Schizophrenia is a psychiatric syndrome of delusions, disorganised speech, hallucinations, and impaired executive functioning1. Despite affecting approximately 1% of the global population, poor treatment adherence remains as an unmet need associated with worse clinical outcomes1,2. In the scientific symposium organised by Janssen Pharmaceuticals on the 12th of March 2024, two renowned experts in Psychiatry shared their clinical strategies for long-acting injectable (LAI) utilisation in managing schizophrenia patients.

Relapse Worsens Cognitive Functioning and Treatment Responses
First-episode psychosis (FEP) in schizophrenia is characterised by a high antipsychotic therapy response rate, followed by frequent antipsychotic discontinuation and elevated relapse rates soon after maintenance treatment begins³. Dr. Roma explained that the serious neurobiological adverse effects of psychotic relapse - including neuroinflammation and oxidative stress - may explain the atrophic changes observed during early FEP (Figure 1)³.

Figure 1. Schizophrenia disease progression3.

In fact, in an observational study, Cahn et al. (2002) reported a progressive loss of global grey matter in schizophrenic patients after the first episode that was related not only to the disease process, but also to antipsychotic treatment use⁴.

Dr. Roma explained that there is a strong correlation between further relapses and increased treatment resistance⁵. The study by Takeuchi et al. (2019) further highlighted a significant decline in treatment response at the second episode of schizophrenia compared with the first episode (50% response rate episode 1 vs. episode 2: 10.4% vs 48.7% [week 7]; 27.8% vs 88.2 [week 27], respectively, Figure 2)⁵,

Figure 2. Changes in 50% response rates over time in first vs second episodes5, ***p<0.001, **p<0.01.

suggesting the importance of utilising effective treatment as early as possible in patients with schizophrenia.
 

The Primal Factors Hindering Optimal Outcomes
However, the challenge in managing schizophrenia is not solely dependent on treatment effectiveness. Dr. Roma shared the data from a meta-analysis of 29 studies by Alvarez-Jimenez et al. (2012), where medication nonadherence attributed to a four-fold increased risk for relapse in patients with FEP, followed by persistent substance use disorders (3-fold), caregivers’ excessive criticism (2.3-fold) and poorer premorbid adjustment (2.2-fold) (Figure 3)⁶.

Figure 3. Risk factors for relapse following treatment for first episode psychosis6. Adapted from Alvarez-Jimenez et al. 2012.

In practice, Dr. Roma highlighted that both patients and healthcare professionals may experience reluctance towards LAIs. In the cross-sectional study by Cahling et al. (2017), although patients were concerned that they were obliged to show up at clinics regularly and would experience reduced treatment autonomy, mental healthcare professionals may also overestimate patients' fears of LAIs, and the expressed fears exceeded the actual experiences of patients already on LAIs⁷.

 Paliperidone Palmitate – An Effective LAI Improving Medication Adherence and Clinical Outcomes

Dr. Roma outlined that LAIs overcome certain challenges faced by patients taking oral antipsychotics. She highlighted the findings of an analysis of United States (US) medical claims data by Pilon et al. (2017), where patients initiated on second-generation (SG) LAIs, particularly paliperidone palmitate, were more likely to be adherent to their medication than those on oral atypical antipsychotics (OAAs) as reflected by a higher odds of proportion of days covered (PDC) ≥80% (odds ratio [OR]: 1.28, p<0.001, Figure 4)⁸.

Figure 4. Adjusted comparison of adherence in Medicaid beneficiaries between LAIs and OAAs8, CI: confidence interval, LAI: long-acting injectable, OAA: oral atypical antipsychotic, PDC: proportion of days covered, PP: paliperidone palmitate, SG: second generation, *p<0.001.
Apart from improved adherence, a meta-analysis by Lin et al. (2021) demonstrated that LAIs were also associated with reduced hospitalisations (OR: 0.62) and emergency room admissions (incidence rate ratio [IRR]: 0.86) compared to oral antipsychotics. The higher pharmacy costs were offset by these lower medical costs, resulting in a non-significant difference in total healthcare costs⁹. Notably, Pilon et al. (2017) also found that paliperidone palmitate was the only LAI with statistically significant medical cost savings (mean monthly cost difference: -$225 USD, p<0.001)⁸.

The Exceptional Performance of Twice-Yearly Paliperidone Palmitate

Three dosing regimens of paliperidone palmitate are available, namely once-monthly (PP1M), once-quarterly (PP3M), and twice-yearly (PP6M), with extended- dosing formulas retaining high efficacy and safety¹⁰. A randomised controlled trial (RCT) involving 702 patients with schizophrenia by Najarian et al. (2022) demonstrated that 92.5% of patients receiving PP6M remained relapse-free at 1 year, which was non-inferior to PP3M (95.1%, Figure 5).

