Patient Related Outcome Measures
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`Nonadherence with antipsychotic
`medication in schizophrenia: challenges
`and management strategies
`
`Peter M Haddad1,2
`Cecilia Brain3,4
`Jan Scott5,6
`1Neuroscience and Psychiatry Unit,
`University of Manchester, Manchester,
`2Greater Manchester west Mental
`Health NHS Foundation Trust, Salford,
`UK; 3institute of Neuroscience and
`Physiology, Department of Psychiatry
`and Neurochemistry, Sahlgrenska
`Academy, University of Gothenburg,
`4Nå Ut-teamet, Psychosis Clinic,
`Sahlgrenska University Hospital,
`Gothenburg, Sweden; 5Academic
`Psychiatry, institute of Neuroscience,
`Newcastle University, 6Centre for
`Affective Disorders, institute of
`Psychiatry, London, UK
`
`Correspondence: Peter M Haddad
`Greater Manchester west Mental Health
`NHS Foundation Trust, Cromwell House,
`eccles, Salford, M30 0GT, UK
`Tel +44 161 787 6007
`email peter.haddad@gmw.nhs.uk
`
`Abstract: Nonadherence with medication occurs in all chronic medical disorders. It is a
` particular challenge in schizophrenia due to the illness’s association with social isolation,
`stigma, and comorbid substance misuse, plus the effect of symptom domains on adherence,
`including positive and negative symptoms, lack of insight, depression, and cognitive impairment.
` Nonadherence lies on a spectrum, is often covert, and is underestimated by clinicians, but affects
`more than one third of patients with schizophrenia per annum. It increases the risk of relapse,
`rehospitalization, and self-harm, increases inpatient costs, and lowers quality of life. It results
`from multiple patient, clinician, illness, medication, and service factors, but a useful distinction
`is between intentional and unintentional nonadherence. There is no gold standard approach to
`the measurement of adherence as all methods have pros and cons. Interventions to improve
`adherence include psychoeducation and other psychosocial interventions, antipsychotic long-
`acting injections, electronic reminders, service-based interventions, and financial incentives.
`These overlap, all have some evidence of effectiveness, and the intervention adopted should be
`tailored to the individual. Psychosocial interventions that utilize combined approaches seem more
`effective than unidimensional approaches. There is increasing interest in electronic reminders
`and monitoring systems to enhance adherence, eg, Short Message Service text messaging and
`real-time medication monitoring linked to smart pill containers or an electronic ingestible event
`marker. Financial incentives to enhance antipsychotic adherence raise ethical issues, and their
`place in practice remains unclear. Simple pragmatic strategies to improve medication adherence
`include shared decision-making, regular assessment of adherence, simplification of the medica-
`tion regimen, ensuring that treatment is effective and that side effects are managed, and promoting
`a positive therapeutic alliance and good communication between the clinician and patient. These
`elements remain essential for all patients, not least for the small minority where vulnerability
`and risk issue dictate that compulsory treatment is necessary to ensure adherence.
