Formulary management for psychotropic medications can be more difficult compared to other medication classes, as the same medications can produce significantly different results in individual patients. This article reviews various factors which should be examined when deciding which antipsychotics to include on a formulary.

With an ever-increasing availability of medications, each with its own safety and efficacy profile, a formulary system is the key to the development of an effective medication-use policy within health-systems. The American Society of Health-System Pharmacists (ASHP) has issued a statement to guide the development of a formulary system to optimize patient care by allowing access to appropriate medications.1 A formulary is a list of medications and related information developed and continually updated based on the clinical judgment of healthcare professionals on the treatment of disease. The formulary system, administered by the Pharmacy and Therapeutics (P&T) committee, is the ongoing process utilized by health organizations to establish policies on medically appropriate drug use, based on patient safety, medication efficacy, therapeutic need, and cost effectiveness.1 

Medication-use policies should promote evidence-based, clinically appropriate, safe, and cost-effective medication therapy. Ideally, a P&T committee utilizes a systematic approach to the evaluation, selection, and therapeutic use of medications to achieve this goal. The committee oversees the creation of programs that ensure safe and effective medication therapy, utilizing representatives from appropriate specialties in the development of protocols and pathways. The committee also coordinates communication and education of staff regarding all aspects of the formulary system. Performance improvement activities, adverse drug reactions, medication errors, and the dissemination of this information are also duties of the P&T committee.1 Ultimately, the P&T committee is responsible for supervising the appropriate use of medications in the health care system.

The minimization of therapeutic duplications and the utilization of generic and therapeutic equivalents, which can provide financial benefits for the system, is a key focus in formulary management. Therapeutic duplications, or medications used to treat the same clinical indication with no advantage over available alternative agents are avoided to prevent errors and aid in cost savings. Therapeutic duplications include “me-too” drugs, which remain controversial given that mechanism of action and efficacy are usually identical between agents, with little to no demonstrated clinical advantage of one over the other. Ideally, one preferred agent would be identified and included on the health system's formulary, while other “me-too” agents would be non-preferred medications. With psychotropic drugs, however, elimination of similar agents is controversial, and this difficulty must be weighed against the need to contain healthcare costs.

Formulary management for drugs used to treat mental illness can be more difficult compared to other medication classes. Mental illness displays significant biologic heterogeneity, with the same medication producing significantly different results for individual patients. Patients may fail to respond to one agent within a specific class, but then improve with another despite a similar mechanism of action.2 Currently there are no good predictors for which patient will respond to which medication.3 This means most patient medication regimens are determined through trial and error, rather than a “one-size-fits-all” approach.2 Further, patient-specific factors, including illness duration, history of prior response, prominent symptoms, comorbidities, and financial situation, may impact response to treatment.

Drug specific factors that can potentially alter patient response to treatment include toxicity, efficacy, side effects, cost, route of administration, and drug interactions. Other considerations include storage requirements, required monitoring, ease of reconstitution/administration, and frequency of administration. Rapid onset, availability of multiple formulations, limited drug-drug interactions, and no dose adjustments in renal or hepatic impairments are all favorable drug characteristics that clinicians may consider when determining formulary placement.4 Other factors that affect drug selection include provider familiarity with certain products and, at times, even patient request.5 

The consideration of drug, patient, and provider factors becomes particularly important within the mental health field, where it becomes increasingly difficult to limit medications to patients who struggle with chronic mental illness. Although antipsychotic agents all possess a similar primary mechanism of action, they are very unique in pharmacology, pharmacokinetics, adverse effect profile, and approved indications for use. Head to head comparison data are distinctly lacking; no agent has proven superiority over another, with the exception of clozapine in treatment-resistant schizophrenia.6 The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial failed to demonstrate a difference in clinical effectiveness, defined as time to all-cause discontinuation, between the first generation agent perphenazine, and several second generation agents. While patients remained on olanzapine therapy longer than other agents, patients were more likely to discontinue olanzapine due to intolerability and it was associated with more metabolic side effects.7 Because of this, determining which antipsychotic medications should be included on a health system's formulary can be difficult. Understanding the potential advantages and disadvantages of each agent is imperative given that medication is one of the few factors that can be directly modified by the health care team in the treatment of mental illness.4 

