QUALIFY study
Commentary from Dr. Ofer Agid
Considerable advances have been made in recent decades in the management of schizophrenia. A majority of first-episode patients achieve remission of psychotic symptoms within the first year of treatment (Lieberman et al. Arch Gen Psychiatry 1993;50:369-376), and early recurrence rates are low (Zipursky et al. Schizophr Res 2014;152:408-414).
A more elusive goal is full recovery of social and occupational functioning and improvement in patients’ quality of life. For example, in the Early Psychosis Prevention and Intervention Centre (EPPIC) studies, about 25% of patients with first-episode schizophrenia had achieved symptomatic remission and social/vocational recovery at seven-year follow-up (Henry et al. J Clin Psychiatry 2010;71:716-728). (See also Beyond remission: redefining the goal of schizophrenia management. NeuroSens, August 4, 2015.) Both social/occupational functioning and QoL have been shown to be predictive of relapse (Boyer et al. BMC Psychiatry 2013;13:15; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3544732/pdf/1471-244X-13-15.pdf).
Quality of life (QoL), generally defined as a composite measure of various dimensions of life satisfaction and level of functioning, remains poor for a sizeable proportion of treated patients. Accordingly, recent clinical practice guidelines have recommended QoL improvement as an important therapeutic goal of schizophrenia management (CPA. Can J Psychiatry 2005;50:1S-56S).
A number of studies have suggested that atypical antipsychotic medications improve patient QoL, most notably in the first five years of therapy (Guo et al. Compr Psychiatry 2012;53:1006-1012; Wehmeier et al. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:703-712). However, few studies have examined the effect of long-acting injectable (LAI) atypical antipsychotics on QoL, and none has directly compared LAIs with QoL as a primary endpoint.
QUALIFY study
QUALIFY (Quality of Life with Abilify Maintena) is the first head-to-head study to compare the effect of two LAIs on health-related QoL and functioning. Results were recently published (Naber et al. Schizophr Res 2015; epublished July 28, 2015), with additional analyses presented at the recent 28th European College of Neuropsychopharmacology (ECNP) congress, held August 31–September 1, in Amsterdam. The primary objective of the 28-week open-label phase IIIb study was to compare QoL in patients treated with aripiprazole 400 mg once-monthly or paliperidone 50-150 mg/month (in Canada and EU; 78-234 mg/month as paliperidone palmitate in the US). QUALIFY was a non-inferiority study with a pre-defined analysis to establish superiority if non-inferiority was demonstrated.
Adult subjects (mean age 42 years) were enrolled if they had stable schizophrenia and if, in the clinician’s judgment, they would benefit from a switch to an LAI due to a prior inadequate response, poor tolerability or lack of adherence with an oral antipsychotic medication. A total of 295 patients were randomized to a three-week conversion phase of oral aripiprazole 5-30 mg/day or oral paliperidone 3-12 mg/day. Patients who tolerated treatment initiated LAI therapy over five weeks, followed by a 20-week continuation phase.
The primary endpoint was change from baseline to week 28 on the Heinrichs–Carpenter Quality-of-Life Scale (QLS), which assesses the long-term impact of schizophrenia on social, occupational, and psychological functioning (Heinrichs et al. Schizophr Bull 1984;10:388-398). The 21-item QLS is rated by the clinician based on a semi-structured interview; a 5-point change is considered clinically meaningful (Jones et al. Arch Gen Psychiatry 2006;63:1079-1087; Falissard et al. Int J Methods Psychiatr Res 2015; epublished August 4, 2015). The QLS has been used in other schizophrenia trials (CATIE, CUtLASS), and was selected since it provides an assessment of the long-term impact of schizophrenia on social, occupational and psychological functioning that is relevant to patients. Other measures used were the Clinical Global Impression-Severity (CGI-S) scale, and the 12-item Investigator’s Assessment Questionnaire (IAQ) (Tandon et al. Psychiatry Res 2005;136:211-221), which evaluates the effectiveness of the current treatment relative to previous treatment.
