Medication non-adherence in bipolar disorder: a narrative review

Jawad I1, Watson S2,3, Haddad PM4,5 , Talbot PS 5,6 & McAllister-Williams RH2,3*

1 – Tees, Esk and Wear Valleys NHS Foundation Trust, Middlesbrough, UK

2 – Northern Centre for Mood Disorders and Institute of Neuroscience, Newcastle University,

Newcastle upon Tyne, UK

3 – Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK

4 - Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK

5 - Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK

6 - Division of Neuroscience and Experimental Psychology, School of Biological Sciences,

Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic

Health Science Centre, Manchester M13 9PL, UK

* Corresponding Author:

Academic Psychiatry, Wolfson Research Centre, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL. Email: r.h.mcallister-williams@ncl.ac.uk

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ABSTRACT (271 words)A number of effective maintenance medication options exist for bipolar disorder (BD)

and these are regarded as the foundation of long-term treatment in BD. However,

non-adherence to medication is common in BD. For example, a large data base

study in the USA showed that approximately half of patients with BD were non-

adherent with lithium and maintenance medications over a 12 month period. Such

non-adherence carries a high risk of relapse due to the recurrent nature of the illness

and the fact that abrupt cessation of treatment, particularly lithium, may cause

rebound depression and mania. Indeed, medication non-adherence in BD is

associated with significantly increased risks of relapse, recurrence, hospitalization

and suicide attempt and a decreased likelihood of achieving remission and recovery,

as well as with higher overall treatment costs. Factors associated with non-

adherence include adverse effects of medication, complex medication regimens,

negative patient attitudes to medication, poor insight, rapid cycling BD, comorbid

substance misuse and a poor therapeutic alliance. Clinicians should routinely

enquire about non-adherence in a non-judgmental fashion. Potential steps to

improve adherence include simple pragmatic strategies related to prescribing

including shared decision making, psychoeducation with a clear focus on adherence,

reminders (traditional and digital), potentially using a depot rather than an oral

antipsychotic, managing comorbid substance misuse and improving therapeutic

alliance. Financial incentives have been shown to improve adherence to depot

antipsychotics but this approach raises ethical issues and its long-term effectiveness

is unknown. Often a combination of approaches will be required. The strategies that

are adopted need to be patient specific, reflecting that non-adherence has no single

cause, and chosen by the patient and clinician working together.

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IntroductionThe UK’s National Institute for Health and Clinical Excellence’s (NICE) guidance on

medication adherence defines adherence as ‘the extent to which the patient’s behaviour

matches agreed recommendations from the prescriber’ (1). Adherence, from the Latin

adhaerere (to cleave or stick to), is considered to suggest sustained active decision making

and ownership and is the term used in this manuscript rather than the more paternalistic

‘compliance’, from complere (to fill up, fill out or complete). Non-adherence does not only

involve medication but can occur with other health care recommendations including non-

pharmacological interventions, for example lifestyle changes and psychological treatment,

and with scheduled appointments (2). Non-adherence to medication is a major problem in all

chronic medical and psychiatric disorders. This narrative review discusses the impact of

medication non-adherence in bipolar disorder (BD) including the extent of the problem,

contributory factors and potential management solutions. The published evidence used for

this narrative review was sourced primarily using PubMed with additional use of EMBASE.

Medline and PsycINFO. Initial searches consisted of key words ‘Bipolar’ AND ‘Adherence’

OR ‘Non-adherence’. Systematic reviews, randomised control trials and observational

studies that were published in the English language were reviewed. Qualitative studies were

considered for patient-centred factors influencing adherence. Case reports and case studies

were not included in our literature search. The focus was on adults over the age of 18.

General features of non-adherence Adherence occurs on a spectrum. At one end of the spectrum is total adherence i.e. all

doses of medication are taken at the frequency specified on the prescription. At the other

end of the spectrum is total non-adherence i.e. none of the prescribed medication is taken.

In-between are varying degrees of partial adherence, or partial non-adherence, i.e. some,

but not all, of the prescribed medication is taken. Adherence is dynamic and a patient who

adheres well at one point in time may adhere poorly at another time. Adherence can be

selective in that it only affects some prescribed medications or it may relate to all

medications prescribed at that time point. Non-adherence can also refer to patients taking

more than the dose prescribed but in this review we restrict ourselves to the issue of less

than the prescribed amount of medication being taken as this is a more common problem.

