-cause: RR, 1.61; 95% CI, 1.15-2.32; P = .012; MH related: RR, 1.89; 95% CI, 1.18-2.89; P = .016). ED and outpatient visit rates were similar. Patients in the rejected cohort often never received cariprazine (68.4%), and those who did received it after a 6-month delay on average.

Conclusions: Patients with MDD who had an initial adjunctive cariprazine claim rejected for a formulary-related reason and subsequently received an atypical antipsychotic experienced significantly higher hospitalization rates than those with approved initial cariprazine claims, suggesting that formulary restrictions on adjunctive cariprazine may be associated with negative downstream effects.

Am J Manag Care. 2025;31(7):In Press

Takeaway Points

• Little is known about the effects of formulary-related restrictions on atypical antipsychotics used for adjunctive treatment of major depressive disorder (MDD).
• Patients with MDD who had their initial adjunctive cariprazine (Vraylar) claim rejected for a formulary-related reason had significantly higher rates of all-cause and mental health–related hospitalizations vs patients whose initial cariprazine claim was approved.
• Most patients whose initial cariprazine claim was rejected never subsequently received cariprazine, and those who did received it after a 6-month delay on average.
• These results suggest there may be unintended negative consequences from implementing formulary restrictions on cariprazine for the adjunctive treatment of MDD.

Major depressive disorder (MDD) is a chronic and disabling mood disorder associated with reduced quality of life and considerable economic burden.^1-5 Current MDD guidelines recommend antidepressant monotherapy for initial treatment^6,7; however, most patients do not adequately respond to or achieve remission on first-line medications.⁸ The low remission rates with first-line treatment are especially concerning given that remission is a key goal of treatment and that rates of morbidity and mortality increase with ongoing MDD symptoms.⁹ In cases of inadequate response to first-line antidepressant monotherapy, one guideline-recommended treatment approach is the use of adjunctive therapy with atypical antipsychotics (AAs), which have demonstrated efficacy when used with antidepressants for the treatment of MDD.^6,7,10-12 Cariprazine (Vraylar), a D₃ dopamine–preferring partial agonist at the D₃ and D₂ dopamine receptors and the serotonin 5-HT_1A receptor, has been approved by the FDA to treat bipolar I (BP-I) disorder and schizophrenia since 2015. More recently, cariprazine demonstrated efficacy in reducing depressive symptoms when used with antidepressant therapy (ADT) in adults with inadequate response to ADT alone^13,14 and was approved in 2022 as an adjunct to ADT for the treatment of MDD. Given the medication’s current brand status, however, some commercial health plans may apply formulary restrictions to cariprazine, limiting its access among patients with MDD who do not adequately respond to a first-
line antidepressant.

Formulary restrictions on prescription medications (eg, noncoverage, prior authorization requirements, and step therapy requirements) are designed to ensure appropriate use and minimize pharmacy costs without compromising the quality of patient care. However, formulary restrictions on medications used to treat MDD have been associated with negative consequences for patients, health systems, and payers. For example, results from a claims database study assessing Medicaid formulary restrictions on antidepressants showed that prior authorizations were associated with a 5.7% increase in MDD-related hospitalizations; further, prior authorizations and step therapy combined were associated with a 16.6% increase in MDD-related hospitalizations.¹⁵ Authors noted that the increased hospitalizations led to costs that exceeded pharmacy cost savings, suggesting that restricting access to antidepressants via formulary restrictions failed to result in overall savings.¹⁵ Similarly, a claims database analysis that examined the effects of antidepressant step therapy requirements for patients enrolled in employer plans showed that although medication costs decreased, there was an increase in the number of mental health (MH)–related outpatient visits, emergency department (ED) visits, and inpatient admissions.¹⁶ Further, the analysis found step therapy to be associated with an 8.4% increase in outpatient spending, a 17% increase in inpatient spending, and a 28% increase in ED spending; in contrast, spending on prescription drugs decreased by only 1.7% following step therapy implementation.¹⁶ Together, the data from these studies suggest that formulary restrictions on MDD medications result in modest drug savings that may fail to offset medical expenses, such as those associated with increased ED visits and hospitalizations that burden both patients and the health care system.

