How can the new antipsychotic medications improve quality of life in patients with schizophrenia?

KEYWORDS:

• Second-generation antipsychotic
• clinical effectiveness
• quality of life
• treatment satisfaction
• remission

1. Introduction

Quality of life (QoL) is garnering increasing interest as an important outcome variable in the treatment of schizophrenia, with early QoL improvement predictive of long-term symptomatic and functional remission [1]. Over the last decade, various clinical practice guidelines for the treatment of schizophrenia have emphasized QoL as a component of the major goals of long-term illness management [2]. In fact, QoL is now one of the end points required by European Network for Health Technology Assessment for the Rapid Relative Effectiveness Assessment of Pharmaceuticals [3]. Thus, it behooves clinicians to consider the importance of QoL in the same way that the more traditional domains of efficacy and tolerability are viewed, as all represent components of clinical effectiveness.

Efficacy is typically demonstrated in randomized, controlled trials of fixed duration with select subjects treated according to fixed dosing strategies to an end point involving a defined degree of change on a rating scale from baseline. These data may not generalize to ‘real-world’ clinical settings where patients demonstrate greater range, chronicity, and severity of psychopathology; poorer adherence and comorbidities resulting in polypharmacy; and dosing according to ‘clinical judgment’ [4]. Clinical effectiveness may represent a better test of the ‘real-world’ usefulness of medications, and clinically effective treatments may thus include outcome domains beyond efficacy and tolerability such as functionality, treatment satisfaction, and QoL [5].

2. Assessing QoL

The World Health Organization definition of QoL, ‘an individual’s perception of his/her position in life in the context of the culture and value systems in which he/she lives, and in relation to his/her goals, expectations, standards, and concerns’, is clear and straightforward [6]. However, for individuals suffering from schizophrenia, the core symptoms of the illness impact on subjective experience; thus, subjective and objective evaluation of QoL may show some important differences [7,8]. A patient’s self-evaluation of QoL focuses on what is important to that individual, whereas a clinician typically evaluates aspects such as well-being and functionality that contribute to how effective the intervention is. The complexity of assessment of QoL in schizophrenia is reflected in the fact that there are over 35 QoL scales used, ranging from generic to specific and from subjective to objective; some limitations of these scales include poor sensitivity to change, lack of practicality, poor psychometrics, or use restricted to certain environments [1].

3. Factors associated with QoL

There are many factors associated with decreased QoL in schizophrenia including symptoms, side effects, stigma, adverse life experiences, low socioeconomic status, poor life skills, and limited psychosocial support [7–9]. However, when considering subjective QoL, it is the presence of depressive symptoms that appear to have the most impact, whereas for objective QoL, negative symptoms followed by cognitive symptoms are seen as the relevant symptom domains [10]. Positive symptoms show little correlation with either subjective or objective QoL, but poor life skills impact upon both [9].

4. The role of second-generation antipsychotics

The advent of the second-generation antipsychotics (SGAs) was heralded as an advance in efficacy and tolerability; however, with the exception of clozapine, the degree of differentiation from the first-generation antipsychotics (FGAs), particularly with respect to positive symptoms, is modest. In terms of tolerability, the SGAs are associated with less neurological toxicity than FGAs, but a significantly worse metabolic profile, at least for several of the class. Though still subject to debate in terms of overall benefit, the SGAs do demonstrate greater efficacy with respect to negative and cognitive symptoms, which together with depressive symptoms appear to be among the most relevant domains to QoL [10].

The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study did not find an advantage for oral SGAs over FGAs (oral and long-acting injections [LAIs]) in objective QoL (or symptom control or side effects), measured with the Quality of Life Scale (QLS) [11]. A post hoc analysis of the Clinical Antipsychotic Trial of Intervention Effectiveness study showed no significant differences between any of the antipsychotics (four SGAs and one FGA) on objective QoL, also measured using the QLS [12]; a separate analysis of the data failed to show any differences on a single, self-rated Satisfaction with Life item derived from the Lehman Quality of Life Interview [13]. However, a double-blind, randomized study (Neuroleptic Strategy Study) evaluating subjective QoL as the primary outcome measure with the Short-Form 36 Health Survey coupled with the Clinical Global Impression-Improvement scale found significantly greater improvement with SGAs compared with FGAs [14]. Finally, a recent, randomized, rater-blinded, open-label, non-inferiority study comparing two SGAs (both LAIs, thus adherence was controlled for) on a primary outcome measure of objective QoL using the QLS was conducted [15]. A small (though significant) difference between the two agents was found, and younger patients (≤35 years) compared with older patients (>35 years) responded significantly better on QoL as well as on other measures of efficacy and functionality.

5. Expert opinion

Clinicians have been historically focused primarily on efficacy and tolerability when evaluating antipsychotics in the treatment of schizophrenia; however, other domains that may be of potentially equal or greater importance to patients, i.e., QoL and treatment satisfaction, have not been viewed as perhaps as relevant. Yet, these domains are components of clinical effectiveness that contribute to adherence and persistence with treatment and thus impact upon outcome. Possibly one of the reasons that QoL has not been the focus of attention is because it is difficult to measure, and it is unclear what aspects of QoL are really meaningful to individuals suffering from schizophrenia.

Recent research has demonstrated that subjective and objective QoL represent quite different constructs when applied to schizophrenia, with the former predicated more on the presence of depressive symptoms, while the latter is predicated on the presence of negative, and to a lesser extent, cognitive symptoms; poor life skills contribute to both. It is interesting to note, and perhaps contrary to usual perception, that positive symptoms play little role in determining QoL, whether from a subjective or objective perspective, but early overall symptomatic response is predictive of greater long-term QoL.

While the SGAs potentially have a greater impact on the domains associated with QoL, earlier studies have not found an advantage of SGAs over FGAs in QoL, nor indeed, in very many efficacy or tolerability measures. This debate is ongoing, and it is beyond the scope of this article to address in depth all of the contributory reasons. However, methodological issues have been raised in terms of dropout rates, small numbers of patients per treatment, removal and/or addition of certain antipsychotics during the course of the studies, drug and patient selection not fully randomized, and dosing and formulations differences. Nonetheless, these were large-scale and independent studies with very consistent findings which make it difficult to reconcile with the putative benefits of the SGAs in QoL.

It may be that to fully exploit the advantages of a particular SGA, greater attention to such factors as dosing and titration and the achievement of early response is required. The efficacy of the SGAs at defined dose ranges in affective disorders, and some evidence of their effects on relevant symptom domains in schizophrenia, would suggest that these agents have the potential to target symptoms relevant to QoL. Indeed, the more recent studies of QoL in schizophrenia show a benefit of SGAs when treatment is individualized and for particular patient groups. It remains to be seen whether this effect is greater for subjective or objective QoL, given that these domains are linked to different symptoms. Clearly more research needs to be done to determine the correlates of QoL that can be addressed in order to optimize outcome, as well as to understand the relationships with other components of clinical effectiveness such as treatment satisfaction and functionality. Indeed, the understanding of what constitutes remission in schizophrenia may need to be expanded (>35 years) beyond the symptom control typically captured in standard efficacy measures, to include functionality and QoL.

Declaration of interest

P Chue has previously received research and educational grants as well as honoraria for advisory boards from Janssen, Pfizer, Eli Lilly, AstraZeneca, Otsuka, GlaxoSmithKline, Lundbeck, Bristol-Myers Squibb, Hoffmann la Roche, Sunovion, Mylan, Valeant, Paladin and Novartis. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Funding

No funding or writing assistance of any kind was received for article.