`Keywords: adherence, nonadherence, antipsychotics, schizophrenia, long-acting injections,
`relapse, risk factors
`
`Introduction
`The challenge of patients not following medical advice is not new. In the 4th century
`BC, Hippocrates observed that some patients did not take their prescribed treatments.1
`In the 19th century, Robert Koch, the father of modern bacteriology, was critical of
`patients with tuberculosis who did not adhere to strategies to reduce infection. In 1955,
`soon after the introduction of antibiotics, it was observed that approximately one third
`of patients did not complete a 1-week course of oral penicillin for acute pharyngi-
`tis or otitis media.2 A recent national guideline concluded that between a third and
`one half of medicines that are prescribed for long-term conditions are not taken by
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`Patient Related Outcome Measures 2014:5 43–62
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`patients as recommended by the prescriber.3 Poor adherence
`is not limited to medication-taking and encompasses other
`treatment recommendations or “healthy behaviors”, such as
`exercise and diet. This is recognized by the World Health
`Organization, which defines therapeutic adherence as “the
`extent to which a person’s behavior corresponds with agreed
`recommendations from a health care provider”.4
`Medication adherence can be defined as the extent to
`which a patient’s medication-taking matches that agreed with
`the prescriber. A range of alternative terms have been used,
`including treatment compliance and fidelity, but adherence
`is currently favored partly due to its neutrality. In contrast,
`compliance implies an unequal power balance between
`the prescriber and patient. Medication adherence lies on a
`spectrum ranging from individuals who take no medication,
`despite agreeing with the prescribing clinician to do so, to
`those who take each dose precisely on time. In between
`these two extremes are patients who show varying degrees
`of adherence, taking some medication some of the time but
`not consistently as prescribed. This is termed partial adher-
`ence, and includes those who consistently miss doses on a
`regular basis and those who go through cycles of varying
`levels of adherence over time, eg, taking 100% of medica-
`tion during a relapse but gradually reducing their intake
`when in remission. Problems with adherence can include
`taking excess medication, but this is less common, and this
`review is concerned with those who take less medication than
`prescribed. Adherence is usually dichotomized for research
`purposes and is often defined as missing at least 20% of the
`medication in question. This cutoff has validity in predicting
`subsequent hospitalization across several chronic conditions,5
`although for individual patients the degree of nonadherence
`that affects health outcomes will vary and depend on mul-
`tiple factors including the condition, its severity, the risk of
`recurrence, the relative effectiveness of the medication, and
`its dose and frequency of administration. In this paper, the
`term “nonadherence” is used to refer to total nonadherence
`and clinically relevant degrees of partial adherence.
`Although nonadherence is a problem throughout
`medicine, there are several factors that make it especially
`challenging in schizophrenia. These include lack of illness
`awareness (a term encompassing insight, but also attitudes
`and beliefs about the nature of the illness), the direct impact of
`symptoms (including depression, cognitive impairment, and
`positive and negative symptoms), social isolation, comorbid
`substance misuse, stigma, and the increasing fragmentation
`of mental health services in many countries. Not surprisingly,
`these multiple disadvantages for people with schizophrenia
`
`mean the prevalence of nonadherence in psychosis is at
`least as high if not higher than in many chronic medical
`disorders.6 In this review, we concentrate on nonadherence
`with antipsychotic medication. We consider the prevalence
`of nonadherence, its costs, and the factors that contribute.
`Next we review the assessment of nonadherence in research
`studies and clinical practice. We review a range of inter-
`ventions to improve adherence, including basic strategies
`that should accompany prescribing, specific psychosocial
`interventions, antipsychotic long-acting injections (LAIs),
`electronic reminders, service interventions, and financial
`incentives. In reality, there is overlap between some of
`these approaches. We conclude by highlighting some key
`areas for future research. Strategies to improve adherence
`assume that in clinical practice the benefits of antipsychotic
`medication are often undermined by nonadherence. In view
`of this, we start with a brief review of the evidence base for
`the use of antipsychotic medication in the management of
`schizophrenia.
`
`Antipsychotic medication
`and schizophrenia
`The course and outcome of schizophrenia show consider-
`able variability between individuals.7 A small proportion of
`individuals experience a single psychotic episode, make a full
`recovery, and remain well without medication. However, for
`most of those affected, schizophrenia is a chronic condition,
`although this should not obscure the fact that the long-term
`prognosis is favorable or at least stable for a high proportion.
