The consequences of non-adherence in schizophrenia: What does the latest research reveal?

The outcomes of schizophrenia treatment are dependant on many dimensions. These include symptom control, re-hospitalisation and remission rates, community tenure and stability, academic/occupational performance, economic burden, social functioning, patient satisfaction and quality of life. Over time, these outcomes have improved by early recognition and intervention with more efficacious medications.1

Professor Pierre Chue, Professor of Psychiatry at the University of Alberta, Canada, said, "We have efficacious drugs but have poor adherence, poor persistence and poor consistency." 

In order to improve schizophrenia outcomes, Prof Chue said, "The best ways are to intervene with effective medication early, promote good adherence with persistent, consistent treatment, and to combine with psychosocial interventions." Intervening early with efficacious medications reduces the duration of untreated psychosis, improves core symptoms and decreases side effects.²

The clinical efficacy of prescribed medications largely revolves around patient acceptability. This is determined by the drug’s efficacy, tolerability and safety as well as the patient’s functionality. Poor adherence, inadequate persistence and limited psychosocial interventions are all factors that limit the ability of medications to lead to successful outcomes.^3-6

Medications available for the treatment of schizophrenia are available in a variety of formulations, including oral formulations which may be in liquid (e.g. risperidone) or tablet (e.g. olanzapine) form, and intramuscular injections which may be short (e.g. ziprasidone), intermediate (e.g. zuclopenthixol) or long acting (e.g. risperidone).⁷ Some clinicians have a negative perception of injectables, and oral atypical antipsychotics are often used as first line treatment in the management of first episode psychosis.⁸

However, it may be that injectable antipsychotics can circumvent many of the difficulties faced in the treatment of schizophrenia, and first episode psychosis in particular. Although first episode psychosis is most responsive to treatment, patients are more likely to discontinue treatment. Patients typically have limited insight; are highly sensitive to side effects; often suffer from substance abuse disorders and co-morbid symptoms, including depression and anxiety; and are at a greater risk of suicide.^8,9

Data presented at the 63rd Annual Meeting of the Society of Biological Psychiatry¹⁰ demonstrated that the use of long acting injectable antipsychotics such as risperidone long acting injection (RLAI) is associated with significant reductions in suicidal ideation, violent behaviour and deliberate self-harm. Results from several clinical trials have also shown benefits with the use of injectable antipsychotics. Early phase sub-analysis of the StoRMi study showed statistically significant improvements in the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions of Severity (CGI-S) scale.¹¹ It was shown in a separate study (RIS-PSY-301) that RLAI resulted in a greater than 50% clinical response in 78% of participants at six months with statistically significant improvements in the CGI-S, Social and Occupational Functioning Assessment (SOFA), and physical component of SF-12.¹²

Importantly, a history of substance abuse does not significantly influence adherence to or the effectiveness of RLAI treatment.¹³

Professor Chue said:

"Remission is the new standard we are trying to apply in terms of outcomes. When they [patients] achieve remission, they develop insight and improve functionality in other domains of their daily life."

In a 12 month open-label study with RLAI, for those in remission at baseline, 85% maintained remission criteria at endpoint. For those patients who stabilised, but did not meet remission criteria, it was shown that one out of five will achieve full remission after one year of RLAI.¹⁴

Improved remission rates were also observed in the RIS-PSY-301 study¹² with greater than 40% achieving sustained remission at 12 months. These patients showed greater improvement in occupational status, decreased emergency centre visits, decreased hospitalisations and SF-12 Mental Component Summary scores. The implications of improved remission include greater quality of life, increased functionality, neuropsychological improvement, more insight, improved attitude to treatment, reduced relapse and decreased hospitalisation leading to better outcome.¹²

CATIE (clinical antipsychotic trials in intervention effectiveness), a large multicentre study,¹⁵ used the primary outcome measure of ‘all-cause treatment discontinuation’ to investigate broad treatment response to all second-generation drugs and compare their effectiveness to various atypicals.

Professor Chue said:

"CATIE showed that about two thirds of patients will discontinue an oral treatment within six months or less, regardless of the medication. eSTAR [electronic schizophrenia treatment adherence registery] found that, contrary to CATIE, the majority of patients who receive RLAI stick to their treatment – two thirds continue rather than discontinue."