Because of their relatively high acquisition costs,¹⁷ AAs are a common target for formulary restrictions. However, patient response may vary across AAs even within the same class, as these medications exhibit a wide range of pharmacologic, tolerability, and efficacy profiles.¹⁸ For this reason, AAs are not considered therapeutically interchangeable and may not be suitable candidates for some types of formulary restrictions.¹⁹ This is evident from previous research suggesting that formulary restrictions on AAs are associated with decreased medication adherence, more hospitalizations, and increased costs in patients with bipolar disorder and schizophrenia.^17,20 Moreover, findings from a narrative literature review of 15 studies that assessed cost or health outcomes associated with restricted access to AAs among patients with bipolar disorder or schizophrenia revealed that restricting access to AAs tends to shift pharmacy costs to medical costs, rather than achieving their intended purpose of overall savings.¹⁸

The unintended consequences of restricting access to antidepressants for the treatment of MDD and to AAs for the treatment of bipolar disorder and schizophrenia have been previously evaluated.^15-21 However, less is known about the effects of formulary restrictions on specific AAs, particularly cariprazine, as an adjunctive treatment for MDD. Because cariprazine has recently demonstrated efficacy as an adjunctive treatment for MDD but is currently only available as a branded medication, it is important to assess how formulary restrictions impact patients prescribed this medication. To address this gap, we conducted a retrospective claims database analysis to evaluate the health care resource utilization (HCRU) and treatment patterns of patients with MDD and an initial claim for cariprazine that was either approved or rejected for
a formulary-related reason.

METHODS

Data Source

Data from March 1, 2015, through October 31, 2020, were derived from Symphony Health, an ICON plc Company, Integrated Dataverse (IDV). Symphony Health IDV is a nationally representative claims database that covers approximately three-fourths of the US population and comprises medical, hospital, and pharmacy claims data submitted to all payer types, such as commercial plans, Medicare Part D, cash assistance programs, and Medicaid.²² The database includes information on approved, reversed, and rejected pharmacy claims as well as the reasons for rejection, which are provided according to the National Council for Prescription Drug Programs standard. Socioeconomic variables, such as annual household income (< $30,000, $30,000-$39,999, $40,000-$49,999, $50,000-$74,999, $75,000-$99,999, ≥ $100,000, unknown), were also available for some patients and were coded as dichotomous variables. Patients without these data were included in the “unknown” category. Data in Symphony Health IDV were deidentified and complied with the Health Insurance Portability and Accountability Act; therefore, no institutional review board review was required.

Study Sample

The study included adults 18 years and older with commercial health insurance at first cariprazine claim, an MDD diagnosis, and 1 or more pharmacy claims for cariprazine (eAppendix Table 1 [eAppendix available at ajmc.com]). The index date was defined as the date of the first cariprazine claim, which was either rejected for a formulary-related reason or approved (eAppendix Figure 1). Eligible patients were required to have at least 6 months of continuous clinical activity prior to the index date (baseline period). Clinical activity was defined as at least 1 pharmacy or medical claim per quarter and was used as a proxy for health plan enrollment given the lack of eligibility files in Symphony Health IDV. In addition, eligible patients had at least 1 ADT dispensing in the 90 days preindex and at least 1 ADT dispensing in the 90 days post index with at least 14 days of overlapping supply with cariprazine to ensure that cariprazine was being prescribed for adjunctive use. The overlapping ADT dispensing could have occurred either preindex or post index. Only patients with an initial cariprazine rejection who received a subsequent AA (cariprazine or other) in the follow-up period were included in the rejected cohort. This ensured patients in both cohorts received at least 1 AA and therefore had similar treatment requirements as determined by their provider. Patients were excluded from the analysis if they did not have commercial health insurance on the index date or if they had a bipolar disorder diagnosis (comprising BP-I and bipolar II disorder) during the baseline period or on the index date.