`In a 5-year follow-up of patients who experienced a first epi-
`sode of psychosis, the cumulative first relapse rate was 82%
`and the second relapse rate was 78%.8 A systematic review of
`longitudinal studies in first-episode psychosis, with a mean
`follow-up of 35 months, reported a good outcome for 42%
`and a poor outcome for 27% of individuals.9
`The efficacy of antipsychotic medication in the acute and
`maintenance treatment of schizophrenia is clear from large
`meta-analyses of placebo-controlled trials. A meta-analysis
`of 38 randomized controlled trials (RCTs) that compared
`second-generation antipsychotics with placebo in acute
`treatment of schizophrenia showed a moderate effect size
`of approximately 0.5, with a number needed to treat of six
`for response.10 Another meta-analysis of 65 trials, in which
`patients stabilized on antipsychotic medication were random-
`ized to continue medication or switch to placebo, showed
`that antipsychotics significantly reduced the rate of relapse
`at 1 year compared with placebo, with a number needed
`to treat to benefit of three (Figure 1).11 Those treated with
`
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`Nonadherence with antipsychotic medication in schizophrenia
`
` antipsychotic drugs were also less likely to be admitted to
`hospital or to drop out for inefficacy or for any reason.11
`Antipsychotics are not a panacea. Their benefit in acute
`treatment is largely in terms of the treatment of positive
`symptoms while other symptom domains, particularly
`negative symptoms, show less improvement. Some patients
`do not respond to antipsychotic medication including
`clozapine; the proportion of such patients is higher in ter-
`tiary services12 but treatment resistance occurs, albeit less
`frequently, in first-episode patients.13 Maintenance antipsy-
`chotic treatment does not eliminate the risk of relapse, but
`does reduce it. Antipsychotics can have a wide range of side
`effects.14 In the maintenance meta-analysis by Leucht et al,
`weight gain, sedation, and movement disorders were more
`common in those treated with antipsychotic medication
`than in those treated with placebo (Figure 1).11 Antipsy-
`chotic-induced weight gain,15 metabolic disturbance,16 and
`hyperprolactinemia17 are particularly important due to their
`potential impact on future physical health. Antipsychotics
`can also impair cognition.18 Many of these adverse effects
`are dose-related.14
`There is growing interest in the possibility that carefully
`selected patients with schizophrenia may be able to be treated
`both acutely and long-term with psychological interventions
`as an alternative to medication.19 At present, the data are
`limited and such an approach cannot be advocated as routine
`
`practice. Most guidelines for the treatment of schizophrenia
`recommend that pharmacological relapse prevention strate-
`gies are considered for every patient diagnosed with schizo-
`phrenia, with treatment being continued for between 1 and 2
`years after a first episode.20 In clinical practice, the duration
`of maintenance treatment needs to be determined on an
`individual patient basis by weighing up its advantages and
`disadvantages. Many patients require indefinite antipsychotic
`treatment, although this should be at the lowest effective dose
`and combined with psychosocial approaches and regular
`follow-up that includes monitoring for side effects, with
`intervention as appropriate.
`
`Prevalence of antipsychotic
`nonadherence
`Nonadherence with medication is a problem in all chronic
`medical conditions including, for example, the use of
`insulin in diabetes,21 antihypertensives in hypertension,22
`brimonidine in glaucoma,23 antiretroviral therapy in those
`with human immunodeficiency virus,24 and statins in those
`with hyperlipidemia.25 A review of medication adherence in
`psychiatric and physical disorders, spanning papers published
`between 1975 and 1996, reported the mean amount of pre-
`scribed medication taken to be 58% for patients prescribed
`antipsychotics, 65% for those prescribed antidepressants, and
`76% for those prescribed medication for physical disorders.6
`
`Number
` of
`studies
`included
`
`Drug group
`
