Comment by Dr. William MacEwan
In recent years, the goals of schizophrenia management have moved beyond the traditional model of treating positive and negative symptoms to a more holistic approach that emphasizes functional recovery, psychosocial functioning and quality of life (QoL) (Juckel & Morosini. Curr Opin Psychiatry 2008;21:630-639). Indeed, over a decade ago, Naber and colleagues proposed that quality of life should be considered as important as psychopathology in managing patients with schizophrenia (Naber et al. Schizophr Res 2001;50:79-88). To be sure, achieving symptomatic remission with antipsychotic medications is the necessary first step to functional recovery (Kokaçya et al. Noro Psikiyatr Ars 2016;53:328-333), and the prevention of clinical relapses will have the greatest impact on QoL (Briggs et al. Health Qual Life Outcomes 2008;6:105-13). A caveat, however, is that clinical effectiveness alone may not necessarily translate to improvements in QoL and patient self-rated life satisfaction, as the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study reported (Fervaha et al. Eur Neuropsychopharmacol 2014;24:1078-1085).
Second-generation antipsychotic agents are now the mainstay of treatment due to their broader efficacy and improved tolerability, with associated gains in functional outcomes and QoL (Remington et al. CNS Drugs 2010;24:9-20). As these agents are roughly comparable with regard to efficacy, treatment selection may be based in part on a drug’s unique mode of action, which may be beneficial or detrimental to the individual patient’s comorbid medical and psychiatric conditions; and its side effect profile, which may affect QoL, treatment satisfaction and adherence. The route of administration is also a consideration; a long-acting injectable (LAI) formulation may be preferred to avoid peak/trough effects and improve long-term adherence to the regimen.
A number of recent studies have examined QoL with antipsychotic agents. In the double-blind Neuroleptic Strategy Study, patients were randomized to either a first- or second-generation antipsychotic (Grunder et al. Lancet Psychiatry 2016;3:717-729). At 24-week follow-up, QoL, as assessed with the Short Form (SF)-36, was superior with a second-generation agent. A unique feature of the study was that the treatments used were individualized to the patient. In the Antipsychotic Long-acting Injection in Schizophrenia (ALTO), a non-interventional study in Europe, patients treated with an LAI reported a good level of well-being overall (Llorca et al. Eur Psychiatry 2018;52:85-94). QoL scores were higher in those receiving a second-generation rather than a first-generation LAI, although it should be noted that FGA LAIs were generally reserved for more severe patients.
Two atypical antipsychotic LAIs, aripiprazole and paliperidone, were compared in the 28-week QUALIFY study (Naber et al. Schizophr Res 2015;168:498-504). Aripiprazole 400 mg once-monthly was superior to paliperidone once-monthly on the physician-rated Heinrichs-Carpenter Quality of Life Scale (QLS) (see also Quality of life in schizophrenia: the QUALIFY trial, NeuroSens, October 14, 2015, with commentary by Dr. Ofer Agid). A post-hoc analysis reported that aripiprazole LAI was also superior on patient-rated scales for subjective well-being (SWN-K) and tolerability/QoL (Potkin et al. Int Clin Psychopharmacol 2017;20:40-49). Improvements in QoL were maintained and increased slightly over the 24-week extension study (Naber et al. Schizophr Res 2018;192:205-210). The differences in QoL between these two agents were attributed to an improvement in clinical symptoms and better effectiveness with aripiprazole LAI; effectiveness included improvements in symptoms and functioning, a favourable tolerability profile and a lower all-cause discontinuation rate (Naber 2015).
Also important to QoL is sexual functioning during treatment (reviewed in Just MJ. Neuropsychiatr Dis Treat 2015;11:1655-1661). In QUALIFY, the risk of sexual dysfunction was 71% lower at week 28 with aripiprazole LAI compared to paliperidone LAI (odds ratio 0.33 for men, 0.14 for women) (Potkin et al. Int Clin Psychopharmacol 2017;32:147-154). This was attributed to the prolactin-sparing effects of aripiprazole: mean prolactin concentrations decreased with aripiprazole LAI (-150.6 mIU/L) and increased with paliperidone LAI (+867.5 mIU/L). Patients who switched from sexual dysfunction at baseline to no dysfunction at endpoint showed a trend to greater improvement in QLS scores.
An emerging area of interest is multimorbidity and its impact on QoL in patients with schizophrenia (Bhalla et al. Schizophr Res 2018;201:39-45); multimorbidity comprises other psychiatric diagnoses and/or substance use disorders (SUD) in patients with schizophrenia. This issue was examined in a recent in-patient study of adults with psychosis (schizophrenia spectrum, other psychotic disorders, bipolar disorder with psychotic features) and SUD, defined according to DSM-5 criteria (Cuomo et al. Neuropsychiatr Dis Treat 2018;14:1645-1656; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC6016599/pdf/ndt-14-1645.pdf). Patients were randomized to aripiprazole 400 mg once-monthly or paliperidone 100 mg once-monthly for one year; patients remained hospitalized until stable, then were followed as outpatients. QoL was evaluated with the World Health Organization (WHOQOL-BREF) scale, which assesses 26 items in four domains (physical and psychological health, social relationships and environment). Substance craving was evaluated with the VAScrav tool. At one year, mean scores on all four WHOQOL domains were significantly better in the aripiprazole LAI group compared to paliperidone LAI; the scores were 82.00 vs. 66.26 for aripiprazole and paliperidone, respectively, for physical health; 82.62 vs. 60.27 for psychological health; 81.02 vs. 65.41 for social relationships; and 85.44 vs. 71.04 for environment.