The follow-up (observation) period began on the index date and continued until the earliest of either the end of clinical activity or the end of data availability. Patient demographics were collected at the index date, and clinical characteristics, such as comorbidities and prior medication use, were collected during the 6 months prior to the index date (baseline period).

Formulary Restrictions

Formulary-related cariprazine claim rejections were categorized into 1 of 3 types: formulary noncoverage, prior authorization requirement, and step therapy requirement (Table 1). Claims with unclear rejection reasons (eg, duplicates, refill too soon) were not included in the analysis. In addition, the following other rejection reasons were not considered formulary related and therefore were not included in the analysis: plan limitations exceeded; filled after coverage terminated; claim not processed; patient not covered; submit bill to other processor or primary payer; product service ID carve out, bill Medicaid fee-for-service; cost exceedsmaximum; filled after coverage expired; and product/service not covered for patient age (eAppendix Table 2). Reversed initial cariprazine claims, such as prescriptions that were sent to the pharmacy and approved by the payer/clearinghouse but never picked up by the patient, were not assessed.

Patients whose index cariprazine claim was approved were assigned to the approved cariprazine claim cohort and patients whose initial cariprazine claim was rejected for a formulary-related reason were assigned to the rejected cariprazine claim cohort. Patients with an initial rejection who had a subsequent approved cariprazine claim within 30 days after initial rejection were allocated to the approved cohort to allow patients with approved prior authorizations to still be analyzed in the approved cohort.

Outcomes

Outcomes were evaluated during the follow-up period and included all-cause and MH-related HCRU, consisting of hospitalizations, ED visits, and outpatient visits. MH-related HCRU visits were defined as visits containing a claim with a primary or secondary International Classification of Diseases, Ninth Revision or International Statistical Classification of Diseases, Tenth Revision diagnosis code for an MH-related condition (eAppendix Table 3).

Treatment patterns were also analyzed. Cariprazine-related treatment patterns included cariprazine use after initial rejection, time to first dispensing, number of dispensings, and days of supply per dispensing. The duration of cariprazine treatment was also analyzed and was defined as the number of days from the first approved cariprazine dispensing to the end of the days’ supply of the last approved cariprazine dispensing prior to the end of follow-up. Time to other AA use after cariprazine rejection was also assessed, as was the use of antidepressants, mood stabilizers/anticonvulsants, or other therapies (ie, serotonin-norepinephrine reuptake inhibitors [SNRIs], monoamine oxidase inhibitors [MAOIs], adjunctive selective serotonin reuptake inhibitors, and bupropion, clonazepam, ketamine, armodafinil, modafinil, and first-generation antipsychotics).

Statistical Analysis

Patients in the rejected cohort were matched 1:2 to patients in the approved cohort based on their propensity scores, using random selection within each of the 10 deciles of the propensity score distribution of the combined cohorts. Variables included in the propensity calculation were age at the index date, sex, race or ethnicity, annual household income, region, year of index date, commercial insurance type, physician specialty of cariprazine prescriber, baseline Quan-Charlson comorbidity index score,²³ baseline medication use, number of AAs used in the baseline period, psychotherapy during the baseline period, psychiatric diagnostic evaluation during the baseline period, all-cause and MH-related HCRU during the baseline period, plan-paid pharmacy costs during the baseline period, and comorbidities of interest with a prevalence of 5% or greater (ie, Elixhauser comorbidities,²⁴ Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] comorbidities, select BP-I disorder comorbidities, and MH-related comorbidities). The propensity score distributions are reported in eAppendix Figure 2. The balance of baseline patient characteristics between the matched approved and rejected cohorts was assessed using standardized differences, with a difference of more than 10% considered to be an important difference.^25-27 HCRU was reported as rates per patient-year (PPY) and compared between matched cohorts using rate ratios (RRs); 95% CIs and P values were calculated using nonparametric bootstrap procedures with 499 replications.²⁸ For all outcomes, P values below .05 were considered evidence of statistically significant results. Treatment patterns were evaluated descriptively using mean and SD values for continuous variables and frequencies and proportions for categorical variables. Where applicable, treatment patterns were compared between the matched cohorts using standardized differences.

