Evaluation of haloperidol decanoate initiation dosing in inpatients with serious mental illness

Abstract

Introduction

Manufacturer labeling for haloperidol decanoate recommends an initial dose of 10 to 20 times the daily oral dose; however, significant heterogeneity in dosing practices exists. The purpose of this medication use evaluation was to assess initial haloperidol decanoate dosing in psychiatric inpatients.

Methods

An institutional review board–exempt retrospective chart review was conducted using data from University of California Health Data Warehouse (UCHDW) from June 1, 2014, to June 1, 2024. Inpatients diagnosed with schizophrenia or schizoaffective disorder aged 18 years or older receiving an initial dose of haloperidol decanoate were included. Patients on dual antipsychotics or those without oral haloperidol within 24 hours before decanoate administration were excluded. The primary outcome was the proportion of patients receiving 10 to 20 times the oral haloperidol dose as per the manufacturer’s package insert. Secondary outcomes included dosing characterization and incidence of extrapyramidal symptoms. Descriptive statistics were employed.

Results

A total of 147 eligible patients were included, with a mean age of 49 years; 62% of participants were male. The mean oral dose of haloperidol before decanoate initiation was 20.7 mg, and the mean initial dose of haloperidol decanoate was 178 mg. The primary outcome was observed in 47.6% of patients. Of those who received doses outside of the recommended range, 41.5% received a dose less than 10 times the oral haloperidol dose, while 10.9% received a dose exceeding 20 times the oral dose.

Conclusion

Fewer than half of the patients evaluated received an initial dose of haloperidol decanoate as recommended by the manufacturer’s labeling. These findings underscore the need to further investigate clinician attitudes, comfort, and knowledge on haloperidol decanoate prescribing.

Introduction

Haloperidol is a high-potency, first-generation antipsychotic (FGA) indicated for the treatment of schizophrenia and bipolar disorder. It is available in several formulations, including oral tablets, an oral solution, an immediate-release intramuscular injection, and a long-acting injectable (LAI) decanoate formulation.¹ Haloperidol is often used in settings where patients are unable to tolerate second-generation antipsychotics (SGAs) due to metabolic adverse effects, have demonstrated treatment resistance following multiple SGA trials, or require an LAI formulation but have limited access to costlier SGA LAIs. For patients who respond to and tolerate oral haloperidol, transitioning to the LAI formulation may improve adherence, especially among those with a history of poor adherence or a preference for the injectable formulation. LAIs, including haloperidol decanoate, offer several benefits for those with serious mental illness, as outlined in the 2020 American Psychiatric Association guidelines.²

Haloperidol decanoate dosing is not standardized and varies significantly by prescriber and institution. The manufacturer recommends an initial dose conversion of 10 to 20 times the previous daily oral haloperidol dose.¹ For patients receiving lower oral doses, such as elderly individuals, an initial dose of 10 to 15 times the daily oral dose is suggested.¹ In contrast, for patients receiving higher oral doses and at risk for decompensation, up to 20 times the oral dose may be considered with a downward taper on succeeding injections.^1,3 Regardless of a high or low oral to LAI dose conversion, the initial dose should not exceed 100 mg, thus requiring a split initial dose separated by 3 to 7 days as needed. Owing to the delayed intramuscular absorption of haloperidol decanoate, oral haloperidol supplementation may be required during the first 6 weeks of therapy.⁴ Anecdotally, the duration of oral supplementation is often continued beyond 6 weeks to ensure therapeutic concentrations are maintained and to minimize the risk of relapse. Additionally, several haloperidol decanoate loading-dose protocols have been evaluated, all generally adhering to the 10 to 20 times oral dose conversion.^4-6 Despite these recommendations, anecdotal evidence suggests that prescribers are initiating doses outside of the recommended range, potentially placing patients at risk for extrapyramidal symptoms (EPS) or relapse.

Because of the great heterogeneity in haloperidol decanoate dosing and oral supplementation approaches, there is a need to examine institutional dosing practices of haloperidol decanoate. Specifically, evaluating and characterizing current prescribing patterns that deviate from manufacturer labeling-based dosing will provide clarity. The purpose of this medication use evaluation was to assess prescribing patterns in adult inpatients with schizophrenia or schizoaffective disorder for initial haloperidol decanoate administration and to analyze associated secondary factors.

Methods

Study Design

This retrospective, cross-sectional chart review was conducted using inpatient data from the University of California Health Data Warehouse (UCHDW), spanning a 10-year period from June 2014 to June 2024. Data were previously deidentified in accordance with Health Insurance Portability and Accountability Act compliance standards and were institutional review board exempt.

Patients were eligible for inclusion if they met the following criteria: age 18 or older; inpatient status during new initiation of haloperidol decanoate; diagnosis of schizophrenia or schizoaffective disorder; receipt of an initial dose of haloperidol decanoate; and administration of a documented dose of oral haloperidol within 24 hours before decanoate injection. Initial doses were calculated based on the total daily scheduled and as-needed doses of oral haloperidol administered within 24 hours of decanoate administration. To account for variability in administration regimens, all inpatient haloperidol decanoate administrations within 14 days of the initial injection were included in the calculation of the total initiation dose. Patients were excluded if they were on dual antipsychotic therapy, had a history of prior haloperidol decanoate administration, or did not receive at least 1 dose of oral haloperidol within the 24 hours before initiating haloperidol decanoate.