In most research studies adherence is dichotomised, with patients being considered as

adherent or non-adherent, though the definitions used to make this categorisation vary. As a

result, it can be difficult to compare studies. For example, Hong (2011) defined non-adherent

patients as those who took medication for at least half the time (3) .In contrast, other

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researchers have defined non-adherence as the patient missing at least 20% of the total

prescribed medication over a specified time period (4). Definitions apart, another

methodological issue relates to how adherence is measured. A distinction can be made

between subjective measures, such as a patient’s diary, report or questionnaires, and more

objective measures, such as pill counting, monitoring drug serum levels or medication

containers with inbuilt electronics to record when the container is opened. (5). In the latter

case, it is assumed that opening the container equates to taking medication but in reality this

is not always the case, so even this apparent ‘gold standard’ method may over-estimate

adherence.

In clinical practice, non-adherence may be covert or overt. Sometimes non-adherence is

rather simplistically divided into deliberate and non-intentional (6). Cited examples of non-

intentional non-adherence include forgetting to take medication, the inability to meet the

financial cost of the prescription, or misunderstanding the instructions regarding medication

taking. Misunderstandings are considered to occur in various ways, for example due to

language barriers, a patient with poor eyesight who cannot read the instructions on the

medication container label, or a doctor who did not explain the instructions clearly, especially

if the patient was distracted in the consultation. Deliberate non-adherence is said to occur

when the individual makes a conscious decision to take less than the prescribed amount of

medication. In practice such categorisations are unhelpful and adherence reflects the

person’s attitudes and beliefs about the medication, the underlying illness and the relative

importance they give to the pros and cons of taking medication.

Costs of Non-adherence in bipolar disorderAlthough many psychiatric disorders follow a relapsing-remitting condition, BD has a higher

frequency of relapses than, for example, unipolar depression and the relapse risk remains

constant throughout the life span (7). As such, on average, it is reasonable to assume that

non-adherence in BD is more likely to be associated with relapse over a given time period

than non-adherence in a less recurrent illness such as unipolar depression. While some

patients with BD undoubtedly have long spells of recovery, long-term follow up shows that,

on average, patients are symptomatic around 50% of the time (8;9). During much of this

time patients are suffering from sub-syndromal symptoms (8;9), but even low levels of

symptoms are associated with impaired psychosocial functioning (10;11). Prophylactic

medication, ideally supported by psychosocial interventions such as psychoeducation

(12;13), is regarded as the cornerstone of managing BD (14;15).

A recurrence in BD can have a high cost for the individual. BD has the highest suicide rate of

any psychiatric condition (16). Most suicides occur in depressive episodes, though mixed

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episodes also carry significant risk. Manic episodes can result in inappropriate behaviour

that can have a marked impact on a person’s future in terms of employment and personal

life, particularly if the inappropriate behaviour involves finance or sexual behaviour. Long

term pharmacological treatment of BD has been shown to be associated with a significantly

lower suicide rate (17) which may in part relate to the specific anti-suicidal effect of lithium

(18). The effects of medication non-adherence in BD were investigated in an analysis using

data from the EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication)

study, a 21-month prospective observational study of patients who had experienced a manic

or mixed episode. Adherence was based on clinician ratings. Non-adherence was

associated with a significantly increased risk of relapse, recurrence, hospitalization and

suicide attempts, and a decreased likelihood of achieving remission and recovery (3).

Non-adherence in BD has a major economic cost for health services. The annual cost to the

National Health Service (NHS) in the UK was estimated to be £342 million at 2009/2010

prices, with 60% of this accounted for by inpatient admissions (19). In the EMBLEM study,

the total costs incurred by non-adherent (ranging from never taking medications to taking

them approximately half the time) compared with adherent (almost always taking their

medications) BD patients over a 21-month period of follow up was £10,231 compared to

£7,379 (p <0.05) (3). The difference was in large part due to the costs of inpatient care,

which averaged £4796 for the non-adherent group but £2150 for the adherent group (3).

Consistent with this data, Gianfrancesco et al (2008) conducted a claims database study in

the USA that showed that improved adherence to antipsychotic medication in BD was

associated with lower total and outpatient mental health care expenditures (20).

Lithium remains the gold standard medication for long term prophylaxis of BD (14;15).

However, abrupt discontinuation of lithium is associated with an increased risk of relapse

(21). Baldessarini et al (1996) assessed the effect of discontinuing treatment abruptly (1-14

days) or gradually (15-30 days) in patients with BD (22). The median time to recurrence +/-

SE was fivefold greater in the rapid discontinuation group (20.0 +/- 5.8 vs. 4.0 +/- 0.7

months; p < 0.0001). The increased relapse risk was seen for both depressive and manic

relapses and in people with bipolar I and II disorders, though it was greater in bipolar II

patients. These observations led Goodwin to argue that lithium’s benefits are only likely to

be realised if taken for at least two years with complete adherence (23). Observational data

from a 6 year study of 1,594 lithium users aged 15 year and above from a Health

Maintenance Organisation (HMO) based in the USA suggests that the median duration of

continuous lithium adherence is just 72 days (24) and a more recent nationwide study in

Denmark found a median of just 181 days before lithium was discontinued (25).

