Treatment in Schizophrenia: Factors For Adherence: Francisca Caiado de Bragança

2019/2020
Francisca Caiado de Bragança

Treatment in Schizophrenia: factors for adherence
Fevereiro, 2020
Mestrado Integrado em Medicina
Área: Psiquiatria e Saúde Mental

Tipologia: Monografia
Trabalho efetuado sob a Orientação de:

Professor Doutor Manuel António Fernandez Esteves
Trabalho organizado de acordo com as normas da revista:

Comprehensive Psychiatry
Fevereiro, 2020
Aos meus pais
Francisca Caiado de Bragança1, Manuel António Fernandez Esteves2

1
Faculty of Medicine, University of Porto, Porto, Portugal; Alameda Prof. Hernâni
Monteiro, 4200-319 PORTO, Porto, Portugal
2
Department of Clinical Neuroscience and Mental Health, Faculty of Medicine, University
of Porto, Porto, Portugal; Alameda Prof. Hernâni Monteiro, 4200-319 PORTO, Porto,
Portugal
Corresponding author:
Faculdade de Medicina da Universidade do Porto
Alameda Prof. Hernâni Monteiro, 4200-319 PORTO, Porto, Portugal
E-mail: [email protected]
1
Abstract
This narrative review analyzes the existing scientific evidence on factors related
to medication adherence in schizophrenia.
Using PubMed as the database, a research was conducted targeting articles
published between 2009 and 2019, written in English or Portuguese, about predictors of
antipsychotic compliance in schizophrenia.
Factors affecting adherence have been generally subdivided into 4 categories:
disease-related, patient-related, medication-related and environmental-related. Factors
which were found to be consistently associated with poor adherence include poverty,
high symptom burden, high levels of hostility, poor insight, presence of substance abuse,
negative attitudes toward medication and antipsychotic side-effects. On the other hand,
variables such as neurocognitive dysfunction, type of antipsychotic, social support and
demographic parameters often yielded contradictory results.
Variables consistently associated with non-adherence should be assessed in
clinical practice and strategies put in place to correct them or dampen their effect. Since
conflicting results are often found regarding several studied variables, future research
should aim at identifying further predictors of adherence in order to better guide clinicians
and maximize the patient’s benefit of treatment.
Keywords: schizophrenia; adherence; antipsychotics.
2
1. Introduction
Schizophrenia is a disabling chronic illness that affects aproximatelly 0,5%-0,7%

