REVIEWER: Marc-André Roy, MD, Associate Professor of Psychiatry and Neurosciences, Université Laval, Québec City, Canada
Remission vs. functional recovery
Continuum of treatment goals
An important goal of schizophrenia management is to reduce the frequency, severity and duration of psychotic episodes (Hasan et al. World J Biol Psychiatry 2012;13: 318-378; Lehman et al. APA, NGC-3572, 2008). Indeed, it has been shown that about 70-80% of first-episode patients do achieve a remission of psychotic symptoms within the first year of treatment (Lieberman et al. Arch Gen Psychiatry 1993;50:369-376). Among patients receiving maintenance antipsychotic therapy, a systematic review estimated that the one-year recurrence rate was only 3%, compared to a 90% risk of relapse at two years in those who discontinued medication (Zipursky et al. Schizophr Res 2014;152:408-414).
However, while conventional measures of treatment success such as symptom remission and reduced hospitalization rates are achievable in a majority of patients, recovery rates are not as high as they could be. In addition, quality of life (QoL), a composite measure combining various dimensions of life satisfaction and level of functioning, remains poor for a sizeable proportion of patients. Accordingly, there remains a need to achieve the therapeutic goals of optimizing functional recovery (self-care, social relationships, ability to learn and work) and improving QoL, as recommended in current clinical practice guidelines (CPA. Can J Psychiatry 2005;50:1S-56S).
Remission vs. functional recovery
Symptomatic remission has been defined as improvement in a series of symptoms from the psychoticism, disorganization and negative dimensions, that should be rated (based either on the SAPS/SANS, PANSS or BPRS) as mild or less for a minimum six-month period (Andreasen et al. Am J Psychiatry 2005;162:441-449; free full text at http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.162.3.441). In contrast, recovery implies the ability to function in the community socially and vocationally. Hence, although remission facilitates recovery, these two concepts capture two overlapping yet distinct dimensions of outcome. Remission is a necessary but not sufficient step toward recovery.
At least three prospective studies on first-episode psychoses (FEP) have shown that functional recovery is less frequent than symptom remission and that only a minority of patients achieve both. Symptom remission and functional recovery were prospectively assessed in FEP patients with schizophrenia (Lambert et al. Acta Psychiatr Scand 2008;118:220-229). At three-year follow-up, symptomatic remission was achieved in 60.3%. However, only 17.1% met the criteria for symptomatic, functional and QoL recovery.
Similar results were reported in a longer term follow-up of FEP (schizophrenia or schizoaffective disorder) (Robinson et al. Am J Psychiatry 2004;161:473-479). The criteria for full recovery were remission of positive and negative symptoms; and adequate social/vocational functioning (fulfillment of role expectations, performance of daily living tasks without supervision, engagement in social interactions). At five years, 47.2% had remission of symptoms, but only 25.5% had adequate social functioning for >2 years; 13.7% met the criteria for full recovery. In one of the Early Psychosis Prevention and Intervention Centre (EPPIC) studies, about 25% of patients with FEP had achieved symptomatic remission and social/vocational recovery at seven-year follow-up (Henry et al. J Clin Psychiatry 2010;71:716-728).
A meta-analysis of 50 studies examining the proportion of patients who achieved both clinical remission and social recovery observed no increase over recent decades despite improvements in clinical management (Jaaskelainen et al. Schizophr Bull 2013; 39: 1296-1306).
An important first step to facilitate functional recovery is remission of positive and negative symptoms. In an analysis of patients entered in the Prevention and Early Intervention Program for Psychoses in Montreal, Canada, for the period 2003-2009, the duration of remission of positive and negative symptoms had the greatest impact on functioning (Jordan et al. J Clin Psychiatry 2014;75:e566-572). Similarly, a post-hoc analysis of the Schizophrenia Outpatients Health Outcomes (SOHO) study reported that patient QoL and social functioning were significantly higher for patients in symptomatic remission throughout the 36-month observation period (Haro et al. Psychiatry Res 2014;220:163-169). Factors associated with better QoL included paid employment, social activity, and higher cognitive scores. Of particular importance is remission of negative symptoms, which is associated with better psychosocial functioning, less impairment in relationships and improved work performance (Schennach-Wolff R et al. Schizophr Res 2009;113:210-217; Lysaker & Davis. Health Qual Life Outcomes 2004;2:15-20; Ventura et al. Schizophr Res 2015;161:407-413).
While the studies above indicate that not all patients with clinical remission achieve functional recovery, there is also evidence that some patients achieve recovery without achieving remission, and that factors other than remission may sustain recovery. For example, a study of 68 patients with schizophrenia spectrum disorders found that QoL was associated with self-perceived recovery even if substantial positive symptoms were present (Kukla et al. Compr Psychiatry 2014;55:1363-1368).