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Prevalence of medication non-adherence in bipolar disorderPrevalence of non-adherence will be influenced by the methodology adopted to assess it as

well as the characteristics of the patients being studied. This probably explains the wide

variation in rates of non-adherence reported in the literature across medical disorders, with

BD (26) (27) being no exception. However, non-adherence rates of approximately 50% are

commonly reported for patients with BD (28-31) and in a survey of over 2000 psychiatrists,

based in eight European countries, the respondents estimated that the majority of patients

(57%) with BD were non-adherent or partially adherent to treatment (32).

The medication possession ratio (MPR) is a method of monitoring adherence based on

pharmacy refills of medications. Since it does not directly record tablet ingestion it is likely to

overestimate adherence. Sajatovic and colleagues used the MPR to examine a patient

register in the USA to assess adherence to lithium and anticonvulsant mood stabilisers in BD

and found that over half the sample had an MPR of less than 0.50 (30). Patients were

divided into three groups according to whether they were non-adherent (MPR < 0.50; 54% of

the sample), partially adherent (MPR 0.50 to 0.80; 24%) or fully adherent (MPR >0.80; 21%).

In an earlier study, Scott and Pope (2002) interviewed 98 patients with affective disorders

who were prescribed a mood stabilizer (i.e. lithium, carbamazepine, and/or valproate). The

majority of the patients had a diagnosis of BD (n=78) and the remainder (n=20) had a

diagnosis of major depressive disorder. Approximately half reported some degree of

medication non-adherence in the last 2 years and nearly one third reported missing 30% or

more of their prescribed medication in the last month (29). Being only partially adherent, and

having sub-therapeutic plasma levels, were the most significant predictors of admission to

hospital over the following 18 months (Cox regression analysis p=0.001). Interestingly, there

was little correlation between subjective reporting of adherence and objective measurement

with drug plasma levels (29).

The high prevalence of non-adherence in BD and the high associated costs make it

imperative that clinicians routinely and non-judgementally, enquire about, quantify, and

explore non-adherence during patient review.

Factors influencing adherence Sociodemographic factors

Sociodemographic factors, including socioeconomic status, do not appear to be major

determinants of adherence. However an online survey suggests that younger patients are

more likely to be non-adherent to lithium and anticonvulsants with adherence increasing

after the age of 41 (33). Kessing and colleagues have also identified that adherence was

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lowest among patients below the age of 40, however rates were also lower above the age of

60 (25). Other social factors, include being non-white, unmarried, homeless and having a

diagnosis of substance misuse disorder have been reported as being associated with non-

adherence (30).

The role of gender and gender identity in adherence has been explored by Sajatovic and

colleagues in a cross sectional study of BD patients. Overall there appears to be no

significant differences in adherence between men and women. However, men with high

masculinity attitudes and perception scores had lower adherence to medications compared

to other men. For women, there was no relationship between masculinity scores and

adherence (34). This is slightly at odds with a study of 225 patients with bipolar I or

schizoaffective disorder which found that women were more likely to be represented in the

non-adherent subgroup (35).

Attitudes to medication

Given that general demographic features have limited ability to predict levels of adherence

(36), coupled with a move away from the concept of ‘compliance’ to the more collaborative

‘adherence’ (37), has led to a shift from an ‘illness-centred’ to a ‘patient-centred’ approach to

medication usage. Such a shift has been argued to improve understanding of non-

adherence by emphasising the importance of negative attitudes, beliefs, and stigma (38).

The perception of the strength of the ‘therapeutic alliance’ between patient and care giver,

and the optimisation of this collaborative relationship, can itself be seen as a management

approach to bipolar disorder. Stronger alliance has been associated with a reduction in

manic symptoms with less negative attitudes about medication and reduced perception of

stigma regarding bipolar disorder (39).

Patients knowledge about their illness and medications can also impact on adherence. In a

study of 223 patients using the Satisfaction with Information about Medicines Scale (SIMS)

those whose perception that they have received less than satisfactory knowledge about their

medications presented with significantly lower adherence rates (40). A belief that

antipsychotic medications are exclusively for schizophrenia, and a reluctance to discuss side

effects such as weight gain, can also potentially lead to non-adherence (41).

In a study using the Lithium Attitudes Questionnaire (LAQ) and the Lithium Knowledge Test

(LKT), Rosa and colleagues found that in a sample of 106 outpatients with BD better

pharmacological knowledge on the LKT was associated with lithium levels being in the

therapeutic range. In contrast, the main factor of ‘denial of disease’ in the LAQ significantly

contributed to lower plasma levels. Interestingly, younger patients had better understanding

of lithium (42). The relationship between negative attitudes to medication and non-

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adherence has also been shown in studies examining other medication in BD (43;44).

