Inappropriate quetiapine use at a large academic medical center: frequency of misuse and associated costs of adverse effects

Abstract

Background:

Quetiapine is an antipsychotic with dose-related receptor affinity, which is commonly prescribed by specialties outside of psychiatry. Quetiapine can have adverse effects including weight gain, hyperglycemia, and falls. Therefore, quetiapine is a good focus medication to assess the need for an antipsychotic stewardship protocol.

Objective:

To assess the need for an antipsychotic stewardship protocol at a large, urban academic medical center by evaluating quetiapine usage.

Design:

A retrospective review of quetiapine dispensing history for all strengths (immediate release: 25, 50, 100, 200, 300 mg; extended release: 50, 150, 200, 300 mg) over 1 year (1 December 2021 to 30 November 2022) in patients aged 18 and older was conducted at a large, urban academic medical center.

Methods:

An antipsychotic protocol for safe and effective quetiapine use was developed utilizing its package insert, clinical guidelines, and primary peer-reviewed literature. Once identified by prescription fill, a retrospective chart review was completed for quetiapine indication, dose, and frequency. Each prescription was reviewed for appropriateness using the antipsychotic stewardship protocol.

Results:

Out of 521 quetiapine prescriptions for 181 unique patients, 67% of scripts were inappropriate. The costs associated with this inappropriate use were extrapolated to be over $350,000 per year when accounting for long-term harms associated with the development of type 2 diabetes mellitus and falls in older adults.

Conclusion:

Promoting the safe and effective use of antipsychotics through developing and implementing an antipsychotic stewardship protocol may reduce patient harm and associated costs from inappropriate use.

Plain language summary

Inappropriate quetiapine use at a large academic medical center

Psychotropic stewardship aims to improve patient outcomes and minimize side effects associated with psychotropic use – including antipsychotics. Studies have investigated psychotropic stewardship in elderly patients but have not reviewed its utility in the general adult population. Quetiapine is an antipsychotic with dose-related receptor affinity, meaning that at different doses of the medication, it acts on different receptors and exerts different clinical effects as a sedative, antidepressant, or antipsychotic. Quetiapine is commonly prescribed across medical specialties and can have significant adverse effects, including weight gain, hyperglycemia, and falls. Therefore, quetiapine is a suitable focus medication to assess the need for an antipsychotic stewardship protocol.

We developed a protocol for safe and effective quetiapine use utilizing its package insert, clinical guidelines, and primary peer-reviewed literature. We reviewed the dispensing history of quetiapine over one year at two pharmacies at a large, urban academic medical center. Once identified by prescription fill, we completed a retrospective chart review for quetiapine indication, dose, and frequency. We reviewed each prescription for appropriateness using our antipsychotic stewardship protocol.

Of 521 quetiapine prescriptions for 181 unique patients filled over one year, 67% of scripts were inappropriate. We extrapolated the costs associated with this inappropriate use to be over $350,000 per year when accounting for long-term harms associated with quetiapine use, including the development of type 2 diabetes mellitus and falls in older adults.

Our findings illustrate that promoting the safe and effective use of antipsychotics through developing and implementing an antipsychotic stewardship protocol may reduce patient harm and associated costs from inappropriate use. Psychiatric pharmacists are well-positioned to manage these stewardship program’s development, implementation, and dissemination.

Introduction

Approximately one in five adult Americans lives with mental illness. ¹ When psychiatric conditions are undertreated, patients are at risk of poor outcomes, including mortality. ² Psychiatric medications, such as antipsychotics, can be lifesaving when used appropriately but can have undesirable adverse events including weight gain, hyperglycemia, and involuntary movement disorders. ³ In addition, inappropriate psychotropic use can have negative financial consequences to the healthcare system leading to increased cost of care. ⁴ Thus, psychiatric medications should be appropriately managed to prevent adverse patient outcomes, from both undertreatment of mental illness and over-utilization or inappropriate use of psychotropics.

