The Patient, Investigator, Nurse, Carer Questionnaire (PINC-Q): a cross-sectional, retrospective, non-interventional study exploring the impact of less frequent medication administration with paliperidone palmitate 3-monthly as maintenance treatment for schizophrenia

Non-adherence to antipsychotic treatment is common in patients with schizophrenia [1, 2]. Lack of continuous maintenance treatment can put the patient at risk of relapse, as well as increased treatment resistance, residual symptom severity, cerebral toxicity, cognitive decline, functional impairment and premature mortality [3‐7]. Long-acting injectable antipsychotic treatments (LATs) have been developed to overcome the need for daily dosing of oral antipsychotic medication and are a valuable treatment option to enhance treatment continuation [8, 9]. LATs not only reduce dose administration frequency versus oral antipsychotics, but also offer reliable medication delivery, less fluctuation in plasma levels and transparency of dose administration compared with oral antipsychotics, aiding treatment continuation [8, 9].

Paliperidone palmitate 3-monthly (PP3M) is a LAT formulation approved for maintenance treatment of schizophrenia in patients previously stabilised with paliperidone palmitate 1-monthly (PP1M) [10, 11] and requires only four administrations per year. The efficacy and safety of PP3M have been established in two pivotal phase 3 studies [12, 13]. PP3M demonstrated favourable clinical outcomes, including delayed time to relapse, symptomatic remission and functional recovery [12, 13]. More recent naturalistic studies have demonstrated the efficacy of PP3M in terms of achieving remission [14]; however, the real impact of PP3M for patients and, consequently, for physicians, nurses and carers may not be fully understood.

The objective of the present study was to explore the experience of PP3M treatment in patients with schizophrenia and their corresponding physicians, nurses and carers to understand a more complete view of the qualitative impact of less frequent administration. The study was also designed to investigate the degree of alignment between these stakeholders at an individual patient level.

This was a cross-sectional, retrospective, non-interventional study conducted in 37 centres across seven countries. Patients and their physician, nurse and carer (where applicable) each completed a one-time questionnaire (Patient, Investigator, Nurse, Carer Questionnaire [PINC-Q]).

The questionnaires were developed specifically for this study, with input from an advisory board of physicians and nurses, and in collaboration with representatives from Global Alliance of Mental Illness Advocacy Networks (GAMIAN) Europe and European Families Affected by Mental Health (EUFAMI).

Input from these groups was critical in ensuring that the questionnaires were designed and worded appropriately, considering potential variation in healthcare and cultural differences between countries. Questionnaires assessed the same topics across all stakeholders, but language was tailored as appropriate to ensure that each point was examined consistently. All questionnaires were translated into local language.

The study was conducted in accordance with the Declaration of Helsinki and was approved by all relevant institutional ethics committees. All participating patients and carers provided written informed consent prior to taking part in the study.

Physicians at participating centres offered enrolment to all eligible patients aged ≥18 years with a diagnosis of schizophrenia (according to International Classification of Diseases; ICD-10) who were currently receiving PP3M, previously received 4–6 PP3M administrations (i.e. approximately 9 to 15 months of PP3M treatment, thereby ensuring that PP3M treatment was well established prior to the questionnaire and to allow sufficient time to assess its impact), and were capable and willing to participate. Patients were excluded if they had received involuntary treatment with PP3M or were switched to PP3M during a clinical trial. Patients were evaluable if they, and at least one other associated stakeholder, completed the questionnaire.

Questionnaires were completed separately by patients and their physician, nurse and/or carer at a single data collection point. After receiving guidance on questionnaire completion, the questionnaire was completed by patients at the study site during a routine clinic visit and by carers at the same visit or within 2 weeks after the patient’s visit.

Physician questionnaires included an assessment of the patient’s level of illness for correlation with questionnaire responses. Level of illness was assessed using the Clinical Global Impression-Severity (CGI-S) scale and the Positive and Negative Syndrome Scale (PANSS) item G12 (lack of judgement and insight). Patients reported their level of illness using the European Quality of Life-5 dimension-5 level (EQ-5D-5L) questionnaire (patient-reported general health status), consisting of the EQ-5D-5L descriptive system and the EQ visual analogue scale [15].