Importantly, patients with positive attitudes towards medication have significantly greater

clinical stability (44).

In addition to patient attitudes, the patient’s perceived criticism from family attitudes and

knowledge towards medication may also influence adherence and thus clinical outcome

(45). This is supported by data showing that positive medication attitudes were seen in

patients with BD who had good social networks and who had an external locus of control,

holding the belief that others such as clinicians and family determined their clinical outcomes

(46). Similarly, it has been reported that if a caregiver is emotionally over-involved with a

patient with BD, this is associated with reduced medication adherence (47).

Insight

Studies in schizophrenia suggest that lack of insight is the most common driver for poor

adherence (48). Consistent with this, non-adherent BD patients have been shown to have

lower levels of insight compared to adherent patients (43) and that better insight is

associated with higher adherence (49). However, some studies in BD have failed to find this

relationship (44;50). A limitation of these studies is that they primarily used subjective

reporting of adherence.

Course of Illness

It is important to consider that the level of adherence to medication may fluctuate with

changes in the mental state of patients with BD (51). Poor adherence has been associated

with rapid cycling, previous suicide attempts, earlier onset of illness, active anxiety or alcohol

use disorder, a greater number and severity of affective symptoms, not being in full

remission, having co-morbid obsessive compulsive disorder, and having suffered from a

recent manic or hypomanic episode (52-54).

Substance misuse

Substance misuse is a common comorbidity in BD (55;56) that can have a negative impact

on outcome. For example, alcohol misuse is related to increased mood fluctuation (57) and

increased suicide risk (58). Multiple studies have shown an association between non-

adherence to prescribed medication and substance misuse. Montes (2013) found a greater

prevalence of co-morbid substance abuse and dependence (of alcohol, cocaine and

cannabis) in patients with BD who had poor medication adherence (59). Similarly, Manwani

and colleagues compared adherence to mood stabilisers between BD patients with and

without co-morbid substance misuse and found significantly lower adherence rates in those

who misused illicit substances (60). The association between non-adherence and substance

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misuse is complex, with several different paths of causality. For example, some patients

who don’t adhere to prescribed mood stabilizers will relapse as a consequence and the

deterioration in their mental state can lead to substance misuse through attempts to alleviate

symptoms (self-medication) or through increased impulsivity and recklessness (for example,

when manic). Substance misuse may also destabilise the mental state which then leads to

non-adherence. Another pathway between substance misuse and non-adherence is that the

substance misuse leads to a chaotic lifestyle that makes regular medication-taking difficult.

Cognition

BD is associated with a range of well described cognitive dysfunctions as detailed in an individual

patient data meta-analysis of 2876 subjects (61). It is seen across all clinical subgroups (62),

including in patients when euthymic (63;64), and there is little evidence of progression of

dysfunction over time (65). The dysfunction may relate to underlying attentional and processing

speed abnormalities (66) but deficits are seen across all cognitive domains including memory (61).

Around 40% of patients with BD score below the 5th percentile for their age and gender in two or

more cognitive domains (67). These may particularly be patients who are experiencing a sleep

disorder – insomnia, hypersomnia, circadian rhythm disorder or obstructive sleep apnoea

(McAllister-Williams et al. 2018 under review).

There have been two previous studies involving euthymic BD outpatients examining the relationship

between cognition and adherence. The first studied 103 patients and found impaired ability on the

trail-making task and spatial memory deficits were associated with reduce adherence rates (68). The

second study of 353 euthymic outpatients found a relationship between poor inhibitory control and

reduced adherence (69). However it is not possible to conclude the direction of causality between

cognitive dysfunction and adherence from either of these studies.

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Complexity of the medication regimen

In other areas of medicine, increased complexity of medication regimes is associated with

decreased adherence rates. For example, a systematic review of 76 studies (mainly in

cardiovascular disease) that used electronic monitoring devices found significantly higher

adherence with once daily dosing compared to three times a day, though not twice daily

dosing schedules (36). If non-adherence is not recognised by the prescriber, and it is

wrongly assumed that a patient is treatment resistant, additional drugs may be added to the

regimen which may reduce adherence further.

Medication side effects

Side effects can be an important factor contributing to non-adherence. However it is the

patient’s perception of side effects and how this compares to their perception of the benefits

of medication that is key in determining whether side effects impact on adherence. An online

survey of 469 patients with self-reported BD identified that weight gain within 3 months was

the side effect most likely to impact on adherence to bipolar medications, followed by

cognitive side effects (33). A 2005 study comparing divalproex with lithium in rapid-cycling

BD found that in the double-blind monotherapy phase, tremors, polydipsia and polyuria were

significantly more common with lithium compared to divalproex. However the study did not

establish significant differences in the discontinuation rates due to side effects between

these treatment arms (34). The side effect profiles of medications used in BD differ

markedly and this provides scope for patients and clinicians to work together to prevent or

alleviate certain side effects.