Psychotropic stewardship aims to improve patient outcomes and minimize side effects associated with psychotropic medication use. In 2022, the American Association of Psychiatric Pharmacists developed a vision paper involving the expansion of psychotropic stewardship through the utilization of Board Certified Psychiatric Pharmacists (BCPP) for medication management of psychotropics in partnership with an interprofessional team. BCPPs can utilize their expertise to prevent excess costs and improve patient outcomes through comprehensive medication management and psychotropic stewardship. ⁵

Psychotropic stewardship involving pharmacists has been found to improve outcomes in the geriatric population. Previous literature has shown that a psychotropic team, including a pharmacist, supports psychotropic de-escalation for geriatric patients admitted to the general medicine inpatient team; this multidisciplinary approach was found to be effective in de-escalating psychotropic therapy at discharge. ⁶ In addition, a pharmacist-led initiative to notify prescribers of inappropriate psychotropic medication use in geriatric patients was effective in identifying approximately one patient per week at risk of inappropriate medication use and supported by all involved prescribers for improving their psychotropic prescribing practices. ⁷ When comparing a multidisciplinary team involving a clinical pharmacist to one without, it was found that medication appropriateness, considering both under and overuse of medications, was only statistically significant in the clinical pharmacist intervention group. ⁸ Involving pharmacists on the interprofessional team, to identify inappropriate psychotropic medication usage and recommend adjustments to medication therapy, has improved appropriate psychotropic medication use in the geriatric population. However, there is a gap in the literature for psychotropic stewardship in the general adult population.

Quetiapine is a unique antipsychotic in that it has different clinical effects at different doses, owing to its receptor affinity profile. At low doses (⩽50 mg), it acts as a hypnotic due to strong histamine activity. It begins to have a clinically meaningful affinity for the serotonin receptors at 300 mg and acts like an antipsychotic through dopamine receptor-blocking affinity at higher doses (⩾400 mg). ⁹ Therefore, to correctly treat patients for their psychiatric diagnosis with quetiapine, it is important to have a correct diagnosis and titrate this medication accordingly. Quetiapine can have metabolic side effects including weight gain, hyperglycemia including the development of diabetes mellitus, and dyslipidemia, ¹⁰ which can occur even at low doses.^11,12

Quetiapine is commonly prescribed by physicians outside of the psychiatric setting and typically for off-label indications. ¹³ This prescribing practice is consistent in the internal medicine setting, with many patients initiated on quetiapine for the off-label indication of sleep while admitted to the hospital, and half of these new initiations continued at discharge. ¹⁴ When quetiapine’s use in the family medicine setting was reviewed, it was found that even with its common utilization, family physicians were unaware of the drug’s adverse effect profile. ¹⁵ Quetiapine’s unique pharmacological profile, risk of adverse effects, and common use across medical specialties make it a good initial focus medication to evaluate the need for an antipsychotic stewardship protocol.

In this study, we reviewed quetiapine fill history over 1 year at pharmacies at a large urban academic medical center and assessed the appropriateness of the drug to determine the need for an antipsychotic stewardship protocol. We hypothesized that many of the quetiapine prescriptions would not be in accordance with the internally developed quetiapine protocol. We also assessed the potential for cost savings associated with the implementation of the quetiapine protocol based on alignment with the antipsychotic cost-effectiveness literature.

Methods

Design

This is a retrospective study that occurred at a large urban academic medical center serving a predominantly Medicaid population in the heart of the Los Angeles area. The medical center is a Level-One trauma center with 670 inpatient beds and contains several outpatient specialty clinics including, but not limited to primary care, psychiatry, cardiology, geriatrics, and HIV. In addition, at the medical center are two pharmacies that together fill approximately 1500 scripts per day. Our medical center has a limited number of BCPPs responsible for managing specific psychiatric treatments in subspecialty clinics or inpatient units and is not involved in the verification or dispensing of prescriptions. We assessed the appropriateness of quetiapine use based on an internally developed quetiapine protocol (Appendix 1). A quetiapine protocol was developed with information from various credible resources, including the clinical guidelines for depression, anxiety, schizophrenia, bipolar disorder, and insomnia; the quetiapine package insert; and peer-reviewed literature on quetiapine’s use in clinical practice. The protocol included (1) documentation of a clear and appropriate indication for antipsychotic use; (2) factors that affect the efficacy of a drug, including appropriate dosing for indication; and (3) factors that affect the safety of a drug. This protocol was evaluated by BCPP.