of the adult population worldwide.1 Typically developing in late adolescence and early
adult life, it is caractherized by cognitive changes, lack of insight, and both positive and
negative symptoms, reflecting, respectively, a distortion and excess or a reduction in
normal functions.2 3 4
The primary treatment, adressing symptom burden and relapse
5
risk, includes both antipsychotic medication and psychossocial interventions, such as
cognitive-behavioral, compliance and family therapy and psychoeducation.2 4
Adherence to treatment is not an all or nothing phenomenon.6 Although both
adherence and compliance are plausible terms to describe the extent to which a patient
takes the medication prescribed by an healthcare provider, some authors prefer the term
adherence, as compliance generally involves deliberate treatment engagement. As the
two may be imperfect, both will be used interchangeably in this review.
Since schizophrenia is a chronic mental illness and adherence tends to be worse
with a prolonged disease course, non-adherence to antipsychotics is one of the most
important aspects of treatment.7 8
Patients’ low insight for the disease makes this
problem even more pronounced, with the decreased motivation to be treated being the
cause of highly detrimental consequences to the patient.8
In the literature, poor adherence in schizophrenia has been shown to be a strong
predictor of relapse, which is two to five times more likely to occur in non-compliant
patients.9 Non-adherence has also been associated with poor symptom outcome,
substance abuse, longer inpatient treatment, increased re-hospitalization, social
alienation, arrest, violence and greater economic burden.4 10 Besides this, non-adherent
patients are more likely to suffer from neurocognitive, occupational and social
dysfunction and ultimately to become a danger to themselves and others.11 12
In this setting, rates of non-adherence vary between 70% to 95%,13 although
naturalistic studies point to rates between 25 to 50%.14 In the CATIE study, a double-
blind trial that included 1493 patients, 74% of patients discontinued their medication
within 18 months, with no distinction between first and second generation
antipsychotics.3
Medication adherence is, in this way, a central aspect in the management of
these patients, and the factors affecting it have been studied for several years now.10
While for some the evidence consistently points to a direction of impact, for others the
results are many times inconsistent and contraditory.7 Putative predictors have been
generally categorized as disease-related, medication-related, environmental-related and
patient-related.14 The aim of this narrative review is to study how these factors affect
antipsychotic adherence in schizophrenia.
3
2. Methods
A research was conducted using the PUBMED database on the 10th September
2019, using the following query: ((((("schizophrenia"[MeSH Terms]) OR schizophre*))
AND ((("risk factors"[MeSH Terms]) OR predictors) OR reasons)) AND (((("treatment
adherence and compliance"[MeSH Terms])) OR "medication adherence"[MeSH Terms])
OR non adherence)) AND "antipsychotic agents"[MeSH Terms]. Articles were included
if written in English or Portuguese, published between 2009 and 2019, related to
humans.
The database returned a total of 181 references. After reading the title and
abstract, 115 articles were excluded for not being related to the theme. After the full
reading of the remaining 66 articles, 27 were excluded due to information that did not
apply to this study. To this total of 39 articles, 10 were added after a hand search of
relevant content found in references of selected articles. Thus, 49 articles were included
in this review.
4
3. Results
3.1. Disease-related factors
3.1.1. Illness duration
A shorter illness duration was found to be significantly associated with higher

rates of treatment discontinuation.5 In fact, patients with less than a five-year disease
course were found to be 2,7 times more likely to discontinue medication in comparison
to those with a course of over five years.5 Patients early in the course of disease seem
to have less insight, which is a strong predictor of non-adherence. However, illness
duration may also act as a proxy for other factors such as duration of maintenance
therapy.9 A longer duration of maintenance therapy has been shown to predict higher
adherence.15
3.1.2. Symptomology
The efficacy of antipsychotics in decreasing symptom burden is consistently

considered the core driver of the patient’s decision to comply with therapy.16 Studies go
further to state that symptomatic worsening during treatment is a stronger predictor of
discontinuation than medication intolerance.16 17
However, the degree of improvement in specific symptom clusters appear to be
more relevant in this behavior.17 Positive symptoms improvement has been pointed as
the most important symptom cluster predictor of treatment compliance.16 17 18 19 Besides
this cluster, only improvement in hostility levels and depressive symptoms predicted
adherence.17 Hallucinations and delusions of grandiosity impair the patient’s ability of
acknowledging the need to take the medication, making them reluctant to adhere.20 On
the other hand, improvement of negative symptoms hasn’t been a consistent predictor
of adherence.17 20
The positive valorization of symptoms has been an understudied subject, since
most patients seeking treatment refer more detrimental than advantageous effects.21
However, positive attitudes or ambivalence toward symptoms exists and have been
found more frequently in positive symptoms such as hallucinations and delusions.21 22
Some patients describe psychosis as fascinating, with an undisputable risk of attachment

to their delusional narratives.21 22
Paranoid patients convinced to be in possession of
special powers have high self-esteem, which can be a barrier to comply with treatment.22
Auditory hallucinations of benevolent content have been associated with decreased
5
compliance, especially when patients perceive paranoia as a survival strategy.21 22
A
study assessing the way patients perceive the possible gain from illness showed that
28% of patients discontinue their medication due to increased necessity of “importance
and power”, desire of “becoming another person” or “missing voices”.21 It is, thus, crucial
to assess how patients feel about their symptoms, in order to better guide the choice of
therapy.22
3.1.3. Neurocognitive dysfunction
Cognitive dysfunction is a robust feature of schizophrenia and has been pointed

