AbstractBackground

Several guidelines recommend ongoing clinical monitoring of mood stabilizers. However, only one-third to one-half of patients taking a mood stabilizer are appropriately monitored.

Objectives

This study aimed to determine whether a newly implemented pharmacist-led laboratory monitoring protocol ensures guideline-recommended monitoring of mood stabilizers of inpatients with psychiatric disorders.

Methods

This quasi-experimental, prospective study took place at a single-center and evaluated 120 inpatient adults on a mood stabilizer of any dosage over a 3-month period. A newly implemented, pharmacist-led mood stabilizer laboratory monitoring protocol was used that allowed pharmacists to order guideline-recommended laboratory tests for patients taking a mood stabilizer for a mood disorder. The primary outcome was to identify the number of subjects with pharmacist interventions completed regarding laboratory monitoring of mood stabilizers with protocol utilization.

Results

Pharmacist interventions regarding laboratory or therapeutic drug monitoring of mood stabilizers were completed in 54 of 120 total subjects (45%) included. Seventeen subjects had one or more monitoring tests outside the target parameter(s), regardless of who ordered it. The number of pharmacist recommendations made, other than laboratory intervention per protocol, was 24, of which 15 were accepted by providers (62.5%). Pharmacists ordered 76 tests per protocol including therapeutic drug levels (29.2%), lipid panels (19.2%), liver function tests (5%), thyroid function tests (5%), urinalyses (1.7%), complete blood counts (0.83%), electrolytes (0.83%), renal function tests (0.83%), and fasting glucose levels (0.83%).

Conclusion

In inpatients with psychiatric disorders receiving a mood stabilizer for a mood disorder, a pharmacist has a beneficial impact on mood stabilizer monitoring in accordance with guideline recommendations.