The study’s inclusion criteria are patients 18 years and older who received and filled a prescription for quetiapine from the pharmacies at the medical center between 1 December 2021 and 30 November 2022. Patients under the age of 18 years old at the time of quetiapine prescription fill were excluded from the study. We obtained the fill history for quetiapine in all strengths (immediate release: 25, 50, 100, 200, 300 mg; extended release: 50, 150, 200, 300 mg). Then, we reviewed the electronic medical records to extract the intended quetiapine diagnosis, dose, frequency of administration, and specialty of the physician who prescribed the medication. These data were reviewed for appropriateness in accordance with our quetiapine protocol and coded as ‘appropriate’ or ‘inappropriate’. All data were collected and managed using REDCap, a HIPAA-compliant web-based software platform.^16,17

Analytical strategy

Our analyses utilized descriptive statistics to determine the number of prescriptions in alignment with our protocol, diagnoses associated with quetiapine prescription, and specialties of physicians that prescribed quetiapine. To extrapolate costs associated with quetiapine adverse events, the risk of adverse event development – specifically, development of diabetes mellitus type II (T2DM) and falls in older adults – and associated costs were gathered from the literature. Previous literature has detailed the 20% increased risk of developing diabetes in patients on quetiapine therapy, ¹⁸ and the American Diabetes Association estimates that the average cost per year to patients with diabetes is $9600. ¹⁹ This was applied to our sample by multiplying the number of inappropriate quetiapine prescriptions by the risk and the cost of diabetes (daily and yearly) to estimate the average daily and yearly cost of diabetes associated with inappropriate quetiapine use. The estimation of fall risk was calculated similarly. Studies have shown varying risk of falls in elderly patients on antipsychotics ranging from 4% to 52%.^20,21 Therefore, we used an estimation of the average value of a 23% increased risk of falls. This was multiplied by the number of inappropriate quetiapine prescriptions in patients 65 years and older to estimate the number of yearly falls in elderly patients associated with inappropriate quetiapine use. In addition, the costs of falls in older adults vary based on its outcome – fatal or nonfatal. In 2015, the total cost of fatal falls was estimated to be $754 million, while the cost per nonfatal fall was $9780.^22,23 This was applied to our sample by multiplying the number of inappropriate quetiapine prescriptions in patients 65 years and older by the risk and yearly cost associated with fatal and nonfatal falls to estimate the yearly cost of falls in elderly patients associated with inappropriate quetiapine use.

Results

There were a total of 521 initial fills or refills for quetiapine at the medical center’s two pharmacies from 1 December 2021 to 30 November 2022. Of these fills, there were 181 unique patients that received quetiapine during this 1-year period. Half of the study population were male, Hispanic/Latinx with an average age of 52 years old. Twenty percent of patients were 65 years and older. The most common medical comorbidities were substance use disorder (39%), depressive disorder (29%), hypertension (28%), anxiety disorder (23%), psychotic disorder (20%), and diabetes mellitus (17%) (Table 1).

Table 1.

Demographics and medical comorbidities of adult patients that received at least one quetiapine prescription.