out as a strong predictor of functional outcome,7 although there is still debate as whether
it does so independently or through non-compliance.14 Though studies assessing
neurocognition and adherence have reached different conclusions,7 14 15
memory
impairment and executive dysfunction have been found to be the most relevant
predictors of non-adherence in schizophrenia.14
In the memory field, adherent patients exhibit an overall better memory
performance, especially in verbal memory,14 while non-adherent patients have a worse
immediate recall ability, which hinders their capacity to comply.14 In fact, forgetting to
take the medication has been reported as the most frequent reason for non-adherent
behavior.23 9
In relation to executive functioning, patients that don’t adhere to antipsychotic
medication show significantly lower scores in tests evaluating attention, abstraction, and
cognitive flexibility.14 15
They also display impaired task-shifting abilities, which reflects
dysfunction in domains such as planning, problem solving and conceptualization,14 and
this has also been correlated to non-adherence.15
Other studies, however, have reached opposite conclusions, with non-adherent
patients exhibiting a higher level of neurocognition, exemplified by better verbal learning
and memory skills, executive functions and a higher IQ.7 Authors speculate that patients
with a higher cognitive performance may have a stronger belief in their ability to cope
without medication, and hence choose to discontinue it.7
In the field of language, verbal fluency has been found to be one the most
impaired cognitive domains in schizophrenia.15 A study has found that language
impairment, reflected by poor performances in verbal fluency tests, conferred a moderate
risk for non-adherence.15
Despite the debate around this topic, it is generally accepted that cognitive
dysfunction in schizophrenia impacts adherence both through decreased motivation and
impaired ability to engage in therapy.14
6
The premorbid functioning level of a patient who develops schizophrenia and its
impact on adherence is understudied and subject to conjecture.14 Those with higher
premorbid intellectual function, itself affected by the neurodevelopmental nature of
schizophrenia, are thought to better deal with the neural insult of the disease.24 An
improved cognitive reserve is thought to increase the ability to inhibit the abnormal neural
processes responsible for psychotic symptoms.24 Thus, it possibly translates into a
diminished symptom burden, which by itself improves adherence.14
3.1.4. Insight level
The multidimensional concept of insight includes the awareness of being ill, the
recognition of symptoms, the ability to attribute deficits to the disease and the
understanding of the need for treatment.25 26
The level of insight may be modulated by
the presence of neurocognitive deficits or coping mechanisms.25 18 In the literature, low
insight has been consistently associated with non-adherence.19 27 7 28 29
Patients with preserved insight are more able to lable psychotic symptoms as
pathological, have a greater awareness of the social consequences of the disease and
are ultimately more likely to find the treatment both reasonable and necessary.7 11 18
It is also noteworthy that, although impaired insight is a well-established predictor
of non-adherence, patients taking long-acting injectable antipsychotics may be adherent
despite having poor insight, making these medications a reasonable option to improve
outcomes in patients whose insight is impaired.25
3.1.5. Hostility
Patients exhibiting high hostility were found to be less adherent to treatment.30 25

29 28
Hostility and insight are often seen as concomitant factors impacting adherence and
for this reason should be assessed together.29 This is further supported by the fact that
hostile patients with decreased insight showed over 90% probability of not complying
with medication.25 Hence, hostility is found to be both a predictor of non-adherence and
an amplifier of the correlation between insight and adherence.25
7
3.2. Patient-related factors
3.2.1. Socio-demographics
There are conflicting results regarding the relationship between demographic