`Control group
`
`Mean study
`duration*
`(months)
`
`Risk ratio (95% CI)
`
`Absolute difference
` (95% CI)
`
`NNTB/H
`(95% CI)
`
`Relapse 7–12 months
`Relapse independent of duration
`Participants readmitted to hospital
`Dropout for any reason
`Dropout because of inefficacy
`Participants unimproved/worse
`Violent/aggressive behavior
`Participants employed
`Death (any)
`Suicide
`Death from natural causes
`Dropout because of AE
`At least one AE
`At least one MD
`Dyskinesia
`Use of antiparkinsonian medication
`
`Sedation
`Weight gain
`
`24
`62
`16
`57
`46
`14
`5
`2
`14
`8
`84
`43
`10
`22
`13
`7
`
`10
`10
`
`773/1,204 (64%)
`392/1,465 (27%)
`744/3,395 (22%) 1,718/2,997 (57%)
`112/1,132 (10%)
`245/958 (26%)
`802/2,642 (30%) 1,130/2,076 (54%)
`412/2,539 (16%)
`830/2007 (41%)
`614/880 (70%)
`569/644 (88%)
`9/403 (2%)
`34/277 (12%)
`63/130 (48%)
`65/129 (50%)
`5/1,240 (<1%)
`7/1,116 (1%)
`0/1,021
`2/920 (<1%)
`5/1,272 (1%)
`3/1,129 (<1%)
`129/2,437 (5%)
`78/1,896 (4%)
`575/1,188 (48%)
`450/996 (45%)
`304/1,901 (16%)
`134/1,510 (9%)
`18/1,051 (2%)
`37/769 (5%)
`182/748 (24%)
`90/569 (16%)
`
`158/1,174 (13%)
`128/1,231 (10%)
`
`85/972 (9%)
`61/1,090 (6%)
`
`11
`9
`13
`9
`8
`5
`8
`11
`7
`6
`7
`8
`7
`7
`9
`7
`
`6
`7
`
`0.40 (0.33 to 0.49)
`0.35 (0.29 to 0.41)
`0.38 (0.27 to 0.55)
`0.53 (0.46 to 0.61)
`0.37 (0.31 to 0.44)
`0.73 (0.64 to 0.84)
`0.27 (0.15 to 0.52)
`0.96 (0.75 to 1.23)
`0.77 (0.28 to 2.11)
`0.34 (0.04 to 3.28)
`1.24 (0.39 to 3.97)
`1.16 (0.70 to 1.91)
`1.01 (0.87 to 1.18)
`1.55 (1.25 to 1.93)
`0.52 (0.28 to 0.97)
`1.40 (1.03 to 1.89)
`
`1.50 (1.22 to 1.84)
`2.07 (2.31 to 3.25)
`
`−0.39 (−0.46 to −0.32)
`−0.38 (−0.43 to −0.33)
`−0.19 (−0.27 to −0.11)
`−0.24 (−0.30 to −0.17)
`−0.27 (−0.34 to −0.19)
`−0.25 (0.35 to 0.14)
`−0.09 (−0.17 to −0.01)
`−0.02 (−0.14 to 0.10)
`0.00 (−0.01 to 0.00)
`0.00 (−0.01 to 0.00)
`0.00 (0.00 to 0.01)
`0.00 (−0.01 to 0.02)
`
`0.01 (−0.06 to −0.08)
`0.06 (0.03 to 0.10)
`−0.01 (−0.02 to 0.01)
`0.09 (0.02 to 0.16)
`
`0.05 (0.00 to 0.10)
`0.05 (0.03 to 0.07)
`
`3 (2 to 3)
`3 (2 to 3)
`5 (4 to 9)
`4 (3 to 6)
`4 (3 to 5)
`4 (3 to 7)
`11 (6 to 100)
`50 (H7 to B10)†
`∞
`∞
`∞
`∞
`100 (H17 to B13)†
`17 (10 to 33)
`100 (H50 to B100)†
`11 (6 to 50)
`20 (B=∞ to H10)†
`20 (14 to 33)
`
`0.1
`
`Favours drug
`
`1.0
`
`10
`Favours placebo
`
`Figure 1 Efficacy of maintenance antipsychotic medication versus placebo in schizophrenia (65 trials, n=6,493).
`Notes: Data are n/N (%) unless otherwise stated. The random effects model by DerSimonian and Laird144 was used throughout, with weights calculated by the Mantel–
`Haenszel method. *weighted by sample size of individual trials. †Because of space limitations, we did not use the display suggested by Altman.145 Reprinted from The Lancet,
`379, Leucht S, Tardy M, Komossa K, et al, Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis, 2063–2071,
`Copyright © 2012, with permission from elsevier.11
`Abbreviations: AE, adverse event; MD, movement disorder; n, number of participants with an event; N, number of studies; CI, confidence interval; NNTB/NNTH, number
`needed to treat to benefit/harm; H, harm; B, benefit.
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`The authors concluded that nonadherence may be a greater
`issue in psychiatry than in general medicine, but that the
`difference could reflect differences in the methodology
`used to assess adherence. Studies using electronic monitor-
`ing show that the extent of antipsychotic nonadherence is
`underestimated by psychiatrists.26
`The rate of nonadherence with antipsychotics in schizo-
`phrenia varies between studies, reflecting differences in the
`populations studied and the methodology used in terms
`of the definition and measurement of adherence and the
`period of time over which it is assessed (see Assessment
`of nonadherence section). However, there is a clear con-
`sensus that nonadherence is a major problem. A systematic
`review of 39 studies reported a mean rate of medication
`nonadherence in schizophrenia of 41%.27 When the analysis
`was restricted to the five methodologically most rigor-
`ous studies, which included defining adherence as taking
`medication at least 75% of the time, the nonadherence rate
`increased to 50%.