BackgroundBipolar disorder (BD) is reported to be the sixth leading cause of disability worldwide in those aged 15-44 years old.1Strategies for monitoring outcomes in patients with bipolar disorder. Although schizoaffective disorder is rare, it is also found to be one of the most debilitating disease states. First-line recommended treatment for these debilitating disorders includes management with a mood stabilizer such as lithium, divalproex, lamotrigine, carbamazepine, and oxcarbazepine.2Yatham L.N. Kennedy S.H. Parikh S.V. et al.Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. In addition, evidence shows mood stabilizers can treat resistant depression and borderline personality disorder. Lifelong treatment of mood disorders is often required for patients to mitigate negative outcomes of the disease and to prevent relapses, hospitalization, functional impairment, and suicide.3Mannapperuma U. Galappatthy P. Jayakody R.L. Mendis J. de Silva V.A. Hanwella R. Safety monitoring of treatment in bipolar disorder in a tertiary care setting in Sri Lanka and recommendations for improved monitoring in resource limited settings. Unfortunately, studies show that 60% of patients with BD are nonadherent to their medications, and the lifetime risk of recurrence of mood episodes is approximately 90% in individuals who have had a single manic episode.1Strategies for monitoring outcomes in patients with bipolar disorder.,4Gaudiano B.A. Weinstock L.M. Miller I.W. Improving treatment adherence in bipolar disorder: a review of current psychosocial treatment efficacy and recommendations for future treatment development. Therefore, it is important to manage these patients appropriately.A crucial part of maintenance treatment with these mood stabilizers is ongoing laboratory monitoring to improve clinical outcomes and medication adherence, detect early symptoms of recurrence, and reduce adverse drug reactions.2Yatham L.N. Kennedy S.H. Parikh S.V. et al.Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. These recommendations are given by several organizations such as the International Society for Bipolar Disorders,5Ng F. Mammen O.K. Wilting I. et al.The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments. Canadian Network for Mood and Anxiety Treatments,2Yatham L.N. Kennedy S.H. Parikh S.V. et al.Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. and National Institute for Clinical Excellence.6Bipolar disorder: assessment and management. Safety and effectiveness monitoring is especially important for lithium and carbamazepine, given that they possess a narrow therapeutic index. Minor alterations in plasma concentrations can have substantial clinical impacts.4Gaudiano B.A. Weinstock L.M. Miller I.W. Improving treatment adherence in bipolar disorder: a review of current psychosocial treatment efficacy and recommendations for future treatment development. In addition, mood stabilizers can cause metabolic adverse effects. For example, lithium has been associated with acute and chronic renal failure.3Mannapperuma U. Galappatthy P. Jayakody R.L. Mendis J. de Silva V.A. Hanwella R. Safety monitoring of treatment in bipolar disorder in a tertiary care setting in Sri Lanka and recommendations for improved monitoring in resource limited settings. All of the mentioned mood stabilizers have at least one boxed warning for serious adverse effects, which further justifies the need to regularly monitor these patients.3Mannapperuma U. Galappatthy P. Jayakody R.L. Mendis J. de Silva V.A. Hanwella R. Safety monitoring of treatment in bipolar disorder in a tertiary care setting in Sri Lanka and recommendations for improved monitoring in resource limited settings.Toxicity, such as agranulocytosis, aplastic anemia, and dermatologic reactions, can be minimized, and medication adherence can be assessed with standard recommended monitoring.3Mannapperuma U. Galappatthy P. Jayakody R.L. Mendis J. de Silva V.A. Hanwella R. Safety monitoring of treatment in bipolar disorder in a tertiary care setting in Sri Lanka and recommendations for improved monitoring in resource limited settings. According to guideline recommendations, there are several laboratory tests to monitor.5Ng F. Mammen O.K. Wilting I. et al.The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments., 6Bipolar disorder: assessment and management., 7Thompson Micromedex
HealthCare series. DRUGDEX Evaluations. Lithium. Copyright., 8Thompson Micromedex
HealthCare series. DRUGDEX Evaluations., 9Thompson Micromedex
HealthCare series. DRUGDEX Evaluations., 10Thompson Micromedex
HealthCare series. DRUGDEX Evaluations., 11Thompson Micromedex
HealthCare series. DRUGDEX Evaluations. However, only one-third to one-half of patients taking a mood stabilizer are appropriately monitored.12Cullison S.K. Resch W.J. Thomas C.J. How should you use the lab to monitor patients taking a mood stabilizer?. In fact, studies have shown some patients have received no therapeutic drug monitoring at all despite these guideline recommendations.13Ooba N. Tsutsumi D. Kobayashi N. et al.Prevalence of therapeutic drug monitoring for lithium and the impact of regulatory warnings: analysis using Japanese claims database.,14Marcus C.S. Olfson M. Pincus H.A. et al.Therapeutic drug monitoring of mood stabilizers in Medicaid patients with bipolar disorder.Pharmacy interventions have been shown to elevate the standard of care and prevent potentially life-threatening events.15Chin J.M. Muller R.J. Lucarelli C.D. A pharmacy intervention program: recognizing pharmacy’s contribution to improving patient care. Additionally, clinical monitoring of medications is essential to achieve positive outcomes across the continuum of care and is an integral factor of comprehensive medication management.16ASHP statement on the pharmacist’s role in clinical pharmacokinetic monitoring. Ratanajamit et al., demonstrated the importance of these 2 components, focusing on how pharmacists can intervene on anticonvulsant montioring.17Ratanajamit C. Kaewpibal P. Setthawacharavanich S. Faroongsarng D. Effect of pharmacist participation in the health care team on therapeutic drug monitoring utilization for antiepileptic drugs. The authors of the study found higher rates of anticonvulsant monitoring during a pharmacist intervention period than a period with no pharmacist intervention. This difference was found to be statistically significant, and the authors concluded that the pharmacist intervention period improved appropriateness of therapeutic drug monitoring and reduced unnecessary costs.17Ratanajamit C. Kaewpibal P. Setthawacharavanich S. Faroongsarng D. Effect of pharmacist participation in the health care team on therapeutic drug monitoring utilization for antiepileptic drugs. Of note, this study did not target inpatients with psychiatric disorders. Pharmacists play an essential role within the comprehensive medication management process, and they can help to ensure safety and effectiveness of medications that require extensive monitoring.Objectives

The purpose of this study was to determine whether a newly implemented pharmacist-led laboratory monitoring protocol ensures guideline-recommended monitoring of mood stabilizers in inpatients with psychiatric disorders.

MethodsStudy design

This prospective quasi-experimental study occurred from November 2, 2020, to January 31, 2021. It took place at a 90-bed inpatient psychiatric institution located within a 250-bed, level 3 trauma community hospital located in an industrial suburb of Ohio.