Data from each question were summarised separately for patients, physicians, nurses and carers; questionnaire items were presented descriptively using frequency and percentages for categorical data, as well as count, mean, standard deviation (SD) and minimum and maximum for ordinal responses. The following categories were used in the questionnaire:

There was no imputation of missing data for the questionnaires.

Inter-rater alignment assesses the level of agreement between stakeholders when answering questions about a specific patient. The degree of inter-rater alignment of responses across the stakeholders overall and for individual pairings was examined using Cohen’s (weighted) kappa for categorical data and Lin’s concordance correlation coefficient (CCC) for continuous/ordinal data.

Spearman’s correlation was used to explore correlations between patients’ level of judgement and insight (PANSS item G12) and their level of illness (CGI-S and EQ-5D-5L) and the number of years since their schizophrenia diagnosis. Furthermore, associations between patients’ level of judgement/insight and treatment experience with PP3M and the change in carer time required for patient support were explored using the Chi-square test.

The outcomes of this cross-sectional study show the qualitative impact of successfully switching adult patients with schizophrenia from PP1M to PP3M on the patient as well as their physician, nurse and carer.

The majority of responses from all four stakeholders indicated that switching to PP3M helped patients, despite patients being stable on PP1M and receiving PP1M for an average of 2 years before switching to PP3M. Furthermore, a degree of improvement was seen across multiple areas of schizophrenia management, suggesting gains in addition to maintaining symptom control over time with continued medication. Improvements included increases in patient activity, improved quality of physician–patient and nurse–patient communication, increased communication between the patient and family, friends or other people, and reductions in the amount of time required for the carer to support the patient. The results of the exploratory analysis suggest that lower illness severity in this patient population was associated with better patient judgement and insight. It should however be noted that other studies have reported a persistent lack of patient judgement and insight despite a favourable treatment response in patients with schizophrenia [18]. Less frequent dosing with LATs, particularly 3-monthly administration, may be perceived by patients and carers as the patient being ‘on the road to recovery’, and associated with hope, improved social acceptability, reduced stigma and greater involvement in daily activities [19]. In the current study, stakeholders most commonly reported that the reason for switch to PP3M was to allow the patient ‘to live life as normally as possible’ (with ‘patient convenience’ also an important reason for the switch).

Encouragingly, one-third of patients and almost half of other stakeholders, reported an increase in patient activity following switch to PP3M, with social interactions being most commonly improved. This is a key benefit in patients with schizophrenia, for whom reduced social participation is associated with negative outcomes [20, 21], while social networks provide multiple benefits including reducing feelings of psychological distress, increasing engagement with mental health services and improving quality of life [20, 22]. In addition, 31–65% of stakeholders reported that switch to PP3M decreased the patient’s feeling of being stigmatised. These results, along with the finding that switch to PP3M was perceived by all stakeholders to have ‘helped the patient’ overall, indicate that the impact of PP3M addressed stakeholders’ main reasons for the treatment switch. Switching to PP3M from PP1M provides a longer interval between dosing, resulting in less frequent reminders for patients about their schizophrenia, which may account for the decrease in patients’ feeling of being stigmatised.

Promisingly, all stakeholders most frequently considered that the explanation given by the physician regarding the switch to PP3M was ‘very clear’ and very few reported that no explanation was given at all. However, it should be noted that a larger proportion of physicians considered their explanation to be very clear compared with the proportion of patients and carers. Similarly, following the switch to PP3M, an improvement was reported in the frequency and the quality of communication between physicians/nurses and patients/carers; however, a larger proportion of physicians and nurses reported these improvements in communication compared with patients and carers.