Assessing medication side effects can be problematic, both in clinical practice and in clinical

trials. Symptoms of BD can sometimes be misattributed to side effects, and vice versa. For

example, sedation from a medication may be difficult to differentiate from lethargy

associated with a depressive episode. Furthermore mood states such as depression can

impact on the subjective reporting of side effects. Moreover, being on multiple medications

will have an impact on the patient’s overall side effect profile. Side effects may also change

during the course of treatment. For example, with lithium polydipsia and polyuria become

increasingly problematic in the longer term, with rates of up to 70% (35).

Improving adherence in bipolar disorderAs described above, poor adherence can have many causes. It is therefore important to

understand at an individual patient level why non-adherence has occurred as this can help

the clinician to formulate a specific treatment plan. Potential strategies to improve

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adherence in BD are reviewed below though it should be noted that these strategies often

overlap.

Simple prescribing strategies

There are a number of simple prescribing strategies that can be employed to try to maximise

adherence (5). These include adopting shared decision making, using as simple a

medication regimen as possible in terms of both the number of medications and the

frequency of medicating taking, and effective management of side effects. At the outset, it is

vital to as far as possible have full and frank discussions about treatment and the different

medication options that are available, as well as the benefits and risks of each. This also

applies to individuals considering not altering their current medication or not starting

medication at all. A mutual agreement should be reached on the treatment plan. The NICE

guidelines for Bipolar Disorder Assessment and Management advise that for

pharmacological interventions clinicians must take into account any advance statements, the

patient’s preference, and clinical factors such as co-morbid physical ill health and previous

adverse reactions to treatment (14).

Managing medication side effects is a crucial part of good clinical care. It starts before

medication is prescribed with the patient and clinician considering the likely impact of side

effects for that person, the side effect profiles of potential medication and factoring this in to

a shared decision about the most appropriate medication(s) to use. Throughout treatment

side effects should be screened for regularly and managed when they occur. It is outside the

remit of this paper to consider the management of side effects but we briefly mention weight

gain as an example, as this is particularly distressing to patients and occurs with many

medications used in BD including antipsychotics, lithium and valproate. Antipsychotics differ

significantly in their propensity to cause weight gain and will usually be a factor that patients

and prescribers consider when making joint decisions about selecting medication. Switching

to an antipsychotic with lower risk of weight gain can help reduce antipsychotic associated

weight gain (70). Weight management, including dietary change and encouraging physical

activity, are effective in reducing antipsychotic associated weight gain. Metformin is effective

in reducing antipsychotic induced weight gain (71) and can be considered on a case by case

basis though it is important to highlight that this is an off-label indication.

Improving therapeutic alliance

The therapeutic alliance between patients and health care professionals has a key role in

supporting adherence to medication. A study of 3037 patients with BD found that patients'

perceptions of collaboration, empathy, and accessibility of their psychiatrist were significantly

associated with adherence to treatment (72). Similarly, it has also been shown that a positive

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therapeutic alliance is associated with better adherence (73). In terms of improving

adherence, assessment of a patient’s understanding of their diagnosis, symptoms and the

potential risks associated with stopping medications, is likely to be critical. The

communication style of the doctor is important to their ability to forge a therapeutic alliance.

Alliance may be weakened when a patient’s’ care lacks clinical continuity e.g. they see

different doctors at different appointments or receive their care from different teams at

different time points e.g. community mental health team, inpatient team and crisis home

treatment team. Sometimes the involvement of multiple teams is unavoidable and it may

carry some advantages for example in terms of specialisation and greater input at a time of

high clinical need. However services need to ensure a seamless transfer between teams

with timely handovers.

An additional concern that may affect adherence is that regarding the impact of medication

in pregnancy for women with BD, particularly given the concerns of teratogenic and other

adverse outcomes for infants exposed in utero to a number of commonly used BD

medications (74). It is important for prescribers to anticipate such concerns in all women of

child bearing potential with BD.

Psychoeducation

There is a lack of strong evidence supporting specific psychotherapies for BD (15). However

there is some evidence that psychoeducation improves medication adherence and short

term knowledge about medication (75) and that this can have long term beneficial effects on

patient outcomes (12). Psychoeducation is very broad concept and cover many areas; it is

more likely to improve adherence if there is a clear focus on adherence and incorporating

behavioural interventions (76).