Demographics (N = 181)
Sex, n (%)
Male	100 (55)
Ethnicity, n (%)
Hispanic/Latinx	98 (54)
Non-Hispanic/Latinx	83 (44)
Age, n (%)
18–24	5 (3)
25–34	30 (16)
35–44	27 (15)
45–54	36 (20)
55–64	48 (26)
65–74	18 (10)
75+	18 (10)
Comorbidities, n (%)
Substance use disorder	70 (39)
Depressive disorder	53 (29)
Hypertension	50 (28)
Anxiety disorder	42 (23)
Psychotic disorder	37 (20)
Diabetes mellitus	31 (17)
Bipolar disorder	26 (14)
Post-traumatic stress disorder (PTSD)	25 (14)
Lipid disorder	18 (10)
Seizure disorder	14 (8)
Neurocognitive disorder	12 (7)
Lung disorder	11 (6)
Chronic pain	10 (5.5)
Cerebral Vascular Accident (CVA)	9 (5)
Heart failure	9 (5)
Thyroid disorder	9 (5)
Gastroesophageal Reflux Disease (GERD)/Peptic Ulcer Disease (PUD)	8 (4)
HIV	8 (4)
Homelessness	8 (4)
Osteoarthritis (OA)/ Rheumatoid arthritis (RA)	8 (4)
Personality disorder	7 (4)
Brain trauma	6 (3)
Chronic kidney disease	6 (3)
Insomnia	5 (3)
Pre-diabetes	5 (3)
Unspecified mood disorder	5 (3)
Benign prostatic hyperplasia (BPH)	4 (2)
Cancer	4 (2)
Afib	3 (1.5)
Cerebral palsy	3 (1.5)
Encephalopathy	3 (1.5)
Autoimmune disease	2 (1)
Blindness	2 (1)
Chromosomal abnormality	2 (1)
Genitourinary disorder	2 (1)
Liver disorder	2 (1)
Obstructive sleep apnea (OSA)	2 (1)
Surgical	2 (1)
Attention-deficit/hyperactivity disorder (ADHD)	1 (0.5)
Central DI	1 (0.5)
Clotting disorder	1 (0.5)
Cardiovascular Disease (CVD)	1 (0.5)
Huntington disease	1 (0.5)
Obesity	1 (0.5)
Peripheral Artery Disease (PAD)	1 (0.5)
Birth defect	1 (0.5)

The intended diagnoses for quetiapine use were as follows: schizophrenia (11%), depression (12%), anxiety (5%), bipolar I disorder (6%), bipolar II disorder (1%), sleep (18%), and ‘other’ (47%). Within the ‘other’ category, the most common diagnoses included: unknown diagnosis (17%), unspecified mood disorder (13%), unspecified psychosis (15%), dementia-related agitation (12%), agitation (8%), and delirium (5%) (Figure 1; Table 2).

Figure 1.

Diagnoses associated with quetiapine prescriptions.

Table 2.

Diagnoses for quetiapine from the ‘Other’ category.

‘Other’ diagnoses (N = 103)
Unknown	17
Unspecified psychosis	15
Unspecified mood disorder	13
Dementia-related agitation	12
Agitation	8
Delirium	5
Amphetamine-induced psychosis	4
PTSD	4
Impulse control disorder/impulsivity	3
Depression with psychotic features	3
Borderline personality disorder	2
Delusions	2
Auditory hallucinations	2
Huntington’s chorea	2
Acute manic episode	1
Acute encephalopathy	1
Panic disorder	1
Adjustment disorder with mixed anxiety/depressed mood	1
Grief	1
Tactile hallucinations	1
Depressed mood	1
Epilepsy	1
Drug-induced Parkinsonism	1
Sedation	1
Parkinson’s disease	1

Quetiapine was commonly prescribed across all specialties at the medical center. Thirty-nine percent of quetiapine prescriptions were from psychiatry (inpatient, outpatient, or emergency department), 22% from internal medicine, 15% from emergency department, 10% from primary care, 5% from neurology, and 5% from geriatrics (Figure 2).

Figure 2.

Provider specialty of written quetiapine script.

Our review of the appropriateness of quetiapine refills found that 67% of quetiapine prescriptions were inappropriate in accordance with the protocol and 33% were appropriate. The reasons for inappropriate quetiapine use were the dose not being optimized (39%), an inappropriate diagnosis for use (35%), and an unknown indication for use (26%) (Figure 3).

Figure 3.

Reasons for quetiapine prescriptions being inappropriate per psychotropic stewardship protocol.