variables and compliance with treatment in schizophrenic patients.30
While some don’t find an association between the patient’s age and adherence
behavior,25 27
an older age has been associated with decreased compliance with
treatment.31 This latter finding has been attributed to a higher pill burden in this age
group, in addition to common memory and executive functioning deficits.31 However,
other studies find opposite results,32 15 3
with increasing age having a positive influence
on compliance.3 23 33
The decreased independence and mobility of older individuals
seems to ease clinical monitoring, contributing to higher adherence rates.34 In the same
line of thought, patients who are early in their disease course and haven’t experienced
repeated relapses may be more willing to take risks in order to assess their ability to
remain well without medication.9
The influence of gender in adherence is highly controversial. While some studies
report female gender as a negative determinant of adherence,23 12
others found no
9 25
association. In an homeless French population, female gender was found to be a risk
factor for non-adherence mostly due to increased reported side-effects and increased
negative attitudes towards medication.12 Women seem to experience more negative
side-effects probably due to biological differences impacting drug metabolism,
particularly because antipsychotics are mostly tested in middle-aged men to avoid the
concerns with pregnancy.12
Non-adherent patients are more likely to live alone than adherent patients, which
may mirror an inadequate support by relatives and caregivers.18
Full adherent patients have been shown to have a higher body mass index (BMI)
in comparison to those with partial adherence.7 30
Overweight patients are unlikely to
gain extra weight during treatment and/or are more likely to accept this medication’s side-
effect.7 30 Although this is a plausible explanation, others have attributed this association
to naturalistic study designs, where patients who comply with medication over time are
more likely to gain weight.7 On the other hand, a strong correlation has also been
reported between a higher BMI and non-adherence, which can be due to the distress
caused by weight gain.35
The influence of employment and educational status in compliance with treatment
has also been studied.18 23 31
Illiterate schizophrenic patients were found to be
significantly less adherent to medication.31 In the same way, being employed full-time or
8
having a significant higher educational level (of 13 or more years) was shown to improve
adherence.23 18 Patients who are employed and have a higher educational level appear
to have a higher level of insight and functioning, which may contribute to improved
adherence.18 However, a higher educational level has also been associated with worse
compliance,3 possibly due to other intervening variables such as negative attitudes
toward medication.3
3.2.2. Adherence background
Previous non-adherence to medication is also an important factor impacting

future compliance.30 A study has found that non-adherence in the 4 weeks prior to the
start of a new medication was the strongest predictor of subsequent non-adherence.30
Moreover, patients starting antipsychotics were more frequently non-adherent than those
with previous consistent use of the same drugs, implying that patients need time to adjust
and become adherent to an antipsychotic.32 8
3.2.3. Alcohol and drug use
Past or current alcohol and drug use is common amongst schizophrenic patients
and most studies have considered these risk factors for medication non-adherence.9 30
15 33
Patients with addictions are, in many cases, primarily concerned with short-term
demands, investing less on long-term goals, including those related to their own health.
Furthermore, these patients often exhibit psychiatric comorbidities and are commonly
stigmatized within medical environments, generating mistrust and fueling avoidance of
the system.36 There is still debate, however, on whether substance abuse is a cause or
a consequence of non-adherence.28 To better answer this question, detailed prospective
studies will be needed.28
3.2.4. Social functioning
In the context of schizophrenia, being socially active relates to better adherence

to treatment.30 This is thought to be mediated by the severity of patients’ positive
symptoms, which highly impact their social skills.30 A good psychosocial function,
especially in the areas of self-care and social networks, was also shown to be one of the
two best predictors of compliance.19 The engagement in activities such as art therapy,
social skills training and cognitive behavioral therapy also had a positive impact on
adherence.18
9
3.2.5. Religion
Religion can provide support for patients whose social life and individual identity
has been hindered by the disease, fostering feelings of hope and purpose.6 However,
religious beliefs can also lead to the replacement or delay of medical treatment, since
some groups focus solely on spiritual healing and perceive suffering as salutary.6
Christianity was found to be a predictive factor of adherence.4 Christian patients
were found to be 3,23 times more likely to commit to treatment than Buddhists, Muslims,
Hindus and free thinkers.4 Authors attribute this to the fact that Christians tend to be less
stigmatized by their religious peers,4 and that Christianity is more receptive to science-
based and less supportive of superstition-based treatments.4
In a study conducted in the United Arab Emirates, the involvement of patients
with faith healers was significantly associated with non-adherence,27 and
recommendations were made to educate patients and families on the consequences of
such practices.27
3.2.6. Attitudes toward medication
It is known that the patient’s attitudes toward medication may not translate directly
into behaviors of adherence and non-adherence.20 A patient may forget to take the
medication even though he understands its benefits.20 The same happens with someone
who, although believing the medication is unnatural, harmful, lenghty or unnecessary,
takes it for other reasons, such as pressure from others.20
Other studies have reached different results, with a negative attitude towards
medication predicting non-adherence directly.19 31 These patients have also been shown
to have lower levels of insight, more medication side-effects and diminished trust in the
doctor-patient relationship.37 11
It seems that several variables are able to change the
patient’s view and attitude towards the treatment, ultimately impacting adherence.
Concerning patients exhibiting positive attitudes, 85% were adherent to
medication,20 and this pattern has been found in independent studies.11 31 18
10
3.3. Environmental-related factors
3.3.1. Living area
Improved medication adherence has been observed in schizophrenic patients