RESULTS

A total of 566 patients were included in the rejected cariprazine claim cohort, and 1132 matched patients were included in the approved cariprazine claim cohort (Figure 1). Baseline demographics and clinical characteristics were balanced across matched cohorts; the mean age was approximately 42 years, and the majority of patients were female (Table 2). In both cohorts, the mean (SD) follow-up period was 1.8 (1.2) years. Baseline comorbidities were also similar between matched cohorts (eAppendix Table 4). In the rejected claim cohort, patients’ initial cariprazine claim was rejected most commonly due to formulary noncoverage (n = 294; 51.9%), followed by prior authorization requirement (n = 246; 43.5%) and step therapy requirement (n = 26; 4.6%).

HCRU

Patients with an initial cariprazine claim rejected for a formulary-related reason had significantly higher rates of all-cause and MH-related hospitalizations PPY than patients whose first cariprazine claim was approved (Figure 2 [A]). Compared with patients in the approved cohort, patients in the rejected cohort experienced a 61% higher rate of all-cause hospitalizations and an 89% higher rate of MH-related hospitalizations (all-cause RR, 1.61; 95% CI, 1.15-2.32; P = .012; MH-related RR, 1.89; 95% CI, 1.18-2.89; P = .016).

Compared with patients in the approved cohort, patients in the rejected cohort had numerically higher rates of all-cause and MH-related ED visits PPY, although differences between cohorts were not statistically significant (Figure 2 [B]). Similar trends were observed for outpatient visits (all-cause RR, 1.08; 95% CI, 0.91-1.26; P = .397; MH-related RR, 1.14; 95% CI, 0.92-1.40; P = .216) (Figure 2 [C]), including the subset of office/clinic visits (all-cause RR, 1.08; 95% CI, 0.88-1.29; P = .469; MH-related RR, 1.16; 95% CI, 0.89-1.48; P = .228).

Treatment Patterns

Table 3 summarizes treatment patterns of rejected and approved cohorts during follow-up. In the rejected cohort, 68.4% of patients never received cariprazine after an initial rejection. Of the 31.6% of patients who did eventually receive cariprazine during follow-up, the mean time to first dispensing was approximately 6 months (181 days) after the initial rejection. Further, patients in the rejected cohort had a higher mean number of antidepressant switches (1.92 vs 1.80 in the approved cohort; standardized difference, 10.0%) during follow-up. The use of mood stabilizers/anticonvulsants and other therapies (eg, SNRI/MAOI, clonazepam, nonpharmacotherapy) was generally similar between cohorts; the use of SNRI/MAOI therapy was slightly higher in the rejected cohort (n = 261; 46.1%) vs the approved cohort (n = 463; 40.9%; standardized difference, 10.5%) (eAppendix Table 5).

DISCUSSION

To our knowledge, this retrospective claims database study is the first to examine the effects of formulary-related rejections of cariprazine for the adjunctive treatment of MDD. Our results showed that patients whose initial cariprazine claim was rejected for a formulary-related reason and who had a subsequent approved AA claim experienced a 61% higher rate of all-cause hospitalizations and an 89% higher rate of MH-related hospitalizations relative to patients whose initial claim was approved. For the 32% of patients in the rejected cohort who subsequently received cariprazine, the mean time to first dispensing was approximately 6 months from the initial rejection. Additionally, compared with patients whose initial cariprazine claim was approved, patients with rejected initial claims and subsequent AA treatment used a slightly higher number of different antidepressant medications during follow-up. This could be indicative of a greater frequency of antidepressant switching, which is associated with negative outcomes.^29,30 However, we did not evaluate lines of therapy in this analysis because it was beyond the scope of the study. Overall, these results highlight the potential downstream effects associated with restricting access to cariprazine for the adjunctive treatment of MDD among patients who receive AA treatment (after initial rejection in the rejected cohort and at approval for the approved cohort).