Family and carer attitudes towards BD and its treatment can have a major impact on patient

adherence (77). It is therefore potentially important to consider some form of

psychoeducation for significant individuals in a patient’s life if this is at all possible or

practical (78). A recent study of 270 patients, of which 136 in the experimental group

received five sessions of motivational interviewing and psychoeducation with family

members, identified increased adherence rates when using the Medication Adherence

Rating Scale (79). Addressing self-stigmatisation with patients requires not only educating

individual patients but also families, care providers and wider society (41).

Managing substance misuse

Co-morbid alcohol and illicit substance misuse can complicate all psychiatric conditions and

BD is no different. The evidence that substance misuse can be associated with non-

adherence (60) is another reason why it is important to actively address substance use and

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BD at the same time. This may require collaborative work between general adult psychiatry

and addiction services. Increasing patient awareness of substance misuse as a potential

relapse indicator, and ensuring this lead to an urgent assessment, is also important

irrespective of the direction of causality between relapse and substance misuse.

Depot antipsychotics

A significant advantage of a depot antipsychotic (also known as antipsychotic long acting

injections [LAI]) over oral antipsychotic medication is that covert non-adherence is

impossible (5). All clinical guidelines for the management of schizophrenia regard depots as

being an option to manage prior non-adherence with oral medication. However, the

prescription of depot does not necessarily guarantee adherence as the patient must be

agreeable to taking it. A number of guidelines advocate the use of depot treatment in

prophylaxis against manic relapses and in particular those patients who are non-adherent to

oral formulations (see Table 1). It is important to highlight that in general placebo controlled

RCT evidence for the long term use of antipsychotics in BD suggest that they primarily risk

of recurrence of mania and not depression, with the exception that quetiapine (80) (and

possibly lurasidone (81)) protects against depressive relapse as well. Neither quetiapine nor

lurasidone are available in a LAI formulation. It is also assumed that the prophylactic effect

of an antipsychotic against relapse of mania is more likely if there is evidence that an

individual’s previous acute manic episodes have responded to that antipsychotic (usually

given in oral form).

In comparison to schizophrenia the evidence base for the use of depots in the maintenance

treatment of BD is smaller. The efficacy of risperidone LAI in the prevention of relapse in

bipolar I disorder was assessed in a randomized, placebo-controlled study (82). Following

an open-label treatment period with risperidone LAI, stable patients entered an 18-month

double-blind period in which they were randomized to continue treatment with risperidone

LAI or switch to placebo or oral olanzapine. Time to recurrence of any mood episode was

significantly longer with risperidone LAI versus placebo. However, the difference was

significant for time to recurrence of elevated mood episodes but not depressive episodes.

This is consistent with the fact that antipsychotics, other than quetiapine and possibly

lurasidone, have only been shown to have a consistent maintenance effect in BD in terms of

prevention of manic episodes and not depressive episodes. Risperidone LAI was approved

as a maintenance treatment for BD by the FDA in 2009 as a monotherapy as well as an

adjunct to sodium valproate or lithium (83). To date it is the only depot approved for use in

BD. It is not licenced for this indication in Europe.

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The efficacy, safety, and tolerability of aripiprazole once-monthly (AOM) 400mg LAI (400mg)

has recently been assessed as maintenance treatment for bipolar I disorder in a double-

blind, placebo-controlled, 52-week randomized withdrawal study following a manic episode

and stabilization on oral aripiprazole (84). The risk of recurrence of any mood episode over 1

year was reduced by approximately half with AOM 400 compared with placebo, with the

effects observed predominantly on manic and mixed episodes but not depressive episodes.

AOM was generally safe and well tolerated.

A small case series has described the use of paliperidone palmitate LAI in BD. Three

patients with severe psychotic BD, poorly compliant with oral treatment, were started on

(open-label) paliperidone palmitate LAI (100-150 mg monthly) and followed up for 12

months. None of patients relapsed during follow-up or experienced adverse effects or

significant metabolic changes (85).

The choice between using a first-generation antipsychotic (FGA) depot or a second-

generation antipsychotic (SGA) LAI in BD raises several issues. Firstly, no FGA

antipsychotic, oral or depot, is approved for the maintenance treatment of BD. In contrast

several SGA oral antipsychotics (including aripiprazole, olanzapine, quetiapine and

risperidone) are approved for the maintenance treatment of BD if an acute bipolar episode

has responded to that drug (other than with quetiapine, this acute episode is defined as a

manic episode). The efficacy of risperidone LAI has been compared with FGA depots in a