living in a non-metropolitan area.8 In rural areas patients are thought to have a stronger
social support network and a closer relationship with their physician, as well as less
assess to illicit drugs, all factors associated with improved adherence.8
3.3.2. Poverty
In a study conducted in rural Ethiopia, the most common reason for non-
adherence among schizophrenic patients was the lack of assess to basic livelihood, such
as proper food.38 Moreover, in empoverished areas which commonly lack community
mental health care, the support from family members is even more important since it is
often the only one in which the patient can rely.38
In the homeless population, the estimated prevalence of schizophrenia is
approximately 11%.12 Considering the unique difficulties and context of this population,
it is understandable that, to these patients, medication adherence is not a primary
concern. Pharmacological and non-pharmacological strategies should, in this way, be
laid out to better address schizophrenia in the context of homelessness.12
3.3.3. Stigma and support from others
Because of the low mental health literacy among the general population, people
tend to distance themselves from those exhibiting strange behaviour.4 Schizophrenic
patients fear being labeled as mentally ill, since this is frequently associated with fewer
marriage and job opportunities.38 Stigma is, thus, a powerful barrier to adherence.38
On the other hand, patients feel safe and understood sharing their condition with
a significant other who provides support and encouragement.4 19 A caregiver is of great
importance to these patients as it was found by a study that 44% of adherent patients
had a family caregiver, contrasting with only 24,6% of non-adherent patients.18 However,
significant others can also negatively impact adherence,21 as it was noted in a sample of
72 non-adherent patients, in which 20% attributed non-compliance to friends or family
advice against medication intake.21
11
3.3.4. Doctor-patient relationship
Patients who place trust in their doctor and report good relationships with medical
personnel exhibit better medication adherence.4 11
Likewise, when the psychiatrist
includes the patient in the medication decision process, he tends to feel better informed
and more open to discuss fears and uncertainties.39 An important thing to consider is the
confounding effect of insight in the association between the quality of the therapeutic
relationship and adherence.39 The extent to which the patient perceives the relationship
as satisfactory depends on the concordance between doctor’s and patient’s views and
goals, which is naturally increased when the patient has preserved insight.39
3.4. Hospitalizations and medication-related factors
3.4.1. Hospitalizations
Non-adherence is more frequent in patients with multiple past and short-duration