Our findings align with those from a similarly designed study that assessed the effects of formulary restrictions of cariprazine for the treatment of BP-I disorder.²¹ In that study, rates of all-cause and MH-related hospitalizations were also significantly higher for patients with rejected vs approved initial cariprazine claims.²¹ Hospitalizations for MDD are burdensome to patients, caregivers, and the health care system, and they contribute substantially to the economic burden of MDD in the US.^1,31,32 Previous research demonstrates that certain clinical events, such as MDD-related hospitalizations, exacerbate health care costs. In a claims database analysis, Cutler et al reported that patients who experienced an MDD-related hospitalization had 2.2 times the follow-up costs relative to patients with MDD without this event.³² Given the high costs associated with hospitalizations,^31,32 any pharmacy savings associated with formulary restrictions may be outweighed by additional medical costs due to inpatient hospital visits. Although the exact reasons for the higher rate of hospitalizations in the rejected cohort could not be determined from this analysis, efficacy and/or tolerability issues with treatment may have played a role. Our findings of significantly increased hospitalizations in the rejected cohort relative to the approved cohort are concerning and highlight the need for broad access to effective treatment regimens for patients with MDD.

Given the complexity of effectively managing MDD,³³ especially in the context of inadequate response to a first-line medication, the additional challenges and subsequent treatment delays associated with formulary restrictions warrant consideration by payers. Although one of the reasons for formulary restrictions is to promote cost savings without compromising the quality of care, restricting access to newer AAs approved for the adjunctive treatment of MDD may present administrative barriers (eg, prior authorization requirement). These barriers could unintentionally delay the receipt of treatment and negatively affect patient outcomes. Patients in our study who eventually received another AA after an initial formulary-related cariprazine rejection experienced an average delay of approximately 4.5 months. In previously published claims database analyses, Jain et al found that AAs are used infrequently as adjunctive MDD therapy and, when received, are prescribed more than a year after initial antidepressant treatment on average.^30,33 Delays in adequate MDD treatment and the persistence of depressive symptoms may lead to prolonged patient suffering, higher risk of relapse, more rapid relapse, higher suicide risk, increased time to remission, increased costs, and increased risk for future depressive episodes.^34-38 Because the efficacy and tolerability of AAs vary across patients,¹⁸ restricting access to newer AAs for MDD could contribute to an increased number of treatment regimens and treatment cycling. Evidence of this may have been seen in our study, as patients whose first cariprazine claim was rejected had slightly more antidepressant switches during follow-up than those whose initial cariprazine claims were approved. The consequence of multiple treatment switches was illustrated in the STAR*D trial (NCT00021528), a multicenter, prospective, randomized, multistep study analyzing the rates of remission of outpatients with MDD. Results of the STAR*D trial suggested that the likelihood of achieving remission decreases with subsequent treatment steps,²⁹ underscoring the importance of identifying and ensuring access to effective treatment regimens early in the course of MDD treatment and addressing inadequate response to initial ADT in a timely manner.