Figure 5. Percentage of patients without relapse10.

Furthermore, the incidences of treatment-emergent adverse events were similar between PP6M (62.1%) and PP3M (58.5%) with no new safety concerns¹⁰. Dr. Roma concluded that the clinical data supported the sustained efficacy of PP6M in controlling relapse in schizophrenia, with the potential to further enhance patients' medication adherence.

Managing Schizophrenia with Paliperidone Palmitate in Practice
To understand the practical benefits of paliperidone palmitate and switching to extended-dosing regimens, Dr. Roma shared a case of a 26-year-old male with schizophrenia that she had previously treated.
 

Case presentation:
•    A 26-year-old male pharmacist was diagnosed with schizophrenia in his early 20s. He was initially prescribed oral risperidone 4 mg by a different provider but reported to have missed doses several times per week. Moreover, the patient resigned from his job and began to experience an increased paranoia. In addition, he also started to smoke cigarettes and was reported to have become more poorly kempt as he often rummaged through trash containers.
 

Treatment and outcomes:
•    PP1M 100 mg was initiated with the encouragement of his family and the patient showed good stability. 8 months later, he then switched to PP3M 350 mg and took up a career as a pharmacy technician. Since the patient remained clinically stable with no reported adverse events, he was eventually switched.
 

Addressing Questions about Longer Dose LAIs- Dr. Roma's Experience
Dr. Roma summarised the utilisation of LAIs by detailing the possible concerns and her strategies for managing such treatment.

Will patient follow-up be less frequent than every 6 months?
•    In the non-inferiority RCT, 87% of patients with schizophrenia completed the study¹⁰, showing that these patients maintain a high frequency of follow-up. Providers must also continue monitoring relapse or breakthrough symptoms and the other medications schizophrenia patients receive over the 6 months.

What happens when patients are hospitalised and receive additional paliperidone palmitate injections?
•    There is no increased risk for patients with schizophrenia as paliperidone palmitate's insoluble, slow-dissolving formula allows stable blood concentrations without incurring additional side effects¹¹.

How are breakthrough symptoms managed?
•    Breakthrough symptoms are often traced back to inappropriate injection administration. Moreover, flexibility with early/late dosing, gluteal injection options for longer half-lives, and oral medication supplemented as needed may enhance the efficacy of PP-LAIs if necessary.

Which patients are ideal for extended-dosing formulas?
•    The ideal patient for PP6M is young, high functioning, with good insight and with good family support.

How can healthcare providers empower their patients in accepting treatment?
•    Communicate the value of treatment early in the course of their disease. Providers can show patients brain scan images and explain the potential dose reductions after starting PP1M instead of emphasising the injection procedure. Weiden et al. (2015) reported that the proportion of patients willing to try LAIs increased from 48% to 96% after psychiatrists explained the values of LAIs¹².

Local Experience and Salient Points in Managing Schizophrenia with LAIs
Dr. Chang illustrated the local scenario in managing schizophrenia and shared his advice on using LAIs in practice. Like Dr. Roma, he noted that LAIs may address treatment nonadherence: "patients initiated on PP6M should demonstrate good clinical responses, tolerability and stability on PP1M or even PP3M," he remarked. Furthermore, PP6M may be suitable for patients with a good functional status (i.e. with a full-time job) or have good insight into their illness.

However, Dr. Chang emphasised that an extended dosing interval may not completely solve the issues related to treatment adherence. Psychiatric follow-up with reasonable intervals for monitoring remains paramount for identifying breakthrough symptoms and finetuning, especially during the initial phase of the treatment. “More frequent follow-up for clinical monitoring during the initial stage of switching to PP6M is required to ensure that tolerability and sustained treatment response is maintained,”Dr. Chang accentuated.
 

References
1. Velligan DI, Rao S. J Clin Psychiatry 2023;84.  2. Stone WS et al. JAMA Psychiatry 2020;77:1.  3. Gardner K, Nasrallah H. Curr Psychiatr 2015;14:33-e3.  4. Cahn W et al. Arch Gen Psychiatry 2002;59:1002–10. 5. Takeuchi H et al. Neuropsychopharmacology 2019;44:1036.  6. Alvarez-Jimenez M et al. Schizophr Res 2012;139:116–28. 7. Cahling L et al. BJPsych Bull 2017;41:254–9.  8. Pilon D et al. Clin Ther 2017;39:1972-1985.e2. 9. Lin D et al. CNS Drugs 2021;35:469–81.  10. Najarian D et al. IJNP 2022;25:238.  11. Correll, CU, et al. CNS Drugs 2021;35:39–59.  12. Weiden PJ et al. J Clin Psychiatry 2015;76:684–90.