RLAI shows good tolerability with few extrapyramidal symptom-related adverse effects and low rates of tardive dyskinesia. There is also a low incidence of adverse effects leading to discontinuation.^16-18 There are low rates of weight gain, hyperglycaemia and dyslipidaemia. It is well tolerated at the injection site compared to conventional depot.^16,17 Its use is also associated with reductions in the use of concomitant medications, including anticholinergics, anxiolytics and antidepressants.¹⁹

Visual analogue scales for acceptability are significantly higher for RLAI compared to oral atypical antipsychotics.²⁰ Drug attitude inventory ratings indicate high patient satisfaction.²¹ There is also high acceptance (92%) of RLAI in first episode psychosis when presented as part of an integrated treatment approach, despite initial refusal (85%).²² In patients switched from olanzapine, RLAI showed sustained improvement and an increase in satisfaction and quality of life.²³

Overall RLAI is an effective drug, superior to atypical orals and conventional injectables due to improving core symptoms, improved side effect profile, quality of life, social/relational function, patient acceptability and satisfaction, as well as improved likelihood of remission. Its use promotes good adherence by reducing partial adherence and ensures consistent treatment, which is important in the prevention of relapse. It is an optimal choice to achieve long-term preservation of function when offered early in therapy.¹

Professor Chue said:

"Risperidone has the benefits of an atypical combined with a long acting injectable so you can ensure medication delivery. This also brings the patient into regular contact with the treatment team."

This can be particularly useful in terms of maintaining medication adherence.

Adherence can be defined as "the ratio between observed treatment behaviour and accepted treatment standards."²⁴ This encompasses not only taking pharmacotherapy as prescribed, but also following a treatment program that may include psychosocial and behavioural treatments.⁶ Adherence is influenced by multiple factors, including those which are related to the patient, the patient’s environment, the illness, the health care provider, and the treatment.^6,25-26

Professor Chue said, "Adherence is probably one of the most, if not the most, significant outcomes that affects patients in terms of pharmacotherapy."

Partial adherence occurs when patients do not take medications as prescribed; this includes lowering or raising doses, missing doses, inconsistent timing, and drug holidays. Missing appointments, being late and not completing programs are other features of partial adherence.^6,24

Professor Chue said:

"Partial adherence is extremely common – probably 75–80% of patients don’t take the medications as they are prescribed."

A 12-month multicentre randomised naturalistic international study showed that more than 90% of patients on either typical or atypical antipsychotics were only partially adherent; the mean number of days without medication was over 100 in both groups.²⁷

Medication adherence is important in achieving optimal treatment outcomes in patients for several reasons. As the number of days of missed therapy increases, so too does the risk of hospitalisation. Those patients who miss more than 30 days of treatment throughout the year have a four-fold increased risk of hospitalisation.²⁸ The suicide attempt rate increases to 72.1 per 1000 person years for patients who miss more than 30 days of treatment, compared to only 20 for patients without interrupted therapy.²⁹

Professor Chue said:

"It is important to recognise that partial adherence is extremely prevalent, and to begin very early in the course of treatment with a program that addresses adherence issues. Physicians must assume that patients won’t take their medication as prescribed and so develop techniques to deal with this, such as communicating with caregivers or using medication which is easier to administer like a long acting injectable."

In order to optimise outcomes it is important to confirm the correct diagnosis and select medications carefully based upon their side effect profile and safety; broad efficacy as well as in subtypes; and patient acceptability. The therapeutic dose should be promoted by ensuring adequate drug levels, avoiding drug–drug interactions, addressing adherence, and treating any physical illnesses that affect metabolism.¹

In addition, patients should be reviewed regularly and treated adequately with both medical and psychosocial interventions. Remission should be the treatment goal in order to achieve better quality of life and improved insight.¹

Professor Chue said, "Schizophrenia is a complex and difficult illness to treat. However, we have learnt a great deal about the illness and we have medications that are efficacious. Develop realistic goals and outcomes and work with the patient in a collaborative process."

References

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10. Peuskens J, Rodriguez A, Tuma I, Pecenak J, van Kooten M, Eriksson L, et al. Suicidal ideation, violent behavior, and self-injury in schizophrenia patients treated with long acting risperidone: 12-month results from e-Star. Poster presented at the 63rd Annual Society of Biological Psychiatry. Washington, DC, USA: 1-3 May 2008.
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18. Möller HJ, Llorca PM, Sacchetti E, Martin SD, Medori R, Parellada E. Efficacy and safety of direct transition to risperidone long-acting injectable in patients treated with various antipsychotic therapies. Int Clin Psychopharmacol. 2005; 20(3): 121-30.
19. Taylor DM, Young CL, Mace S, Patel MX. Early clinical experience with risperidone long-acting injection:A prospective, 6 month follow up of 100 patients. J Clin Psychiatry. 2004; 65(8): 1076-83.
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