A strong therapeutic alliance between patients and healthcare professionals is important in creating patient-centred, individualised treatment plans and optimising patient outcomes [23‐25]. This is particularly applicable to the initiation of LAT, where patient preconceptions may be a barrier to medication acceptance, therefore, a clear explanation from the medical team regarding the clinical and personal benefits of a treatment is required [26]. In a recent Scandinavian study, patients treated with PP3M who were interviewed about several aspects of their treatment, highlighted the importance of their relationship with their healthcare teams in the success of their schizophrenia treatment [27]. In light of this, the findings of this study encouragingly demonstrate positive overall perceptions of communication between the patient and/or carer and healthcare team, which is an important aspect of shared decision-making and optimisation of personalised care. However, the differences in responses across stakeholders highlight opportunities for improved communication within treatment teams, and with patients and carers. The discrepancy among stakeholders regarding the clarity of explanation provided by the physician regarding the treatment switch indicates a gap in the clinical management of schizophrenia, whereby physicians and treatment teams as a whole should evaluate the clarity and the impact that the information they provide regarding treatment has on both patients and carers. Techniques such as psychoeducation may help to improve the transmission of medical information from healthcare professionals to patients and carers.

Theoretically, switching to less frequent antipsychotic administration should also allow more time to discuss other important topics with the patient, including functional goals that are important to a patient’s recovery, such as improving relationships with friends and family, gaining employment and increasing social activities [19, 28, 29]. In the current study, switching to PP3M resulted in increased time spent discussing non-medication topics for some; however, it was most frequently reported that there was ‘no change’.

A smaller proportion of patients were hospitalised for psychiatric reasons in the 1–1.5 years patients received PP3M compared with the 12 months prior to the treatment switch. It should be noted that the hospitalisation rate was already low in the 12 months prior to the switch, reinforcing the stability of the patient population included in this study.

Previous studies have reported a reduced risk of rehospitalisation and relapse in patients receiving LAT compared with oral antipsychotic treatment [30‐32]. A decrease in hospitalisation rate has also been demonstrated specifically with the introduction of PP1M [33] and in those switching from PP1M to PP3M [14].

The observed decrease in hospitalisation rate in the study may, in part, be due to the longer half-life and therapeutic plasma level of PP3M compared with PP1M, thereby increasing the duration of effective treatment and protection from relapse [10, 11]. This theory is supported with findings from Weiden et al. who compared time to relapse when oral paliperidone, PP1M and PP3M were discontinued; time to relapse was longest for PP3M, followed by PP1M, then oral paliperidone [32]. These findings have also been corroborated by Mathews et al. [31].

It is also possible that with less frequent dosing than PP1M, PP3M may have improved compliance and retention rates. The compliance and retention rate of PP1M have been reported to be relatively high; furthermore, compliance has been shown to be directly associated with rehospitalisation rate [34]. Further research into the role of PP3M in reducing hospitalisation may be of value.

A recent prospective trial in a pragmatic clinical setting reported that, among other benefits, switching stable patients from PP1M to PP3M resulted in reduced carer burden following 12 months of treatment [14]. In the current study, most carers reported no change in time spent caring following switch to PP3M, but over one-quarter reported a decrease, further indicating that the switch has the potential to alleviate carer burden, even in patients who were stable at baseline. Data were not collected regarding the supportive activities that carers engaged in; however, PP3M has the potential to shift a carer’s focus from medication-related issues and non-adherence to other important supportive activities relating to the patient’s health and functioning [35, 36]. Such a change could impact the carer’s perception of their role, thereby reducing carer burden.

Notably, the current study reported a disconnect between the number of hours the carer reported to spend supporting the patient and the hours recognised by the patient, physician and nurse, suggesting that the role of carers is not fully understood and appreciated by other stakeholders. This underscores the issue of ensuring that carers have appropriate support (e.g. psychosocial interventions) to help alleviate carer burden [37].

The results of the PINC-Q study add to the increasing body of evidence supporting the benefits of PP3M in a population representative of real-world clinical practice.

The most frequently reported reasons to switch from PP1M to PP3M were ‘to live life as normally as possible’ and ‘patient convenience’; the improvements reported following the switch, such as increased patient activity and social involvement, as well as a reduction in perceived stigma, appear to address these needs.

This study identified some differences in perception across the different stakeholders, highlighting the need for alignment within the treatment teams as well as improved communication between healthcare professionals and patients/carers, which could further optimise treatment of this patient population.