`Valenstein et al assessed approximately 34,000 Vet-
`erans Affairs patients with schizophrenia.28 Medication
`possession ratios (MPRs, ie, percentage of days with an
`antipsychotic prescription) were calculated for 4 consecu-
`tive years, with good adherence defined as an MPR $0.8
`during a year. Patients were divided into those who had
`consistently poor adherence (MPR ,0.8 in all years) and
`consistency good adherence (MPR $0.8 in all years). The
`cross-sectional prevalence of poor adherence was stable
`
`over time, with about 36% being poorly adherent each
`year. Adherence was not a stable trait, and when assessed
`over 4 years, 18% of subjects had consistently poor adher-
`ence, 39% had consistently good adherence, and 43% were
`inconsistently adherent. Thus, in total, 61% of patients had
`at least 1 year during which they showed poor adherence.
`Those with consistently poor adherence were more likely to
`be younger, nonwhite, have comorbid substance misuse, and
`to have been admitted to a psychiatric hospital. This study,
`like many, would underestimate nonadherence because
`it assumes that collecting medication from a pharmacy
`equates to taking it.
`
`Costs of nonadherence
`Nonadherence with antipsychotic medication can lead to
`relapse for patients in remission and persistent symptoms for
`those with existing symptoms, and both scenarios can cause
`multiple patient and service costs (Figure 2). The costs of
`nonadherence were demonstrated in a 3-year, prospective,
`observational study of schizophrenia in the USA in which a
`composite measure of patient-reported adherence and MPR
`was used to determine adherence.29 Outcome data were
`gathered at regular points throughout the study by reviewing
`medical records and conducting structured interviews with
`the participants. Nonadherence was associated with a signifi-
`cantly higher rate of psychiatric hospitalization, use of emer-
`gency psychiatric services, arrest, violence, victimization,
`and substance use (Figure 3) plus poorer mental functioning,
`
`Effect on treatment
`and services
`
`Increased:
`• Hospitalization
`• Out-pt appointments
`• Crisis attendances
`
`Unrecognized
` nonadherence
`• Unnecessary
` medication changes
`
`• Incorrect diagnosis
` of treatment
` resistance
`
`Relapse
`
`Nonadherence
`
`Persistent
`symptoms
`
`Effect on patients
`
`• Impaired functioning
`• Decreased QoL
`• Self-neglect
`• Self-harm
`• Aggression
`• Substance misuse
`• Vulnerability
`
`Figure 2 Consequences of nonadherence to antipsychotic medication.
`Note: This material was originally published in Antipsychotic long-acting injections (edited by P Haddad, T Lambert and J Lauriello) and has been reproduced by permission
`of Oxford University Press. http://ukcatalogue.oup.com/product/9780199586042.do. For permission to reuse this material, please visit http://www.oup.co.uk/academic/rights/
`permissions.146
`Abbreviation: QoL, Quality of life.
`
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`Nonadherence with antipsychotic medication in schizophrenia
`
`Non-adherent
`
`Adherent
`
`31.1
`
`21.5
`
`10.0
`
`6.0
`
`8.4
`
`3.5
`
`10.8
`
`4.8
`
`15.1
`
`7.8
`
`26.6
`
`14.1
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`% of patients
`
`m erg e n cy p syc h c are
`P syc h h o s pitaliz atio n
`
`E
`
`A rre ste d
`
`Viole nt
`
`Vicit m of cri m e
`
`S u b sta n c e m is u s e
`
`Figure 3 Association between antipsychotic nonadherence and outcome in a 3-year prospective observational US study.
`Notes: Adherence based on patient-reported adherence and medication possession ratio (% days with prescription for any antipsychotic). Data adapted from Ascher-Svanum
`H, Faries De, Zhu B, ernst FR, Swartz MS, Swanson Jw. Medication adherence and long-term functional outcomes in the treatment of schizophrenia in usual care. J Clin
`Psychiatry. 2006;67(3):453–460.29 Copyright © 2006, Physician’s Postgraduate Press, inc.
`Abbreviation: Psych, psychiatric.
`
`poorer life satisfaction, and more alcohol-related problems.