Inclusion and exclusion criteria

Subjects were included in this study if they were admitted to the study institution, were on a mood stabilizer of any dosage for a mood disorder, and were between the ages of 18 and 89 years. Subjects were excluded if they tested positive for coronavirus disease 2019 (COVID-19) at the time of this study. For purposes of the study design and data tracking, subjects were excluded if they were on more than one study protocol mood stabilizer and if they were on this mood stabilizer for an indication other than a mood disorder.

Study procedureThere was not a protocol in place to monitor mood stabilizers for patients admitted at the study site. Hence, a pharmacist-led protocol outlined in Table 1 was developed before the start of the study to better comply with guideline-recommended monitoring. This newly developed pharmacist-led protocol was approved by the institution’s Pharmacy and Therapeutics Committee and the Medication Executive Committee. After approval of the monitoring protocol for hospital use, the institutional review board granted study approval. Based on the protocol, the pharmacist would then review patient charts daily to determine eligibility for inclusion by reviewing an Epic-run report of inpatients prescribed a mood stabilizer. Adherence was confirmed with the medication administration report. Those included in the study were reviewed daily during their inpatient stay. Based on the study protocol, the pharmacist determined what parameter to order and what recommendations to make to the provider after evaluating each subject’s laboratory results. Qualitative variables were collected and included subject age, subject gender, monitoring tests ordered by a pharmacist per protocol, monitoring test results outside the guideline-recommended range, and pharmacist recommendations accepted or rejected.Table 1Pharmacist-led protocol for laboratory monitoring of mood stabilizers7Thompson Micromedex
HealthCare series. DRUGDEX Evaluations. Lithium. Copyright., 8Thompson Micromedex
HealthCare series. DRUGDEX Evaluations., 9Thompson Micromedex
HealthCare series. DRUGDEX Evaluations., 10Thompson Micromedex
HealthCare series. DRUGDEX Evaluations., 11Thompson Micromedex
HealthCare series. DRUGDEX Evaluations.Laboratory monitoring protocolThe pharmacist-led protocol was designed to include all guideline-recommended tests for each drug and the time intervals that each of these tests should be monitored as defined in Table 1.Outcome measuresThe primary outcome was to identify the number of times a pharmacist ordered laboratory monitoring of mood stabilizers based on a newly implemented pharmacist-led protocol. Pharmacist intervention in this study was defined as when the pharmacist ordered a recommended test based on the developed protocol. Secondary outcomes included the percentage of subjects outside of the target range of monitoring parameters in the pharmacist-led protocol, any recommendations made to the providers based on pertinent test results, and the number of recommendations accepted by providers. Recommendations included dose change, additional drug therapy such as a statin, repeat laboratory monitoring owing to drug interaction, and discontinuing therapy as outlined in Table 2.

Table 2Pharmacist recommendations made based on laboratory results

Statistical analysis

Data were collected and assessed using descriptive statistics owing to the study not including a comparator group before the implementation of the pharmacist-led laboratory monitoring protocol.

ResultsEligibility assessment

A total of 179 subjects were admitted to the study institution on a mood stabilizer and were assessed for study inclusion. Of these 179 subjects, 120 subjects were eligible for inclusion, and 59 subjects required exclusion from the study. Of 59 subjects, 34 subjects were excluded owing to the mood stabilizer being indicated for something other than a mood disorder. Other indications most commonly included epilepsy or seizure history, alcohol withdrawal, or agitation in dementia. Of 59 subjects, 15 subjects were excluded solely owing to COVID-19 diagnosis at the time of admission. In addition, 7 subjects were excluded for taking more than one mood stabilizer concomitantly, and 3 subjects were excluded both for taking more than one mood stabilizer concomitantly and for their use in a diagnosis other than a mood disorder.

Baseline characteristics

Of the 120 subjects included in the study, the mean age of study subjects was 37.5 years, with a range of 18-72 years. The study consisted of 63 males (52.5%) and 57 females (47.5%). The breakdown of the number of subjects on each mood stabilizer was 65 divalproex (54.2%), 23 lithium (19.2%), 18 lamotrigine (15%), 10 oxcarbazepine (8.3%), and 4 carbamazepine (3.3%).

Primary outcome

The primary outcome illustrated that 52 of the 120 subjects (43%) included in this study required pharmacist laboratory monitoring intervention. Of the 53 subjects, 41 were on divalproex (78.8%), 9 were on lithium (17.3%), and 2 were on carbamazepine (3.8%).