We extrapolated the cost of common adverse events associated with quetiapine use – the development of T2DM and falls in older adults. There would be approximately 24 patients in our population who would develop T2DM associated with inappropriate quetiapine use. The associated cost for these 24 patients is $641.72 per day or $234,227.80 per year. In our sample, there were 36 patients aged 65 and older. Of these 36 patients, 27 patients were inappropriately prescribed quetiapine. There would be approximately six falls per year in our elderly population associated with inappropriate quetiapine use. The associated cost of these falls across 1 year is $61,160.04, with $426.24 of this cost related to fatal falls and $60,733.80 of this cost related to nonfatal falls (Table 3).

Table 3.

Extrapolated number of events and daily and yearly costs to the healthcare system associated with inappropriate quetiapine use.

Adverse events associated with quetiapine use	Number of events	Daily cost	Yearly cost
Diabetes	24.4	$641.72	$234,227.80
Falls	6.23	–	$61,160.04
Fatal	0.02	–	$426.24
Non-fatal	6.21	–	$60,733.80

Discussion

We reviewed quetiapine fill history over 1 year at a large, urban academic medical center and found that most quetiapine prescriptions (67%) were inappropriate per our developed quetiapine protocol. Approximately one-third of these inappropriate prescriptions were due to underdosing quetiapine for its intended indication, which puts these patients at risk for undertreatment of their mental illness and, therefore, psychiatric relapse. In addition, approximately two-thirds of these inappropriate prescriptions were due to an inappropriate indication for use, which puts these patients at risk for unnecessary adverse effects. Out of the two-thirds of inappropriate quetiapine prescriptions prescribed for an inappropriate indication, approximately 40% had an indication for use that was unknown and not documented in the medical record. Consistent with previous literature, our findings revealed that more than half of the quetiapine prescriptions were for off-label indications. ¹⁰ These prescriptions were prevalent across various medical specialties, including psychiatry, internal medicine, primary care, emergency department, and geriatrics. ¹³ Notably, internal medicine emerged as the second most common specialty for prescribing quetiapine behind psychiatry, highlighting a significant number of patients being discharged with quetiapine prescriptions, particularly in the internal medicine setting. ¹⁴

We used the literature to extrapolate the risk and cost of two common adverse events – T2DM and falls in older adults – associated with quetiapine use. Based on our sample, the cost of developing diabetes per year in our patients inappropriately prescribed quetiapine is approximately $234,000. Using our sample of older adults, 27 had inappropriate quetiapine prescriptions, and the extrapolated cost of falls for older adults inappropriately prescribed quetiapine, including fatal and nonfatal, was over $61,000. In total, the direct healthcare costs of these two adverse events associated with inappropriate quetiapine use are greater than $350,000. While the risk of having a fatal fall in our population was near zero and the associated costs of fatal falls were lower than nonfatal falls, it is important to acknowledge other harms outside of direct costs to the healthcare system associated with fatal falls. These harms are underscored by a loss of productivity, including lost wages. ²⁴ Nonfatal falls can also have associated harms, including the need for long-term care, years lived with disability, and missed work due to medical needs. ²⁵ These extrapolated direct and associated costs from inappropriate quetiapine use underscore the importance of appropriate antipsychotic use, which can be supported through psychotropic stewardship. ⁵

Limitations

This is the first study to document the potential benefits of an antipsychotic stewardship program, but there are limitations. Acknowledging that a stewardship protocol intends to set criteria to guide broad, population-level use of medications is important. However, some patients may benefit from psychotropic medications outside this protocol’s guidelines. An example of this is the use of antipsychotic polypharmacy, which does not often follow evidence-based practice. However, using multiple antipsychotics may be appropriate in cross-tapering, treatment of refractory schizophrenia, or utilizing antipsychotics with complimentary (rather than competing) receptor profiles. ²⁶ Our study intended to review the safety and efficacy of quetiapine use at a population level rather than to review individual cases to consider polypharmacy.