`Nonadherence in the first year predicted significantly poorer
`outcomes in the following 2 years. A 3-year, prospective,
`observational, European study of outpatients with schizo-
`phrenia found that nonadherence was significantly associ-
`ated with an increased risk of relapse, hospitalization, and
`suicide attempts.30 An association between antipsychotic
` nonadherence and an increased rate of self-harm31 and
` suicide32 has been reported in other studies. A recent analysis
`from the CUTLASS (Cost Utility of the Latest Antipsychotic
`Drugs in Schizophrenia Study) clinical trial in the UK showed
`that improved antipsychotic adherence led to improved
` quality of life.33
`Relatively short periods of nonadherence have been linked
`to poorer outcomes. Two US studies, both using pharmacy
`refills to measure adherence, found that missing medication
`for 10 days was associated with an increased risk of psychiat-
`ric hospitalization.34,35 In one study, the risk of hospitalization
`was correlated with the degree of nonadherence, with a gap of
`1–10 days in antipsychotic medication being associated with
`an odds ratio for admission of 1.98, a gap of 11–30 days with
`an odds ratio of 2.81, and a gap of more than 30 days with an
`odds ratio of 3.96.35 It is important to highlight that the degree
`of nonadherence leading to poorer clinical outcomes will vary
`greatly between individuals and be influenced by multiple
`factors. Patients with a low risk of relapse may remain well
`despite marked degrees of nonadherence. This may explain
`
`why some intervention studies of nonadherence report
`improved medication adherence but without improvement
`in clinical outcomes.
`Relapse after a first episode of psychosis can be particu-
`larly damaging, as those affected are likely to be relatively
`young and at a critical period in their life. The only factor
`predictive of relapse in a 3-year follow-up of first-episode
`patients was medication nonadherence.36 In a separate 5-year,
`follow-up study, discontinuation of medication after a first
`psychotic episode increased the risk of relapse by five-fold.8
`Successive relapses in schizophrenia are associated with a
`decrease in treatment response37 and possibly a worsening
`of the disease process38 and brain shrinkage.39 Irrespective
`of organic mechanisms, successive relapse is likely to lead
`to accrual of disability, because each relapse can damage an
`individual’s confidence, social networks, and employment
`opportunities.
`The impact of antipsychotic nonadherence on economic
`costs in people with schizophrenia is complex and varies
`across services.40 QUATRO (Quality of Life following
` Adherence Therapy for People Disabled by Schizophrenia
`and their Carers), a multicenter European RCT, found that
`community-based day service costs and societal costs were
`lower among nonadherent patients with schizophrenia and
`that nonadherence was not significantly associated with
`total health and social care costs.40 In contrast, two system-
`atic reviews, one of seven studies conducted in the USA41
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`and one of eight studies conducted worldwide,42 found that
` nonadherence was associated with higher hospitalization
`rates and direct health care costs. The national rehospitaliza-
`tion cost in the USA attributable to antipsychotic nonadher-
`ence was estimated at approximately $1,500 million per
`year in 2005.41
`When nonadherence is covert, it may lead to the incorrect
`assumption that an antipsychotic drug is ineffective, which
`may result in an inappropriate change of treatment, including
`an increase in the dose of the antipsychotic drug, switching to
`another antipsychotic agent, or the addition of other medications.
`A trial of an antipsychotic LAI can be a helpful way to deter-
`mine whether symptoms in a patient previously prescribed an
`
`oral antipsychotic medication are the result of covert nonadher-
`ence or represent treatment resistance.
`
`Factors associated
`with nonadherence
`A useful way to conceptualize nonadherence is to consider
`intentional and unintentional nonadherence.3 Intentional
`nonadherence occurs when a patient makes a deliberate
`decision not to take medication as prescribed. This is usu-
`ally because the disadvantages of medication are perceived
`as outweighing the benefits, ie, it can be understood by a
`health beliefs model. Unintentional nonadherence occurs
`when practical problems interfere with adherence. Examples
`
`Illness factors
`• Insight
`• Cognitive impairment
`• Positive and negative
` symptoms
`
`• Depression
`• Substance misuse
`
`Nonadherence
`
`Medication factors
`• Effectiveness
`• Side effects
`• Dose frequency
`• Formulation
`• Financial cost to patient
`• Co-prescribed drugs and
` complexity of regimen
`
`• Past medication
` experience
`
`Physician/service
`factors
`
`• Therapeutic alliance
`• Communication
`• Ease of access
`• Clinician attitudes to
` medication
`
`• Discharge planning
`• Communication
` between services
`
`Caregiver factors
`• Attitudes to medication and
` illness
`
`• Ability to supervise/remind
` patient about medication
`
`• Stigma
`
`Patient factors
`• Past history of adherence
`• Attitudes to medication and
` illness
`
`• Stigma
`
`Figure 4 Factors associated with nonadherence.