Secondary outcomesSecondary outcomes revealed that 17 subjects (14.2%) had results outside of the guideline-recommended range. Of 21 laboratories, 17 subjects were out of range. Of these 21 laboratories, 12 laboratories (57.1%) out of range were ordered by a pharmacist, and 19 pharmacist recommendations were made regarding these laboratories. In total, the pharmacist made 24 recommendations, including recommendations based on laboratory results and other recommendations to optimize mood stabilizer therapy. Of the 24 recommendations, 15 were accepted by providers (62.5%). As seen in Table 2, the most common recommendation made by pharmacists to providers based on laboratory results was to increase the mood stabilizer dose, occurring 11 times. Of these recommendations, 5 were accepted by providers (41.1%). Another common recommendation made by pharmacists based on laboratory results was to either add a statin or increase the dose of the subject’s existing statin, occurring 5 times. Of these recommendations regarding statins, 3 were accepted by providers (60%). Other laboratories-based recommendations made by pharmacists included to decrease the mood stabilizer dose, provide patient education, re-time a drug level, repeat liver function tests, order a level to assess toxicity because of a drug interaction, discontinue the drug or change the therapy, and draw the drug level 4-5 days after therapy initiation or dose change to allow for drug concentrations to reach steady state. Each of these recommendations was accepted by the provider except for the last one.Breakdown of appropriate laboratory monitoring

There were a total of 756 total recommended tests to be monitored from the 120 subjects included in the study. Of these, 81 were ordered (10.7%) by a pharmacist per study protocol, and 24 recommendations were made by a pharmacist when reviewing all tests. This is a total of 105 interventions made by a pharmacist.

Of the total 120 subjects, 5 subjects (4.2%) refused laboratory draws, and 116 subjects (96.7%) had all recommended tests appropriately ordered. Of the 4 subjects who were inappropriately monitored, 3 were because the provider ordered levels to be drawn before the drug reached steady state. The fourth was because a thyroid stimulating hormone was missed owing to attempts to minimize laboratories draws for the subject.

Subgroup analysis

An intervention is defined as any laboratory interventions made per protocol and any recommendations made based on laboratory results. The most common mood stabilizer intervened on by a pharmacist was divalproex, with 41 subjects on divalproex (63.1%) requiring pharmacist intervention. This is followed by lithium with 9 subjects on lithium (39.1%) having pharmacist intervention and then carbamazepine with 2 subjects on carbamazepine (50%) having pharmacist intervention. Lamotrigine and oxcarbazepine, the 2 mood stabilizers with the lowest number of guideline-recommended tests to be monitored, had no pharmacist intervention required to comply with guideline-recommended monitoring.

Subjects on divalproex had the highest number of total interventions by a pharmacist, which included 79 of the total 105 pharmacist interventions (75.2%). This is followed by lithium with 9 (39.1%) and then carbamazepine with 2 (1.9%). For both divalproex and lithium, the most common laboratory intervention made by a pharmacist was serum drug level monitoring, with this test encompassing 6 of the total 24 lithium (25%) interventions and 32 of the total 79 divalproex interventions (40.5%). In addition to drug level monitoring for lithium, pharmacists most commonly intervened on thyroid function monitoring, of which 6 of all 24 pharmacist interventions (25%) on lithium were made. Lipid panels and liver function tests were most commonly ordered by a pharmacist per protocol for divalproex monitoring, encompassing 24 (30.4%) and 6 (7.6%), respectively, of all 79 pharmacist interventions completed on divalproex. Pharmacist interventions other than ordering a laboratory test per protocol included 7 of all 24 lithium interventions (29.2%) and 17 of all 79 divalproex interventions (21.5%). All 24 of the pharmacist recommendations discussed in the Secondary Outcomes section were solely for lithium and divalproex. Regarding the pharmacist interventions on the 4 subjects taking carbamazepine, the pharmacist ordered one drug level and one urinalysis per protocol to ensure guideline-recommended monitoring.

The most commonly ordered test per protocol was a therapeutic drug level, which was done on 35 subjects (29%). Other tests most commonly ordered by a pharmacist included lipid panels on 23 subjects (19.2%), liver function tests on 6 subjects (5%), thyroid function tests on 6 subjects (5%), and a urinalysis on 2 subjects (1.7%). All other tests per protocol, except for weight and pregnancy monitoring, did additionally require pharmacist intervention, but each only occurred on one subject (0.83%).