A total of 67.6% of patients in the aripiprazole group and 56.5% in the paliperidone group completed the 28-week study. The least squares mean (LSM) change from baseline on the QLS total score was 7.47 with LAI aripiprazole versus 2.80 with LAI paliperidone. QLS scores with aripiprazole were significantly superior to paliperidone beginning at week 8 and continuing until endpoint. Moreover, there was a significant difference in favour of aripiprazole in LSM change from baseline in CGI-S score starting at week 3 and continuing until endpoint. LSM IAQ total score at week 28 was also significantly improved with aripiprazole versus paliperidone.
In a pre-planned analysis stratified by age, there was a statistically significant treatment difference in favour of aripiprazole LAI at week 28 compared to paliperidone in younger patients (< 35 years), and improvements were observed with aripiprazole in all four QLS domains (Interpersonal Relations, Instrumental Role, Intrapsychic Foundations and Common Objects and Activities) (Naber et al. ECNP 2015; abstract P.3.d.080). In contrast, significant improvement was seen in only one of four domains with paliperidone.
The most common reason for treatment discontinuation was adverse events. The rate of discontinuation due to adverse events was 11.1% with aripiprazole compared to 19.7% with paliperidone. During the continuation phase, the most common adverse events with aripiprazole and paliperidone were increased weight (10.1% vs. 15.6%, respectively), psychotic disorder (2.5% vs. 5.5%), and insomnia (2.5% vs. 5.5%). The mean change in body weight from baseline to week 28 was 0.2 kg with aripiprazole and 1.4 kg with paliperidone; the incidence of clinically significant weight gain (>7% change from baseline) was 11.1% and 14.6%, respectively. Extrapyramidal symptoms were uncommon (<5%) with both treatments.
The authors noted that improvements in functioning appeared to be largely attributable to gains in the underlying intrapsychic foundation (sense of purpose, curiosity, empathy, emotional interaction). They speculated that the greater QoL benefit with aripiprazole may be due to its mechanism of action. Unlike other atypical antipsychotics, aripiprazole is a partial dopamine D2 receptor agonist rather than a D2 receptor antagonist, which may result in modulation of dopaminergic activity and improvements in negative symptoms and cognitive function (Lieberman JA. CNS Drugs 2004;18:251-267).
They concluded that since the greatest impact on QoL was seen in younger patients, earlier treatment with aripiprazole LAI should be considered to prevent deterioration in patients’ daily functioning and quality of life.
Comment
Dr. Ofer Agid: Studies measuring treatment outcome in patients with schizophrenia usually focus on the positive and negative symptom domains. Moreover, the definitions of ‘remission’ and ‘response’ in schizophrenia are usually based on the patients’ scores on these domains.
While the main goal of psychopharmacological treatment in schizophrenia is achieving symptomatic remission, less attention is dedicated to other – no less important – domains. The level of happiness of patients with schizophrenia, their value systems, the personal goals of patients and their quality of life, receive less attention as specific treatment goals of psychopharmacological intervention.
Quality of life (QoL) of patients with schizophrenia is an important goal of treatment. However, it is rarely placed as a therapeutic goal of medical treatment. There are some challenges in investigating QoL in schizophrenia: there is no clear consensus on the definition and the underlying concept of quality of life; there is a need for standardized specific QoL; and there is no one single ‘best fit’ scale for QoL. A body of data shows that QoL is worse in patients with schizophrenia compared with that of healthy controls, and that QoL is correlated with the level of adherence to medications and the risk of relapse.
The QUALIFY study, a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia, suggested superior improvements on clinician-rated health-related QoL for aripiprazole once-monthly vs paliperidone palmitate. This is a ground-breaking study in the sense of suggesting QoL as a treatment goal beyond symptomatic management.
The QUALIFY study suggests a new point of view in investigating treatment response, showing a significant difference in this measure between two atypical long-acting injectable (LAI) antipsychotics. This is the first study comparing LAIs with QoL as a primary endpoint. The results suggest that LAIs might be similar in their efficacy – but not necessarily in terms of their impact on QoL. This difference might be related to the different mechanism of action of these two LAIs (partial dopamine D2 agonism vs. dopamine D2 antagonism), and may offer benefits to a subset of patients in domains beyond symptomatic management.