Case 1: Elderly hostel resident on PP6M
History and previous treatments
The patient was a 70-year-old male hostel resident who was diagnosed with paranoid schizophrenia at the age of 23 years. He had a history of setting fire to a university lecture hall in Germany in 1981 and was subsequently followed up in Hong Kong. He was admitted to a psychiatry ward in 1996, defaulted on treatment in 2008–2015, and had poor compliance with oral antipsychotics.
In 2015, the patient was readmitted to a psychiatry ward for relapse. After stabilizing on first-generation long-acting injectable (LAI) flupentixol 60 mg Q3W and sulpiride 400 mg nocte, he was discharged to a hostel and resided there since. Although he had residual auditory hallucinations (AH), he was not distressed.
In January 2022, the patient experienced extrapyramidal side effects (EPS), including restlessness and tremors, and continued to report AH. Therefore, his treatment was switched to the second-generation LAI antipsychotic, paliperidone palmitate (PP). After using oral paliperidone for 6 weeks, he was switched to monthly PP (PP1M) 100 mg for 6 months, which led to resolution of EPS and AH. In September 2022, treatment was switched to 3-monthly PP (PP3M) 350 mg, and his monitoring interval was extended from 3 to 6 months.
Treatment with PP6M
In June 2025, after being clinically stable for 2.5 years on PP3M, the 6-monthly formulation of PP (PP6M) became available in Hong Kong, and the patient was switched to PP6M 700 mg.
Despite antipsychotic treatment, the patient’s hypertension and hypercholesterolaemia remained well controlled, and his medications for these conditions remained unchanged since 2022.
At the latest follow-up in December 2025, his condition remained stable on PP6M, with no relapses, residual symptoms, or EPS. He went out from the hostel daily and will continue treatment and follow-up every 6 months.
Case 2: Working mother on PP3M
History and previous treatments
A 40-year-old mother who worked as both a piano teacher and an insurance agent presented with psychotic features. She lived with her husband and took care of her 8-year-old son. Due to her busy lifestyle, medication compliance was poor. She experienced four relapses in 2018, 2023, April 2025, and October 2025 — mainly from noncompliance — that resulted in hospital admissions.
In 2018, she was admitted to a psychiatry ward and stabilized on LAI aripiprazole 300 mg Q6W.
In 2023, she had another relapse. Aripiprazole dose was increased to 400 mg Q6W during hospitalization. However, she reported fatigue, and aripiprazole dose was reduced to 300 mg Q6W. She also complained that Q6W injection was too frequent for her busy schedule.
In April 2025, she delayed LAI aripiprazole treatment for 1 month because of work, which led to another relapse.
Treatment with PP3M
To improve compliance, a switch from LAI aripiprazole to PP, which permits a longer dosing interval, was discussed. The patient was put on oral paliperidone for 2 weeks, then switched to PP1M 100 mg for 6 months, and finally to PP3M 175 mg in September 2025.
In October 2025, she had a mild relapse triggered by marital conflict and was admitted for inpatient management. After getting away from stress, she was generally stable in the ward. Oral paliperidone 3 mg daily and clonazepam 0.5 mg BID were added during hospitalization. This led to stabilization in 3 days, and the patient was discharged within a week. Clonazepam was discontinued, and follow-up at the outpatient clinic was scheduled every 6 weeks.
At the latest follow-up in December 2025, the patient remained stable. Oral paliperidone was discontinued and PP3M was uptitrated to 263 mg. Her metabolic profile remained normal throughout LAI antipsychotic treatment. The plan is to switch to PP6M if she remains clinically stable for another 3–4 months.