Outcomes and Data Collection

The primary outcome was the proportion of patients whose initial haloperidol decanoate dose fell within the recommended range of 10 to 20 times the oral daily dose. Baseline demographics and clinical characteristics were collected, including age, sex, race, ethnicity, and initial oral and injectable haloperidol doses. Secondary outcomes included the proportion of patients with oral overlap during the transition, administration of anticholinergic medications within 30 days of haloperidol decanoate injection, and the incidence of EPS based on diagnoses recorded by the provider in deidentified chart notes.

Data Analysis

All variables, including the primary outcome and baseline demographics (age, sex, race, and ethnicity) were characterized using descriptive statistics.

Results

Of the original 505 patients, 271 were excluded for the absence of a schizophrenia or schizoaffective disorder diagnosis, 46 were excluded for receiving haloperidol decanoate without oral haloperidol supplementation, 31 were excluded for receiving haloperidol decanoate as an outpatient, and 10 were excluded for not receiving oral haloperidol supplementation within 24 hours of receiving a dose of haloperidol decanoate (Figure). A total of 147 patients were included in the study. The mean age of participants was 49 years, and 62% were males. Most patients were White (60%), followed by Asian (16%). The mean oral dose of haloperidol was 20.7 mg, and the mean initial dose of haloperidol decanoate was 178 mg (Table 1).

FIGURE.

Cohort formation

TABLE 1.

Baseline characteristics

Characteristic	Total (N = 147)
Age (years), mean ± SD	49 ± 17
Sex, n (%)
Female	56 (38.1)
Male	91 (61.9)
Race, n (%)
White	88 (59.9)
Hispanic or Latino	16 (10.9)
Asian	24 (16.3)
Black or African American	10 (6.8)
Native Hawaiian or Other Pacific Islander	2 (1.4)
Multirace	7 (4.8)
Ethnicity, n (%)
Not Hispanic or Latino/a	86 (58.5)
Hispanic or Latino/a	56 (38.1)
Unknown	5 (3.4)
Initial oral haloperidol dose (mg/day), mean ± SD	20.7 ± 13.4
Initial haloperidol decanoate injection dose (mg), mean ± SD	178 ± 145.5

The primary outcome, defined as the proportion of patients receiving manufacturer-label-recommended dosing of haloperidol decanoate (Table 2), was observed in 70 (47.6%) patients. Of those outside of the oral dosing range, 61 (41.5%) received a dose of haloperidol decanoate less than 10 times the oral haloperidol dose, while 16 (10.9%) received a dose of haloperidol decanoate exceeding 20 times the oral dose. Among secondary outcomes assessing adverse effects (Table 3), 19 (12.9%) patients were documented to have experienced EPS, with 2 (10.5%) receiving a dose that exceeded 20 times the oral dose. Anticholinergic agents were administered on a scheduled and as-needed basis as follows: benztropine in 84 (57.1%) patients and trihexyphenidyl in 7 (4.8%). During the transition to haloperidol decanoate, 130 (88.4%) patients received at least 1 oral haloperidol dose after haloperidol decanoate administration during admission.

TABLE 2.

Haloperidol decanoate dosing

Characteristic	Total (N = 147)
Haloperidol decanoate doses below 10 × oral dose, n (%)	61 (41.5)
Haloperidol decanoate doses (10–20 × oral haloperidol dose), n (%)	70 (47.6)
Haloperidol decanoate doses >20 × initial oral dose, n (%)	16 (10.9)

TABLE 3.

Secondary outcomes

Characteristic	Total (N = 147)
Incidence of extrapyramidal symptoms, n (%)	19 (12.9)
Haloperidol decanoate doses <10 × oral dose	7 (4.8)
Haloperidol decanoate doses 10–20 × oral dose	9 (6.1)
Haloperidol decanoate doses >20 × oral dose	2 (1.4)
Akathisia	8 (5.4%)
Dystonia	5 (3.4%)
Movement disorder (unspecified)	4 (2.7%)
Parkinsonism	2 (1.4%)
Medications taken for adverse effects, n (%)
Benztropine (PO/IM)	84 (57.1)
Trihexyphenidyl (PO)	7 (4.8)
Receipt of at least 1 oral dose of haloperidol after  LAI administration during admission, n (%)	130 (88.4)

IM = intramuscular; LAI = long-acting injectable; PO = by mouth.

Discussion

In this retrospective chart review of inpatient haloperidol decanoate initiation, fewer than half of patients received the recommended initiation dose per manufacturer labeling, defined as 10 to 20 times the total daily oral haloperidol dose.¹ Among the patients who received dosing outside of the recommended range, the majority received doses below the product labeling recommendations. These findings highlight opportunities to optimize haloperidol decanoate initiation in the inpatient setting.