Limitations

To our knowledge, this study is the first to examine the effects of formulary restrictions on cariprazine for the adjunctive treatment of MDD. The use of claims data was useful for providing insight into treatment patterns and HCRU. However, our analysis was subject to limitations that should be taken into consideration when evaluating the results of our study. To begin, our sample selection required patients in the rejected cohort to receive another AA (cariprazine or other) after the initial rejection in order to balance cohorts in terms of disease severity and treatment needs. As such, our study did not compare all patients with an approved or rejected cariprazine claim but rather compared approved patients with rejected patients with a later approved AA claim. This also prevented us from assessing the number of patients who never received any adjunctive therapy following an initial cariprazine rejection. Second, the AA used after rejection was not required to be adjunctive (ie, did not require ≥ 14 days of overlapping supply with ADT), so patients in some cases could have received an AA for another indication besides MDD. Third, the requirement for adjunctive ADT post index may also have resulted in selection bias by selecting for patients who attended follow-up appointments. However, it should be noted that the rate of outpatient visits was similar between the 2 cohorts, indicating this likely affected both cohorts equally. Fourth, patients in Symphony Health IDV may have been counted as multiple patients if seen by different doctors or offices. As with other open-source claims databases,³⁹ the extent of this potential misclassification is unknown. Symphony Health IDV minimizes this possibility with a linking algorithm; however, it is possible that it could have missed extraneous patient IDs, resulting in underestimation of HCRU at the patient level. In addition, the reason for rejection recorded on pharmacy claims may not always be accurate, potentially resulting in misclassification. Symphony Health IDV also does not have access to eligibility data, which may have limited the complete medical and pharmacy claims from being captured, as patients could have received their medication from a location not captured in the data set (eg, a free clinic/pharmacy) or changed insurance. Patients were also only followed until the end of data availability or the end of clinical activity, with clinical activity defined as at least 1 medical or pharmacy claim per quarter; therefore, patients without health care visits or pharmacy dispensings for long periods of time (ie, 3 months) may have been excluded from the analysis or had censored follow-up. Furthermore, medications not recorded in claims data, such as over-the-counter medications or some medications received during an inpatient stay, are not accounted for in the analysis. Also, evidence of a dispensed medication does not indicate that the medication was consumed or that it was taken as prescribed. Given the lack of paid-amount information for medical claims in the data set, we were also unable to assess health care costs in this analysis. Finally, although propensity score matching on preindex variables was used to account for potential differences between rejected and approved cariprazine claim cohorts, the possibility of unobserved confounding cannot be excluded, particularly given that claims data sets lack information on many important clinical variables.

CONCLUSIONS

Patients with an initial pharmacy claim for cariprazine that was rejected for a formulary-related reason and a following approved AA claim experienced significantly higher rates of all-cause and MH-related hospitalizations than patients with approved initial cariprazine claims for the adjunctive treatment of MDD. Patients with rejected initial cariprazine claims often never received cariprazine, and those who did experienced substantial delays. These findings provide insight into the potential negative downstream effects associated with restricting access to cariprazine for the adjunctive treatment of MDD.

Acknowledgments

Medical writing support was provided by Caroline Warren, PharmD, from Citrus Health Group, Inc (Chicago, IL), and funded by AbbVie.

Author Affiliations: AbbVie, North Chicago, IL (NN), and Florham Park, NJ (MP); Groupe d’analyse, Ltée (FL, SDM, SM), Montréal, Canada; Analysis Group, Inc (EZ), Denver, CO; Wade Outcomes Research and Consulting (SWW), Salt Lake City, UT.

Source of Funding: This study was sponsored by AbbVie.

Prior Presentation: Presented at AMCP Nexus 2023; October 16-19, 2023; Orlando, FL.

Author Disclosures: Dr Nabulsi and Ms Parikh are employed by and may hold stock in AbbVie. Mr Laliberté, Dr Zanardo, Mr MacKnight, and Ms Ma are employed by Analysis Group Inc, which was funded by Allergan (prior to its acquisition by AbbVie) to conduct this analysis. Ms Wade is a partner of Wade Outcomes Research and Consulting and a consultant for AbbVie.

Authorship Information: Concept and design (NN, FL, EZ, SDM, SWW, MP); acquisition of data (NN, EZ); analysis and interpretation of data (NN, FL, EZ, SDM, SM, SWW, MP); drafting of the manuscript (NN); critical revision of the manuscript for important intellectual content (NN, FL, EZ, SDM, SM, SWW, MP); statistical analysis (NN, FL, EZ, SDM, SM); obtaining funding (NN, MP); administrative, technical, or logistic support (EZ); and supervision (NN, EZ, SWW).

Address Correspondence to: François Laliberté, MA, Groupe d’analyse, Ltée, 1190 avenue des Canadiens-de-Montréal, Tour Deloitte, Suite 1500, Montréal, Québec H3B 0G7, Canada. Email: francois.laliberte@analysisgroup.com.

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