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Improving long-term outcomes in schizophrenia: Intervene early, aim for recovery

Prof. Silvana Galderisi
University of Luigi Vanvitelli, Naples, Italy
Dr. Ana Catalan
Basurto University Hospital, University of Basque Country, and BioCruces Bizkaia Research Institute, Spain
King’s College London, UK
Prof. Christoph Correll
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, US
Charité – Universitätsmedizin Berlin, Germany
15 Oct 2020

Early intervention is crucial to achieving favourable long-term outcomes in patients with schizophrenia. However, adherence to antipsychotic therapy is often suboptimal, resulting in an increased risk of relapse and impaired functioning. At a Janssen-sponsored symposium during the 33rd European College of Neuropsychopharmacology (ECNP) Congress Virtual, experts discussed the importance of early and holistic treatment of schizophrenia. Recent data on symptomatic and functional remission rates with long-acting injectable (LAI) antipsychotics were reviewed to support their use as maintenance therapy, particularly, early in the course of illness.

Aiming for recovery in schizophrenia

“The goal of schizophrenia management has evolved from relapse prevention to symptom remission and psychosocial functional recovery in real life,” said Professor Silvana Galderisi of the University of Luigi Vanvitelli, Naples, Italy. “However, despite antipsychotic treatment, only 7 percent of patients living in the community achieved symptom remission and functional recovery.” [World Psychiatry 2014;13:275-287; European Arch Psychiat Clin Neurosci 2017;267:285-294]

“Early intervention should be provided to improve recovery rates and to prevent chronicity of illness,” she continued. “Treatment should be personalized and integrated to target multiple determinants of functional outcome, including positive and negative symptoms, cognitive dysfunction, internalized stigma, and resilience. This holistic approach helps patients achieve a meaningful life, with increased life expectancy.” [Psychiatr Serv 2005;56:735-742; Psychiatr Q 2019;90:553-563; World Psychiatry 2014;13:275-287]

First-episode psychosis: Crucial window for intervention

“The early trajectory of illness in first-episode psychosis predicts long-term outcome,” said Dr Ana Catalan of the Basurto University Hospital, University of Basque Country, and BioCruces Bizkaia Research Institute in Spain, and King’s College London, UK. [Front Psychiatry 2018;9:580]

“Early intervention in early-phase psychosis is shown to improve outcomes, including psychiatry hospitalization, severity of positive and negative symptoms, and involvement in school or work, compared with treatment as usual,” she noted. [JAMA Psychiatry 2018;75:555-565] “Early intervention in first-episode psychosis is also cost-effective across different health systems, particularly in high-income countries.” [Br J Psychiatry 2019;215:388-394]

Suboptimal adherence increases relapse risk

“However, patients with psychosis are usually not adherent to antipsychotic therapy, which increases their risk of relapse,” said Catalan.

Among patients hospitalized for schizophrenia for the first time, only 58.2 percent collected their antipsychotic prescription in the first 30 days after hospital discharge, and only 45.7 percent continued their initial treatment for ≥30 days. [Am J Psychiatry 2011;168:603-609] Subtherapeutic antipsychotic plasma levels, indicating suboptimal adherence, are associated with a significantly higher risk of hospitalization in schizophrenia patients. [Acta Psychiatr Scand 2018;137:39-46]

“Patients with remitted first-episode schizophrenia who discontinued antipsychotic treatment had a significantly increased risk of psychotic recurrence at 6–24 months and ≥36 months,” said Catalan. [JAMA Psychiatry 2016;73:211-220] “Those who relapsed in association with treatment nonadherence also had a significantly lower response to the same antipsychotic in their second vs first episode of schizophrenia.” [Neuropsychopharmacology 2019;44:1036-1042]

Poor adherence to antipsychotic therapy is also associated with a significantly increased suicide risk (partial adherence: adjusted odds ratio [aOR], 6.66; 95 percent confidence interval [CI], 1.10 to 128.04) (nonadherence: aOR, 12.43; 95 percent CI, 2.06 to 238.66). [Eur J Clin Pharmacol 2019;75:1421-1430]

“It is therefore important to encourage adherence and act before the first treatment discontinuation,” Catalan emphasized. “Antipsychotic maintenance treatment should be considered a priority to prevent relapses and hospitalizations, along with psychosocial and psychotherapeutic interventions.”

Role of second-generation LAI antipsychotics

“Increased and earlier use of LAI antipsychotics is needed to achieve the best possible outcomes, preserve psychosocial function, prevent stigma, and reduce secondary treatment resistance in schizophrenia. Effective maintenance treatment and relapse prevention can improve functioning, especially early in the course of illness,” said Professor Christoph Correll of the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, US, and CharitéUniversitätsmedizin Berlin, Germany.