Discussion
Patients with schizophrenia are prone to relapses. The most important risk factor for relapse is poor compliance.1,2 Noncompliance rate with oral antipsychotics can reach 50 percent in schizophrenia.3 As observed in case 2, even patients stabilized on LAI antipsychotics with shorter dosing intervals (eg, Q3W–Q4W) may still default on follow-ups or injections due to injection-site pain, fear of needles, or busy schedules. Noncompliance is therefore a major clinical concern that increases risks of relapse, rehospitalization, morbidity, and mortality.2
PP3M and PP6M, which allow less frequent injections, are maintenance treatment options for schizophrenia in adults who have been adequately treated and stabilized on a prior LAI antipsychotic with shorter dosing intervals.4,5
Based on clinical experience, patients are generally eager to initiate and more likely to adhere to PP3M and PP6M. In routine patient management, PP6M and PP3M reduce conflicts over injections between clinicians and patients, decreasing requests to revert to oral therapy due to injection-site pain and the inconvenience of returning monthly to the clinic for injection. In certain cases, patients’ oral medication regimens can be simplified after transitioning to longer-acting LAI formulations.
In a randomized, multicentre, double-blind, noninferiority study, PP3M was as effective as PP1M in relapse prevention at 12 months (relapse-free rate, 91.2 vs 90 percent; difference, 1.2 percent; 95 percent confidence interval [CI], -2.7 to 5.1) in patients with schizophrenia previously stabilized on PP1M. The safety profiles of PP3M and PP1M were similar, without any new safety signals.6
Similarly, a double-blind, randomized, parallel-group study showed that PP6M was noninferior to PP3M in preventing relapses at 12 months (relapse-free rate, 91.9 vs 94.8; difference, -2.9 percent; 95 percent CI, -6.8 to 1.1) in patients with schizophrenia adequately treated with PP1M or PP3M. The incidence of treatment-emergent adverse events (AEs) was similar between PP6M and PP3M (62.1 vs 58.5 percent), and no new safety signals emerged.7
In an open-label extension (OLE) study in adult patients with schizophrenia who remained relapse-free after completing the above 12-month double-blind treatment and chose to continue PP6M for another 24 months, 96.1 percent of patients remained relapse-free at 2 years.7,8 (Figure 1)
These data establish both PP6M and PP3M as effective maintenance therapies, whose efficacy persists after switching from an LAI antipsychotic with a shorter dosing interval.6-8 After switching to PP3M or PP6M, both patients above demonstrated good compliance and remained clinically stable and relapse-free. They were able to fully participate in daily activities (eg, work, social life, and childcare) and did not require frequent follow-ups.
In a retrospective phase IV study, PP6M data were obtained from the single-arm, 2-year OLE study, and PP3M and PP1M external comparator arms were constructed using real-world data from patients with baseline characteristics similar to those in the PP6M group. Relapse-free rates in the PP6M, PP3M and PP1M groups were 96.1, 79.8 and 70.2 percent, respectively. Of note, PP6M significantly reduced relapse rate by 82 percent vs PP3M (hazard ratio [HR], 0.18; 95 percent CI, 0.08–0.40; p<0.001) and by 89 percent vs PP1M (HR, 0.11; 95 percent CI, 0.05–0.25; p<0.001). (Figure 2) The relapse rate was also significantly lower with PP3M vs PP1M (HR, 0.65; 95 percent CI, 0.42–0.99; p=0.043).9
In patients with schizophrenia who experience five relapses, each subsequent relapse increases all-cause mortality hazard by approximately 20 percent.10 Reduction of relapse risk with PP3M or PP6M may potentially lower all-cause mortality.
Suitable candidates for PP3M or PP6M are patients who are stable on monthly LAI therapy, those with poor medication compliance or who prefer fewer pills, and patients seeking to reduce clinic visits or injection frequency.
In my clinical practice, I would first transition patients to PP3M and then consider switching to PP6M if they remain stable for at least 3–4 months on PP3M.
As illustrated by our cases, frequency of monitoring after a treatment switch should be individualized. I typically advise patients to maintain their original follow-up schedule after switching treatment, rather than extending both treatment and monitoring intervals simultaneously. Between follow-up visits, I always instruct patients and caregivers to recognize signs and symptoms of a potential relapse and establish a contingency plan such as arranging an earlier follow-up.
In summary, PP3M and PP6M are at least as effective as PP1M in relapse prevention and have a comparable safety profile.6-8 Switching to PP3M or PP6M may improve compliance, enhance convenience (fewer clinic visits and injections, and less disruption to daily life), and reduce injection-related conflicts between clinicians and patients.