Discussion

The results of this study demonstrate potential areas of improvement in clinical practice. A primary area that could be targeted is pharmacist-led provider education, particularly on the importance of waiting for the drug to reach steady state before drawing a drug level. Early serum drug level monitoring may lead to inappropriate dose increases and toxic drug levels at steady state. Pharmacist-led provider education could also be used to emphasize the importance of medical management for patients on psychiatric medications. For example, a common recommendation made by a pharmacist in this study was to add a statin or increase a statin dose based on laboratory results and guideline recommendations. However, only 60% of these were accepted by providers. This was possibly caused by the provider specialty given that not all patients were seen by an internal medicine specialist while enrolled in the study period.

The study design was a strength because the direct impact of a pharmacist on patient care was able to be evaluated prospectively, and the pharmacist could appropriately intervene without previous approval from the physician. In addition, all interventions were documented in the patient chart for ease of tracking intervention, and evaluation for study inclusion eligibility and laboratory monitoring follow-up was completed daily.

This study took place during the COVID-19 pandemic, and these patients had to be excluded owing to the uncertainty of the disease impact on mood stabilizer monitoring. Other limitations include patient laboratory draw refusals, which limited the ability to best monitor their mood stabilizer, and late laboratory draws, which has the potential to interfere with true trough concentrations. In addition, the external validity of this study is limited because of the single-center setting.

If this study were to be repeated, the authors recommend a larger sample size to better assess the impact of a pharmacist on each monitoring test and mood stabilizer. In addition, a pre-intervention period may be considered to use as a comparator and evaluate statistical significance of the pharmacist-led protocol. To improve patient acceptance with laboratory draws and further improve monitoring, attempts should be made to minimize the number of laboratory draws per patient. Patient education may help to improve laboratory draw acceptance, as well, and could be used more frequently in a study like this one. A potential area of growth for therapeutic monitoring of psychiatric medications is to expand to pharmacist-led antipsychotic monitoring, given that they, like mood stabilizers, also have several guideline-recommended monitoring parameters, a large potential for adverse effects, and low adherence rates.

Conclusion

Pharmacists prompted treatment monitoring in nearly half of inpatients (45%) on a mood stabilizer. Pharmacists ordered monitoring tests that may not have otherwise been checked, particularly with therapeutic drug levels, thyroid tests, lipid panels, and liver function tests. In addition, pharmacists intervened and made recommendations for mood stabilizers, particularly divalproex, lithium, and carbamazepine, based on current guidelines. In conclusion, the authors recommend expanding provider education regarding mood stabilizer monitoring. It is critical that pharmacists additionally continue to advocate and to ensure close monitoring or mood stabilizers to improve patient response, tolerability, and adherence.

Acknowledgments

The authors would like to acknowledge Karen Kier, PhD, MSc, BSPharm, BCPS, BCACP, CTTS, FASHP, FCCP.

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J Med Assoc Thai. 92: 1500-1507Biography

Krista Horvath, PharmD, Patient Care Pharmacist, Mount Carmel East Hospital, Columbus, OH; at time of study: Postgraduate Year 1 Pharmacy Practice Resident, Mercy Health St. Charles Hospital, Oregon, OH

Masa Scott, PharmD, BCPS, BCPP, Inpatient Behavioral Health Pharmacist, Mercy Health St. Charles Hospital, Oregon, OH

Article InfoPublication History

Published online: June 24, 2022

Accepted: June 20, 2022

Received: December 19, 2021

Publication stageIn Press Journal Pre-ProofFootnotes

Disclosure: The authors declare no relevant conflicts of interest or financial relationships.

Previous presentations: This study has been presented at the American Society of Health-System Pharmacists 2020 Virtual Midyear Clinical Meeting on December 10, 2020; Mercy Health 2021 Virtual Research Symposium: Original Research Category Fourth Place Winner on May 19, 2021; and at the 2021 Ohio Pharmacy Residency Virtual Conference on May 21, 2021.

ORCID

Krista Horvath: https://orcid.org/0000-0002-3811-3110

Masa Scott: https://orcid.org/0000-0002-5511-4676

Identification

DOI: https://doi.org/10.1016/j.japh.2022.06.009

Copyright

© 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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