60. SYSTEMATIC REVIEW OF FLUPHENAZINE EFFICACY IN TREATMENT-RESISTANT PSYCHOSIS FOR OLDER ADULTS

Abstract

Introduction

Treatment-resistant psychosis presents significant challenges for the older adult population (> 60 years of age), who are more often vulnerable to medication side effects and with complex medical comorbidities. Fluphenazine, a high-potency typical antipsychotic, has been used to manage symptoms of psychosis for decades. However, the efficacy of fluphenazine compared to other antipsychotics remains under-researched in older adults with treatment-resistant psychosis among other first generation antipsychotics. A recent case series conducted at the University of California San Diego inpatient Geriatric Psychiatry Unit demonstrated marked clinical efficacy of fluphenazine in managing symptoms of treatment-resistant psychosis in the older adult population, guiding further interest in a larger clinical comparison of this medication to other antipsychotics. This review aims to synthesize evidence regarding the effectiveness and safety profile of fluphenazine in older adults with treatment-resistant psychosis.

Methods

We conducted a systematic review in accordance with Prospero guidelines. Studies were identified through searches of PubMed and the Cochrane Library, with the last search conducted on October 13, 2024. Inclusion criteria comprised randomized controlled trials (RCTs), meta-analyses, and case series that compared fluphenazine with typical or atypical antipsychotics in adults, with a particular focus on older patients with treatment-resistant psychosis. Studies had to report clinical outcomes, treatment adherence, or adverse effects. Exclusion criteria included studies that only focused on children (< 18 years) with psychosis, studies with low-quality of evidence, and studies that did not report on treatment-resistant psychosis. Data were synthesized by qualitatively comparing treatment outcomes, treatment adherence, and adverse effects across studies.

Results

Eight studies were included, comprising of 2 RCTs, 3 observational studies, 2 meta-analyses (7 RCTs in Study 1, and 4 RCTs in Study 2), and 1 case series. The studies collectively involved over 4621 participants, ranging from adults aged 18 to older adults with treatment-resistant schizophrenia or schizoaffective disorders. One meta-analysis, including 7 RCTs and 1,567 participants, found no significant differences in treatment response between fluphenazine and low-potency antipsychotics; however, the fluphenazine group had a higher incidence of EPS. Another meta-analysis (4 RCTs, 202 participants) comparing fluphenazine to atypical antipsychotics (risperidone, quetiapine, olanzapine) reported no significant differences in symptom improvement, but more patients on fluphenazine required additional anticholinergic medications. Of note, the two meta-analyses only included RCTs with no older adults represented among the participants. An RCT (n=38) in treatment-resistant schizophrenia showed similar efficacy between fluphenazine and atypical antipsychotics, but adherence rates were lower for fluphenazine. Another RCT (n=60) demonstrated superior improvements in both positive and negative symptoms, as well as lower EPS rates, with olanzapine compared to fluphenazine. The two RCTs only included patients between 18 and 65 years old. The case series of 9 older adults aged 60-80 reported rapid and lasting improvements with fluphenazine in those resistant to atypical antipsychotics, though long-term safety remains uncertain. The overall evidence suggests fluphenazine is comparable to other antipsychotics in terms of symptom control but presents higher risks of EPS, particularly when compared to atypical antipsychotics.

Conclusions

Fluphenazine has shown comparable efficacy to atypical antipsychotics in treatment-resistant psychosis in the adult population, but the higher reported incidence of EPS may limit its current use in the clinical setting. It must be noted that very limited data has been found specific to the use of fluphenazine in the geriatric population and no RCTs were found directly comparing the use of fluphenazine with other antipsychotics in populations > 60 years of age. This strongly suggests that despite broad recommendation and safety guidelines for antipsychotic use in older adult populations, there is little data comparing specific antipsychotics to make more individualized recommendations for highly treatment resistant patients in the geriatric population. One could argue that among populations with overall higher rates of disease comorbidity and vulnerability to medication adverse effects, individualized care develops a more critical meaning/urgency.

Several limitations to the included studies should be noted, including a small sample size, considering studies of both adult and geriatric populations together, the limited data obtained specific to geriatric populations, and potential biases such as imprecision in reporting outcomes and adverse effects among various studies. Additionally, inconsistencies were observed between studies regarding adherence rates and EPS severity, suggesting the need for standardized reporting. A submitted case series of 9 geriatric patients stands out suggesting strong clinical benefit and good tolerance in the geriatric population, particularly those who have failed widely accepted first line atypical antipsychotic agents. Longitudinal follow up data would be essential to draw conclusions about long term side effect profile and tolerance. Further large-scale RCTs and prospective studies that focus on older adults are needed to confirm and establish clear clinical guidelines for the use of fluphenazine in management of treatment-resistant psychosis in older adults.