Because comparative data are limited, formulary managers and the P&T committee must weigh safety, tolerability, and cost when deciding on formulary placement of antipsychotic agents. Indications for use, both approved and off-label, and the supporting data when debating inclusion in the formulary, must also be taken into consideration. With regard to safety, an ideal medication would have no associated toxicity or side effects. However, this is not the reality, as the currently available antipsychotic agents display a wide variety of problematic and unwanted adverse effects. Extrapyramidal side effects, including tardive dyskinesia, are disturbing potential consequences of antipsychotic therapy that can significantly and potentially permanently impact a patient's quality of life. Metabolic side effects, including weight gain, lipid abnormalities, and glucose dysregulation, are adverse effects of antipsychotic drug therapy and can contribute to the morbidity and mortality of patients with mental illness. The extent to which each antipsychotic agent may impact the QT interval is variable, and is an important consideration in patients with a baseline prolonged QTc or who are prescribed other QTc-prolonging drugs. Other unwanted side effects, including sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension can lead to non-compliance in a patient population that already has difficulties with medication adherence.4,8–11 

Having the opportunity to select an agent from a large pool, based on risk of side effects and patient choice, may offer advantages in terms of provider independence and patient satisfaction. However, drug cost is an important factor that cannot be ignored in the face of steadily increasing health care costs. With the exception of the newest antipsychotics, most agents are available as generic products at significantly lower prices than brand name products. Formulary managers are left with the difficult task of weighing patient and drug factors against cost when considering specific antipsychotics for inclusion on the formulary.

One might assume that the newest antipsychotic agents, including iloperidone, lurasidone, and asenapine, offer advantages in comparison to older agents with regards to safety, efficacy, and tolerability. However, there is little to no literature to support this assumption, though each agent has its own unique advantages and disadvantages. Lurasidone is approved as monotherapy for bipolar depression, similar only to quetiapine. Asenapine is available only in a sublingual formulation, which may be helpful for some patients who have difficulty swallowing tablets. These agents also appear to have a lower propensity for clinically significant weight change, glucose, or lipid abnormalities than has been reported for other atypical agents such as olanzapine or clozapine. Lurasidone is dosed once daily, whereas both iloperidone and asenapine require twice daily administration. Unfortunately, iloperidone has a risk of QTc prolongation and requires slow titration to minimize orthostasis, while lurasidone and asenapine are associated with dose-related akathisia.12,13 In terms of cost, these agents are available as brand name only products, offering a distinct disadvantage when compared to generic medications given the lack of clear benefit over other generically available agents. Similar debates exist when considering second-generation long-acting injectable antipsychotics. Though there are no direct comparisons, the agents differ significantly in regard to approved indications, requirements for oral supplementation, reconstitution and storage requirements, post-injection observation period, drug-drug interactions, and adverse reactions.14–17 For these medications, cost is only a fraction of what must be considered when deciding on which to include on formulary.

The decision of where to place newer antipsychotics on a health care system's formulary is complicated. Antipsychotics differ most in the side effect profile rather than in effectiveness.2 There are also differences in dosing frequency and ease of administration which must be considered. Inter-patient responsiveness to medications is unpredictable, both in terms of adverse effects and effectiveness. It seems reasonable to recommend a limited number of generic antipsychotics with varying side effect profiles and routes of administration as first-line formulary agents to offer patients and providers treatment options while maximizing cost-effectiveness. Brand-name only medications would be relegated to second tier, or non-preferred agents, keeping in mind that mental health treatment must always be individualized. Until there is evidence that the newer antipsychotics are superior in their effectiveness and/or safety compared to older agents, there is no clear reason to recommend these agents before older, generic alternatives. More research is needed regarding mechanisms in the psychotic disease processes and adverse effects of the agents utilized in order to make personalized medicine a reality.

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