“Second-generation LAI antipsychotics enable early identification of nonadherence, provide a mechanism for adherence monitoring, avoid the need to remember daily medication intake, ensure regular interactions between patients and medical staff, and are associated with reduced relapse and hospitalization rates,” said Catalan. [Ther Adv Psychopharmacol 2014;4:198-219]

In a real-world study, LAI antipsychotics demonstrated lower risks of psychiatric rehospitalization vs their equivalent oral formulations (hazard ratio [HR], 0.78; 95 percent CI, 0.72 to 0.84) in schizophrenia patients. Among 20 oral or injectable medications evaluated, the risk of psychiatric rehospitalization was the lowest with monthly paliperidone palmitate (PP1M; a second-generation LAI antipsychotic) (HR, 0.51; 95 percent CI, 0.41 to 0.64) vs no antipsychotic treatment. [JAMA Psychiatry 2017;74:686-693]

“In schizophrenia patients with a history of incarceration or substance abuse, PP1M also demonstrated superiority in estimated time to first treatment failure and first psychiatric hospitalization or arrest or incarceration vs oral antipsychotics,” said Correll. [J Clin Psychiatry 2015;76:554-561]

In the event of treatment withdrawal after stabilization, the median time to relapse was 172 days with PP1M and 395 days with 3-monthly paliperidone palmitate (PP3M), compared with 58 days with daily extended-release oral paliperidone. [J Clin Psychiatry 2017;78:e813-e820]

Compared with no antipsychotic treatment, second-generation LAI antipsychotics are also associated with lower mortality rates (HR, 0.38; 95 percent CI, 0.30 to 0.47) than first-generation LAI antipsychotics (HR, 0.52; 95 percent CI, 0.45 to 0.60), second-generation oral antipsychotics (HR, 0.58; 95 percent CI, 0.52 to 0.65), and first-generation oral antipsychotics (HR, 0.75; 95 percent CI, 0.66 to 0.85). “The lowest mortality was observed with PP1M [HR, 0.11; 95 percent CI, 0.03 to 0.43],” noted Correll. [Schizophr Res 2018;197:274-280]

Earlier use of PP1M/PP3M: Greater efficacy

While PP1M has demonstrated improvements in positive and negative symptoms in patients with recently diagnosed (≤2–5 years) or chronic (>5 years) schizophrenia, the efficacy was significantly greater in recently diagnosed patients. “The improvements in symptoms were even more pronounced in patients diagnosed in ≤2 years, highlighting the importance of using LAI antipsychotics at early stages of illness,” said Catalan. [Expert Opin Pharmacother 2017;18:1799-1809]

In another study, a significantly higher rate of response (ie, ≥20 percent improvement in Positive and Negative Syndrome Scale [PANSS] total score from baseline to endpoint) to PP1M was observed in patients with recently diagnosed (≤3 years) vs chronic (>3 years) schizophrenia (71.4 percent vs 59.2 percent; p=0.0028). [Expert Opin Pharmacother 2016;17:1043-1053]

“Hospitalization days were also significantly [p<0.0001] reduced in patients with recent-onset [≤5 years] schizophrenia who were switched from oral antipsychotics to PP1M due to insufficient response to oral treatment,” said Correll. “The mean number of hospitalization days per person per year was reduced from 74.3 in the year before PP1M initiation to 19.7 and 18.9 at 12 months and 18 months after PP1M initiation, respectively.” [Neuropsychiatr Dis Treat 2015;11:657-668]

Improved remission rates and functional outcomes

Treatment with PP1M was shown to provide significant improvements in functioning in patients with recently diagnosed (≤3 years) or chronic (>3 years) schizophrenia, with a significantly higher proportion of recently diagnosed patients achieving mild or no functional impairment at study endpoint vs chronic patients (47.1 percent vs 36.7 percent; p=0.0058). [Expert Opin Pharmacother 2016;17:1043-1053]

“Importantly, employment rates among PP1M-treated patients improved significantly, from 24.3 percent at baseline to 32.5 percent at 1 year and 34.6 percent at 2 years [p<0.001 for both],” said Correll. [Innov Clin Neurosci 2020;17:40-44]

In another recent study, PP1M and PP3M demonstrated significant improvements in positive and negative symptoms as well as functioning in patients with schizophrenia for ≤5 years to >10 years. “Symptomatic and functional remission was maintained in a significantly [p<0.05] higher proportion of patients with earlier-phase [≤5 years and 610 years] vs later-phase [>10 years] schizophrenia, highlighting the importance of LAI antipsychotic treatment particularly in the early phase of illness,” Correll noted. (Figure) [Early Interv Psychiatry 2020;14:428-438]


Offering LAI antipsychotics: Presentation matters

When offering LAI antipsychotics to patients, psychiatrists often focused on the modality of injection (91 percent) and rarely on the benefits (9 percent). As a result, only 33 percent of LAI antipsychotic recommendations were accepted by patients in the initial discussion. However, after a post-visit interview that involved probing of patients’ feelings about medications, 96 percent of patients who declined the initial offer said they would be willing to try a LAI antipsychotic. [J Clin Psychiatry 2015;76:684-690]

In addition to involving patients in treatment decisions, LAI antipsychotic–focused staff training may also enhance the uptake of LAI antipsychotics. In a study, LAI antipsychotic–focused staff training that included shared decision-making and communication strategies, review of frequently asked questions, and skills and solutions to overcome logistical barriers resulted in the use of at least one long-acting antipsychotic injection in 91 percent of patients with early-phase schizophrenia. [J Clin Psychiatry 2019, doi: 10.4088/JCP.18m12546]

“Presentation matters. We can’t be convincing to patients unless we are convinced about the benefits of LAI antipsychotics,” commented Correll.

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