BD retrospective cohort design of 3916 patients in Taiwan (86). The findings demonstrated

that compared with risperidone LAI, the use of FGA depots was associated with a higher

rate of hospitalization for any mood episode and for major depressive episode. Observations

were limited to severe episodes requiring hospitalization, so the findings may not be

generalizable to milder mood episodes. A second issue relates to risk of extrapyramidal side

effects (EPS). Meta-analyses indicate that patients with BD are more prone to develop

extrapyramidal side effects when treated with FGAs than are patients with schizophrenia and

that the vulnerability of BD patients to develop EPS is particularly marked during depressive

episodes schizophrenia (87;88). A third issue is that FGAs may be depressogenic in BD

(89) whereas this has not been shown with SGAs. A meta-analysis of randomised controlled

trials concluded that there was a 42% less risk of switching to depression after treatment of

acute mania with a second-generation antipsychotic (SGA) compared to the use of

haloperidol (90). On the basis of their potential depressogenic effect, Bond et al (2007)

argued that “depot FGAs should be avoided in patients with a high burden of illness from

depressive symptoms and particularly in those judged to be at high risk of suicide” (91). In

summary, current data suggests that SGA LAIs confer several advantages over FGA depots

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in the maintenance phase of BD. The main disadvantage of SGA LAIs is their higher

acquisition cost relative to FGA depots.

Table 1 near here

Page 15 of 28

It should be noted that, even in schizophrenia, the evidence base for the relative

effectiveness of oral and depot antipsychotics is far from clear, with observational studies

tending to be more supportive of depot whereas most RCTs find oral and depot to be equally

effective. The fact that different trial designs give different results is generally regarded as

reflecting methodological issues (5). In particular, RCTs are likely to recruit relatively

adherent patients. Furthermore, in a double-blind design, those in the oral treatment arm will

be reviewed at a frequency equal to that of those in the depot arm in order to ensure

blinding. In reality, a stable patient on oral medication would be reviewed far less frequently

than a patient on depot who will be typically be seen every 2 to 4 weeks for the

administration of their depot. As such the double-blind design distorts the ecological validity

of the findings and the outcome cannot be assumed to represent that seen with oral

antipsychotic treatment in clinical practice (5).

Reminders

Reminders are more likely to be effective if non-adherence is due to forgetfulness as oppose

to intentional. There is a lack of research evidence in mental illness comparing the effect of

simpler reminder interventions from blister packs or multi-compartmental devices, telephone

reminders, or face to face reminders on medication adherence rates. In recent years

attention has focussed on the use of electronic technology systems to assess and improve

adherence.

Medication event monitoring system (MEMS) use micro-technology to detect when a

medication container is opened. Typically this would equate to a medication bottle cap being

removed, though the technology can be adapted to other containers including multi-

compartmental containers labelled with the day and time that each medication is due. There

is then an assumption that an opened container equates to medication being taken. Clearly

there is the possibility that patients open their medication bottle, extract the medication and

throw this away (5). The use of MEMS may still have to be used in conjunction with self-

reporting measures such as the Tablets Routine Questionnaire where issues of cost and

polypharmacy and forgetfulness become an issue with MEMS device. (92). Such data

support MEMS as a measure of adherence rather than an intervention to help improve this.

Further research is required to explore the potential for systems that feedback to patients if a

bottle opening is not detected. This would require remote monitoring and the use of

feedback systems to the patient such as text messaging. Such systems are now available.

An alternative approach to the remote monitoring of patients is the use of digital sensors that

can be imbedded within a tablet (93). Following ingestion, the sensor is activated by gastric

acid and sends a signal to a receiver worn as a patch by the patient. This receiver links by

Page 16 of 28

Bluetooth to the patient’s smart phone which in turn sends a signal to a remote monitoring

centre and feedback on adherence (i.e. ingestion of the ‘sensor) can then be sent to the

patient and/or the medical team looking after them. Feasibility and acceptability has been

confirmed in a small study of 12 non-paranoid patients with BD and 16 with schizophrenia

(94). Ongoing clinical feasibility trials which do not use paranoia as an exclusion factor will

help elucidate the acceptability of this approach in a broader cohort of patients.

Financial incentives

Financial incentives have been shown to reduce tobacco and illicit drug use in people with

serious mental illness (95). A recent RCT showed that financial incentives improved

adherence to antipsychotic depots (96). This study primarily recruited patients with

schizophrenia, though those with schizoaffective disorder and BD were also eligible to enter.

The study only lasted 12 months and so the effectiveness of continuing financial benefits

beyond this is unknown. The approach also raises potential ethical issues.

Conclusion and further researchNon-adherence is a common problem in BD and is strongly associated with poorer clinical

outcomes. It also places an increased demand on mental health services and increases

service costs. It is reasonable to assume that the total costs of BD incurred by society is

increased by poor adherence.