In addition, this study focused on one antipsychotic – quetiapine. While quetiapine is an excellent initial focus medication to determine the need for an antipsychotic stewardship protocol due to its unique dose-related receptor affinity and common prescribing practices across medical specialties,^9,13 it does limit the extrapolation of these results to other antipsychotics and psychotropic medications. Furthermore, this study extrapolated potential harms and costs from other estimates that have been published. Our study was not designed to detect the exact harms and costs to patients who received inappropriate quetiapine therapy. Similarly, we were not able to review the differences in appropriate and inappropriate prescribing practices between prescriber specialties at our medical center. While we do see that quetiapine prescriptions are commonly prescribed across specialties, we cannot determine the breakdown of inappropriate prescribing practices between specialties. Due to our medical center’s inclusion of multispecialty clinics and inpatient units, these prescribing practices represent health systems rather than specific individual medical subspecialties. Finally, approximately 17% of quetiapine prescriptions lacked a clear indication, possibly due to inadequate documentation practices at our medical center.

Despite these limitations, this novel study captures general adult quetiapine use and is consistent with previous literature investigating quetiapine prescribing practices. ¹³ Future studies should investigate the results of inappropriate quetiapine use in terms of the development of adverse events (including T2DM and falls in older adults) and the associated costs to the healthcare system, as well as review the appropriateness of other psychotropic medications following a psychotropic stewardship protocol. The findings of this study suggest that across various medical specialties, from suboptimal dosing to prescribing for inappropriate indications, the inappropriate use of quetiapine is prevalent.

Conclusion

Two-thirds of quetiapine prescriptions over a 1-year period at a large, urban academic medical center were inappropriate and not in accordance with our antipsychotic stewardship protocol. This inappropriate use fell into three main categories: the dose of quetiapine not being optimized, the indication for the use of quetiapine being inappropriate, or the indication for the use of quetiapine being unknown. These findings highlight the additional need for promoting safe and effective antipsychotic use. These needs can be met by developing and implementing a psychotropic stewardship protocol to support optimal prescribing practices, hiring psychiatric pharmacists to promote safe and effective psychotropic use, and educating providers on appropriate antipsychotic prescribing practices.

Appendix 1: Antipsychotic stewardship protocol for quetiapine use

1. Diagnosis for the use of quetiapine is documented, accurate, founded, and sound.

2. Factors that affect the efficacy of a drug:

   1. Dosing is appropriate based on the indication for use:

      1. Schizophrenia: 400–800 mg/day
      2. Depression: ⩾300 mg/day
      3. Anxiety: 50–300 mg/day
      4. Bipolar I and II disorder: ⩾300 mg/day
         *If not at the appropriate dose for prescribed indication at the time of review, clinical notes can specify the titration schedule with documentation of current titration to meet appropriate dosing and be labeled appropriate
   2. Antipsychotics are not indicated for the treatment of sleep/insomnia
   3. When used for bipolar I and bipolar II disorder, antipsychotics should target the patient’s symptoms (bipolar depression and/or mania). See Table A1.

Table A1.

Monotherapy coverage for bipolar disorder.

Medication	Prevention of mania	Prevention of depression	Acute mania	Acute depression
Quetiapine	✓	✓	✓	✓

1. Factors that affect the safety of a drug:

2. Use antipsychotics with the lowest D2 antagonism in patients with comorbid Parkinson’s disease (quetiapine and clozapine)

3. Polypharmacy is not typically indicated and the D2 affinity of the specific antipsychotic needs to be considered (e.g. aripiprazole has strong D2 affinity, which will not allow other antipsychotics to exert much effect and simply increases the risk of side effects associated with H1, muscarinic, and alpha-adrenergic receptor antagonism)

4. Patients should have a documented lipid panel, A1C, and weight prior to initiating antipsychotic therapy

5. Metabolic side effects monitoring (lipid panel, A1C, weight) should be assessed q12 weeks after initiation or dose change of antipsychotics

6. Extrapyramidal side effects (EPS) should be monitored at each visit

7. Vital signs (orthostasis, BP, HR) should be assessed at each visit and more frequently with dose initiation/increases.