The substances abused included alcohol, cannabinoids, cocaine, MDMA (aripiprazole group only), ketamine (aripiprazole group only) and opioids. The aripiprazole group had higher craving scores at baseline, and more cases of multiple drug use. At one year, aripiprazole LAI had a stronger effect on craving reduction than paliperidone LAI. In the subgroup with cannabinoid use disorder (n=61), aripiprazole LAI was associated with significant improvement on the CGIs, VAScrav, and all WHOQOL domains; there were significant improvements with paliperidone on the CGIs and VAScrav, and on only one of the four WHOQOL domains. Subgroup analyses were not performed for other substances.
These results were supported by a post-hoc analysis of patients with comorbid SUD in the QUALIFY study (Naber et al. ACNP 2015; abstract W154). For the subgroup of patients with comorbid SUD (19-22% of total sample), QLS total score improved with aripiprazole LAI and worsened with paliperidone LAI (LSM change from baseline +6.4 vs. -4.7). The authors concluded that the treatment effectiveness of aripiprazole LAI on QoL was not compromised by concomitant recreational drug use.
The different effects on substance craving may be due to the receptor-interaction profile of the two drugs. The neurobiological mechanisms of craving (preoccupation/anticipation stage) have not been fully elucidated but appear to involve dysregulation of dopaminergic function in different brain regions. Paliperidone, the active metabolite of risperidone, is a dopamine D2 and serotonin 5HT2A receptor blocker; no studies have examined its use in comorbid psychosis and SUD. Aripiprazole has mixed receptor effects, including a high affinity for dopamine D2 and D3 receptors and moderate affinity for D4 receptors; of particular interest to SUD is its partial D2 agonist effect. Naber and colleagues suggested that the dopamine partial agonist activity of aripiprazole might spare the dopamine reward system (Naber, ACNP 2015).
In a study of patients with bipolar and schizoaffective disorder with comorbid SUD, switching to aripiprazole from another antipsychotic resulted in a reduction in alcohol craving and use, and reduced cocaine craving (but not use) (Brown et al. J Clin Psychiatry 2005;66:756-760). Two additional pilot studies reported a reduction in cocaine craving and use with aripiprazole in patients with SUD (Meini et al. Curr Pharm Des 2011;17:1376-1383), and with schizophrenia and comorbid SUD (Beresford et al. J Clin Psychopharmacol 2005;25:363-366). A subsequent study by the Beresford group found that cocaine craving was reduced with aripiprazole, but only after a 6-week lag period (Beresford et al. J Clin Psychopharmacol 2017;37:657-663). The authors concluded that dopamine modulation can reduce cocaine cravings but requires an acclimation period; they recommended that a trial of depot aripiprazole may be useful. It could be speculated that a reduction in substance craving would be associated with improvements in QoL, but this has not been investigated.
Second-generation antipsychotics were recommended a decade ago for the treatment of schizophrenia and comorbid SUD (Wobrock & Soyka. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1375-1385). However, there is a need for additional research on the neurobiological and cognitive processes involved in comorbid psychosis and SUD, and to determine whether these processes differ with the substances used (Thoma & Daum. Psychiatry Clin Neurosci 2013;67:367-383). More effective management of comorbid SUD will be a necessary component of the broader initiative of improving and maintaining QOL in patients with schizophrenia.
Dr. William MacEwan: This report addresses two clinical issues: Quality of Life (QoL) as a treatment outcome measure in schizophrenia; and treating psychosis comorbid with substance use disorder (SUD). Are QoL measures the best way to enhance our understanding of outcomes in schizophrenia? Secondly, does partial D2 agonism (e.g. aripiprazole) spare the dopamine reward system, allowing a beneficial effect for both the psychosis and SUD, as suggested by Naber (2015)? The inherent question linking these topics is: do medications that have partial D2 agonism provide better outcomes in both areas?
In treatment studies of schizophrenia using measures of psychosis and QoL, three areas of study have shown improvement. Second-generation oral and long-acting (LAI) antipsychotic medications have been shown to be superior. The QUALIFY study also indicated LAI aripiprazole was superior to LAI paliperidone (Neurosens, Oct 2015). QoL, to be a valid measure of response, has to be able to differentiate improvement in treatment modalities. The Qualify study supports QoL as a valid measure by showing superiority of aripiprazole LAI.
In psychosis comorbid with SUD, clinical improvement with aripiprazole (QoL, psychosis symptoms, drug craving) was seen in two studies, a QUALIFY post-hoc analysis as well as a randomized controlled trial of aripiprazole versus paliperidone. Both showed aripiprazole was superior in reducing psychosis, decreasing drug craving as well as use of drugs of abuse.
A study by Cuomo (2018) highlights how, in schizophrenia, partial dopamine agonism with antipsychotic medications (e.g. aripiprazole) may be key to improving psychosis, QoL, drug craving and use.
Clinicians need to measure quality of life so psychiatric evaluations become more relevant in gauging a patient’s life improvement. Finally, there is a need for further treatment research into patients with psychosis comorbid with SUD so we can provide improved outcomes in this complex patient group.
Dr. MacEwan is Clinical Professor, Department of Psychiatry, University of British Columbia, Vancouver, Canada.