Yet another important outcome measure is patients’ life satisfaction, which has a complex relationship with symptom severity and social functioning. This complexity was seen in an analysis of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study, which found that about one-half of patients reported a high level of life satisfaction despite self-descriptions of being moderately ill, with moderate-to-severe symptoms and severe functional deficits (Fervaha et al. J Nerv Ment Dis 2015;203:187-193). Furthermore, a study of 72 outpatients with chronic, non-remitted schizophrenia reported that the factors associated with an overall sense of happiness were not substantially different from those seen in healthy controls (Palmer et al. Schizophr Res 2014;159:151-156). Levels of happiness were correlated with lower perceived stress, and higher levels of resilience, optimism and personal mastery. Happiness was not related to severity of positive or negative symptoms, physical or cognitive function, medical comorbidity or duration of illness. An ability to work has also been shown to play an important role in fostering well-being, enhancing social inclusion and promoting recovery (Turner et al. Work 2014; epublished May 27, 2014).
Continuum of treatment goals
Achieving remission and recovery, and supporting the person’s satisfaction with life are all treatment goals that will receive different emphases over the stages of treatment. Accordingly, medications, psychotherapy and psychoeducation may be employed to achieve a series of ongoing goals throughout the treatment course. During the acute psychotic phase, the chief objectives are to reduce symptom severity, prevent harm, address trigger factors, develop a therapeutic alliance with the patient and caregivers, improve the level of functioning and formulate a longer term treatment plan (Lehman et al. APA 2008;NGC-3572). During the stabilization and maintenance phases, the goals are to sustain symptomatic remission, manage treatment-related adverse events and maintain adherence, improve functioning, monitor QoL, and enhance the individual’s adaptation to community life (APA 2008).
Treatment may be initiated with an oral or long-acting injectable (LAI) second-generation antipsychotics (Davis & Chen. J Clin Psychiatry 2003;64[Suppl 16]: 24-33). While oral and LAI medications appear to have comparable efficacy in relapse prevention in randomized control trials (Kishimoto et al. Schizophr Bull 2014;40:192-213), this study design is generally thought not to be appropriate to compare the impact of oral versus. LAI antipsychotics on relapse prevention. Patients who are typically recruited in RCTs tend to be adherent to treatment, a characteristics that is further supported by the close follow-up typically provided in such studies; the end result is an underestimation of the effect of LAIs. Hence, studies using a more “naturalistic” design reveal that relapse and hospitalization rates may be lower in the acute and maintenance settings as a result of better treatment adherence with an LAI agent (Kishimoto et al. J Clin Psychiatry 2013;74:957-965; Emsley et al. Clin Ther 2008;30:2378-2386). LAI agents provide additional advantages over oral agents in first-episode patients, notably a lower cumulative drug exposure and a reduced risk of drug-drug interactions due to the route of administration (McEvoy J. J Clin Psychiatry 2006;67[Suppl. 5]:15-18; Gerlach J. Int Clin Psychopharmacol 1995;9[Suppl. 5]: 17-20).
The optimal agent should also facilitate functioning, and improve subjective well-being and QoL (Correll CU. J Clin Psychiatry 2011;72[suppl 1]: 9-13). Improvements in subjective well-being and QoL in the first two weeks of treatment, as evaluated by the Subjective Well-being Under Neuroleptic Treatment Scale (SWN-K) and the 36-item Short Form Health Survey (SF-36), have been shown to be predictive of symptomatic remission (Schennach-Wolff et al. World J Biol Psychiatry 2010;11:729-738). Furthermore, adverse effects should have as little impact as possible on QoL; of particular importance are extrapyramidal symptoms, diabetes and hyperprolactinemia (Briggs et al. Health Qual Life Outcomes 2008;6:105).
Results obtained in the last few years suggest that long-acting aripiprazole may achieve these various goals. Indeed, a pooled analysis of data from two trials reported that aripiprazole 400 mg IM was superior to placebo for several domains of functioning, including Personal and Social Relationships and Self-Care (Fleischhacker et al. Schizophr Res 2014;159:415-420). Cognitive domains, such as verbal memory, reaction time and reaction quality/attention, have also been shown to improve within eight weeks of aripiprazole initiation (Riedel et al. Pharmacopsychiatry 2010;43:50-57).
The effectiveness of two LAIs, aripiprazole 400 mg once-monthly and paliperidone palmitate (50-150 mg or 78-234 mg) once-monthly, was directly compared in the phase IIIb QUALIFY study (Naber et al. Schizophr Res 2015; epublished July 28, 2015). There was a significantly superior improvement in QoL score, as assessed by the Heinrichs-Carpenter QoL scale from baseline to week 28, with aripiprazole versus paliperidone IM (least square mean change 7.47 vs. 1.62). Improvement on the CGI-Severity scale was also superior with aripiprazole IM versus paliperidone IM at endpoint (LSM difference between treatments in change from baseline to Week 28 was -0.28).
Patients’ QoL is poor at first episode and will continue to worsen during the course of illness (Bobes et al. Dialogues Clin Neurosci 2007;9:215-226). While remission of positive and negative symptoms remains the cornerstone of therapy, efforts to improve social/occupational functioning and QoL are integral to improving outcomes during the long-term management of patients with schizophrenia.