`
`48
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`Nonadherence with antipsychotic medication in schizophrenia
`
`include the patient forgetting to take medication, not
`understanding the instructions that they were given about
`medication-taking, or having difficulty collecting repeat
`prescriptions from a pharmacy due to either travel issues or
`the medication cost. Both types of nonadherence may occur
`in the same patient.
`Figure 4 summarizes some of the key factors associ-
`ated with nonadherence based on previous studies.43,44 Poor
`adherence cannot simply be regarded as “difficult” behavior
`on behalf of the patient; rather, it can result from a range of
`factors that encompass the illness, medication, and organiza-
`tion of services, plus attributes of the clinician, patient, and
`caregivers. As a result, improving adherence often requires
`a range of interventions.
`In terms of illness factors, multiple studies have linked
`poor insight, or unawareness of illness and the need for
`treatment, to nonadherence.45,46 Poor insight was regarded
`as the most important factor contributing to nonadherence
`in serious mental illness in a survey of experts.47 Insight
`is not a stable trait and often improves during the course
`of treatment.48 Cognitive impairment is associated with
`nonadherence49 and predicts relapse after a first episode of
`psychosis.50 Psychotic symptoms may impact directly on
`adherence, for example, the content of a delusion may be
`that medication is a poison, while auditory hallucinations
`may instruct a person not to take medication. Negative and
`depressive symptoms can decrease an individual’s motiva-
`tion to collect and take medication.51 Alcohol and illicit drug
`misuse, common comorbidities in schizophrenia,52 both
`predict antipsychotic nonadherence.30
`The effectiveness of antipsychotic medication is a key
`determinant of adherence. In a pooled analysis of data from
`RCTs, reduction in the Positive and Negative Syndrome
`Scale positive factor was the strongest predictor of treatment
`adherence, irrespective of the antipsychotic.53 Conversely,
`a poor response to medication is one of the most frequent
`reasons why patients leave clinical trials. This highlights
`that clinicians should ensure that patients are aware of
`the time course for symptom improvement after starting
`antipsychotic medication and discuss switching to another
`antipsychotic, including clozapine when appropriate, if
`patients do not respond to an adequate trial of a medication.
`The association between side effects and nonadherence
`is complex.27,54 RCTs often report “dropouts” due to side
`effects or adverse effects, but individual perceptions or
`beliefs about the illness or the treatments are not recorded.
`In the real world, patients often suggest that it is not side
`effects per se that are the problem, but lack of knowledge
`
`about the danger or otherwise of each side effect and lack
`of skills or management strategies to cope with side effects,
`ie, subjective or practical issues rather than the objective
`severity of a side effect may be most relevant in dictating
`adherence behaviors.55–57 A patient who perceives a drug as
`beneficial and important to their recovery may continue to
`take it despite it causing significant side effects. In contrast,
`a patient who sees little benefit from medication and is
`unconvinced by the explanation of their diagnosis or need
`for pharmacotherapy may stop treatment at the first sign of
`a side effect that causes relatively minor inconvenience to
`others. In this case, one could argue that it is the patient’s
`attitude to the medication rather than the side effect that is
`the chief cause of nonadherence.
`Another aspect of medication that needs to be consid-
`ered is the financial cost to the patient. A study in the USA
`found that higher patient cost-sharing (eg, copayments or
`coinsurance) was associated with a lower likelihood of
`adherence with antipsychotic medication and a shorter time
`to discontinuation of medication.58 In another study, schizo-
`phrenia patients who perceived copayment burden were less
`than half as likely to have complete adherence.59 This result
`needs to be considered in light of the study’s methodological
`weaknesses that included a cross-sectional design