Antipsychotics remain the mainstay of treatment for schizophrenia. LAI formulations, such as haloperidol decanoate, are particularly advantageous for patients with poor adherence to oral medications and are recommended for this population according to the 2020 American Psychiatric Association guidelines.² However, the pharmacokinetic properties of LAIs differ substantially from their oral counterparts, making standardized dosing more complex and challenging due to the paucity of large-scale pharmacokinetic studies and the guidance provided in manufacturer labeling for some LAIs. Unlike more recently approved SGA LAIs, which are supported by extensive pharmacokinetic modeling and more structured dosing recommendations, FGA LAIs lack the same level of empirical dosing frameworks, complicating efforts to optimize treatment.

Haloperidol decanoate is formulated in a sesame oil vehicle, administered intramuscularly, and exhibits a prolonged release profile. Peak plasma concentrations occur between 3 and 9 days after injection, with an elimination half-life of approximately 21 days, and steady-state levels are achieved over the course of up to 3 months.⁷ This delayed onset presents a challenge during inpatient initiation, as clinicians must balance sustaining symptom control from oral haloperidol against the risk of EPS associated with higher peak concentrations.

Our findings indicate that prescribers frequently opted for conservative dosing, with fewer than half of patients receiving doses within the recommended range of 10 to 20 times the oral dose. Most patients who received a dose outside the recommended range received a lower-than-recommended dose at initiation, highlighting a need for education on appropriate dosing. Owing to the absence of detailed disposition data, we were unable to assess whether lower dosing was associated with an increased risk of relapse. However, we found that nearly 90% of patients received oral haloperidol supplementation while inpatient following the initial injection. This signals that most prescribers are appropriately continuing oral haloperidol after initiation doses; however, we did not capture the duration and dose of oral supplementation administered once discharged, as this was out of the scope of the study. Given the uncertainty around the duration and extent of oral haloperidol supplementation after discharge, it is difficult to ascertain if patients dosed within the recommended range may have benefited from higher initiation decanoate dosing or not.

Notably, only 12.9% of patients in our study were documented to develop EPS during their inpatient hospitalization after decanoate administration, and over half of the patients were prescribed anticholinergics. The EPS documentation was extracted through keywords in chart notes and, therefore, may not have fully captured all patients with this adverse effect. EPS may have developed after discharge, especially for those discharged before haloperidol decanoate reached its peak concentration, up to 9 days later. Patients may have been prescribed prophylactic anticholinergics that prevented EPS or could have received higher doses of oral anticholinergics coadministered with and after the injection. All these potential contributors may explain why reported EPS rates were not the highest among the 20 times oral haloperidol subgroup. The identified EPS rate in this study remains below what is reported in the manufacturer’s labeling and available literature on EPS rates with FGAs.^1,8

These results underscore the need to further evaluate prescriber confidence in LAI antipsychotic dosing and identify opportunities for targeted education on appropriate initiation strategies, especially for FGA LAIs like haloperidol. Previous literature has identified clinician-related factors that may contribute to the variability in LAI prescribing practices.^9-11 In a survey of 380 clinicians, Velligan and colleagues⁹ reported a lack of confidence, knowledge, and training when selecting appropriate dosing intervals or transitioning patients from oral to LAI formulations. Notably, clinicians who reported higher use of LAIs demonstrated greater comfort with dosing decisions and a higher level of knowledge compared with those with lower use rates. Factors associated with increased prescribing confidence included formal residency training, mentorship, and engagement with peer-reviewed literature. These findings highlight the importance of structured education and training in improving clinician comfort and competence in the use of LAI antipsychotics. Educational interventions, including structured didactic sessions for residents and clinicians focused on haloperidol decanoate dosing strategies and incorporating case-based applications, may be particularly beneficial for trainees and may enhance both clinical confidence and subsequent patient care. This represents an opportunity for board-certified psychiatric pharmacists to play a key role in providing targeted education and clinical expertise.

This study has several limitations. First, the lack of a control group limits the ability to compare the appropriateness of dosing with other LAIs or haloperidol decanoate in a different population. Additionally, this study did not quantify the duration or dosage of oral haloperidol or anticholinergic supplementation after LAI administration due to discharge from the facility. Moreover, diphenhydramine administrations for EPS were not included in this analysis because we were not able to separate prophylactic administrations given for agitation from those given for new-onset EPS. Finally, clinical outcomes, such as relapse, emergency room visits, or readmissions, were unable to be assessed, which would have provided valuable insights into the impact of initiation dosing on long-term treatment outcomes.

Conclusion

Fewer than half of patients received an initial dose of haloperidol decanoate consistent with the manufacturer’s label recommendations after inpatient stabilization, with most receiving doses below the manufacturer’s recommendations. These findings underscore the need for targeted clinician education to support appropriate dosing and suggest that further investigation into prescribing attitudes and knowledge is warranted to guide future interventions.