Addressing non-adherence needs to be on an individual patient basis, as factors that

contribute to its occurrence may differ significantly between patients. Further research is

required to establish a better understanding of the complexities of medication adherence in

BD (97). However, there are general principles that clinicians can adopt to reduce the

likelihood of non-adherence. These include ensuring patients have adequate knowledge

about their illness and its management, that any misperceptions are addressed, and that

there is a positive therapeutic alliance.

Prescribing ideally should occur within a shared decision-making process, with the

medication regimen kept as simple as possible. It is important to aim for total symptom

control, as a patient is unlikely to take medication if it is perceived to be of little benefit.

Comorbidities, especially substance misuse, need to be managed. Screening for side

effects, and appropriate intervention when they are detected, needs to be a routine part of

management. Throughout treatment there needs to be non-judgemental exploration of

adherence to prevent it being covert. When non-adherence is identified the factors leading to

it need to be explored as these will guide the intervention that is adopted. A range of

Page 17 of 28

additional interventions are available including psychoeducation, reminders and adherence

aids.

A depot antipsychotic may have a role where there has been non-adherence with an oral

anti-manic maintenance agent. The current data available support the use of risperidone and

aripiprazole LAI for the prophylactic treatment of mania in patients non-adherent to oral

medication. For patients with BD at risk of self-harm or in whom depressive symptoms are or

have been clinically problematic, we would suggest a FGA depot should probably not be

considered due to their potential depressogenic risk. If a LAI antipsychotic is considered

appropriate for a patient with BD (because of poor oral adherence) a SGA LAI should be

chosen as first line treatment over a FGA antipsychotic. Although the majority of the SGA

LAI literature in BD is on risperidone LAI, there is recent support for aripiprazole monthly LAI,

and paliperidone LAI (monthly or 3-monthly) may be considered based on its pharmacology

related to risperidone, tolerability, and patient acceptability. For those rare patients whose

BD includes only manic episodes, it may be reasonable to consider a FGA depot. However,

the evidence base for their effectiveness is inferior to that for SGAs and on these grounds a

SGA LAI is likely to be the more evidence-based choice. Conclusions drawn from the clinical

comparability literature between FGA depots and SGA LAIs in schizophrenia cannot be

extrapolated uncritically to BD.

In terms of future research, further exploration of the attitudes and knowledge of carers

regarding BD and medication used to treat it, and its relationship to patient adherence, would

be valuable (98). Further research is needed on the role of depot antipsychotics in BD,

including the relative risks and benefits of different FGA and SGA medications. Digital

technology, including smart phone apps and smart medication containers, can be used as

platforms to monitor and facilitate adherence (99) but this work is in its infancy (100). The

effectiveness and acceptability of these approaches requires further work but may appeal to

a younger generation given the younger onset of age of BD patients.

Declaration of interestsIn the last 3 years PMH has received honoraria for lecturing and/or consultancy work from

Allergan, Galen, Janssen, Lundbeck, NewBridge Pharmaceuticals, Otsuka, Sunovion and

Teva plus conference support from Janssen, Lundbeck and Sunovion.

In the last three years PST has received honoraria for attending Advisory Board meetings

from Galen Limited; Sunovion Pharmaceuticals Europe Ltd; myTomorrows; LivaNova Ltd.

Page 18 of 28

In the last 3 years RHMW has received support for research, expenses to attend

conferences and fees for lecturing and consultancy work (including attending advisory

boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli

Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier,

SPIMACO and Sunovion.

Page 19 of 28

Table 1

Guidelines RecommendationsCANMAT and ISBD 2013 update (101) Maintenance Treatment for bipolar mania.

Risperidone LAI considered first line.Maudsley Guidelines, 12th edition, 2015 (102)

The use of FGA depots is commonly used in clinical practice but is associated with higher risk of depression.Risperidone LAI shows efficacy in treatment of mania, but due to pharmacokinetics it is considered unsuitable choice for acute treatment of mania.

RANZCP 2015 (103) Maintenance treatment for prevention.LAI risperidone has some support for manic and depressive relapses.

NICE 2016 update (14). The Guideline Development Group (GDG) stress that lithium treatment has the most robust evidence as first line treatment, but that the NICE guidance on Psychosis and Schizophrenia 2014 can be adapted for recommendation for bipolar patients and include risperidone LAI in the review of the evidence, but include no other LAI.

BAP 2016 update (15). Good practice to initiate effective and tolerated dose with oral formulation before switching to LAI.Only risperidone LAI has licensed RCT support and is consistently positive for treating bipolar mania and not depression.Fluphenazine and haloperidol decanoate, olanzapine pamoate, paliperidone and aripiprazole depot can be used. Case by case clinical practice review is advised when considering these alternatives.

Summary of advice on use of antipsychotic long acting injectables in the maintenance

treatment of bipolar disorder in key guidelines.

Page 20 of 28

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