hospitalizations and who required hospitalization at the onset of the disease. 8 18 20 30
Patients who are hospitalized at the onset of illness presumably exhibit more
severe symptomology and that could itself explain the trend to non-adhere.20
Apart from the number of previous hospitalizations which also predicted non-
adherence,18 30 one study showed that patients with an hospitalization of over two weeks
of duration were more likely to be adherent after discharge in comparison to patients with
shorter hospitalizations.8 The latter, who more frequently self-discharge, may do so
owing to a poor therapeutic alliance.8 On the other hand, longer hospitalizations enable
a stronger therapeutic alliance to be established and allows time for a better decision to
be made in relation to the medication discharge plan.8
3.4.2. Medication side-effects
Side-effects from medication are often referred as the most important contributor
to non-adherence, 21 22 although other studies don’t find such association.7 A patient who
had previous negative experiences with medication, either through distressful side-
effects or non-response, is likely to feel skeptical about it.39 Moreover, the weight of
specific side-effects will depend upon study population.22
In general, side-effects strongly associated with non-adherence vary widely
between studies and include extrapyramidal symptoms, such as tardive dyskinesia,
akathisia and parkinsonism, cognitive side-effects such as sedation, sleepiness and
12
dizziness, autonomic side-effects such as diarrhea and nausea and diminished sexual
drive and weight gain.3 7 22
Another point worth noting is the difference between acutely ill and stable patients
on chronic treatment. Acutely ill patients, in which lack of insight and delusions
predominate, are likely to overestimate the improvement in positive symptoms,
underestimating side-effects from medication.16 On the other hand, multiepisode
schizophrenic patients report changes in appearance as a significant reason for non-
adherence, in comparison to first episode patients.40 It is important to take into account
that long term users of antipsychotics may underreport side-effects both because they
get used to them or believe the side-effects are deeply intertwined with the benefits of
treatment.18
The balance between the discomfort from side-effects and the medication’s
benefits seems more relevant in terms of adherence than side-effects alone.18
3.4.3. First- and second-generation antipsychotics
The impact of the type of antipsychotic on adherence has been a matter of debate
and also of controversy since studies differ widely.10 While some don’t find a relationship
between the type of antipsychotic used and the level of medication adherence,11 33 19
adherence was reported to be significantly higher when using typical antipsychotics,23

although the same was found in relation to atypical antipsychotics.18 15
In clinical practice, although metabolic side-effects and weight gain, potential
threats to adherence, are more commonly attributed to atypical antipsychotics, these
seem to have supplanted the real concern with extrapyramidal side-effects more
frequently caused by typical antipsychotics.28 However, some authors don’t see this so
starkly, attributing equal importance to adverse effects arising from both types of
antipsychotics.3
3.4.4. Oral and long-acting injectable (LAI) antipsychotics
One of the aims in the development of LAI antipsychotics, also known as depot
antipsychotics, was improving adherence in schizophrenia.41 These new drugs would
also allow earlier and easier detection of relapse, clearer distinction between lack of
adherence and lack of efficacy, reduced risk of self-poisoning and more stable and
predictable serum concentrations.41 In face of non-adherence, LAI antipsychotics also
would have the advantage of creating a window of opportunity to encourage patient’s
compliance without a precipitous drop in drug levels.42
13
The use of LAI antipsychotics in the treatment of schizophrenia has then been
proposed as an alternative to their oral counterparts when there is a concern of poor
adherence but in real-life discontinuation still occurs, albeit in a smaller percentage
comparing to oral antipsychotics.41 43
However, this benefit on adherence is not
supported by all studies.18
One could hypothesize that LAI antipsychotics would improve adherence mainly
through improved efficacy. In terms of such claim, debate on whether the clinical
outcomes are improved by their use over oral antipsychotics is still ongoing.41 43 A large
randomized control trial concluded LAI antipsychotics were not superior to oral
antipsychotics in terms of time to hospitalization, symptom relief and quality of life.44 On
the contrary, they have shown to reduce hospitalization frequency in a meta-analysis of
mirror-image studies.45
In the clinical setting, LAI antipsychotics still tend to have low prescribing rates,
mostly ascribed to psychiatrists’ concerns.41 These include the potentially stigmatizing
effect of such drugs, concerns about the loss of patient’s autonomy, beliefs that they are
associated with worse side-effects in comparison to their oral counterparts and concerns
related to patient’s acceptance.41 The cost of LAI antipsychotics has also been pointed
as a reason for underprescription, since this drug’s availability is often restricted in certain
areas by the institutions holding the medication budget.41
Although most evidence seems to support the use of LAI antipsychotics to the
benefit of adherence,2 it remains questionable whether depot antipsychotics truly
improve adherence or simply reveal non-adherence in patients with schizophrenia.
3.4.5. Medication scheme
It has been found that a complex regimen comprised of many medications with a
high frequency of administration negatively affects adherence.26 This is especially
pertinent in schizophrenia, since the cognitive deficits associated with the disease further
impact the ability to understand an already complex regimen.26
However, it has been found that patients taking both types of antipsychotics,
instead of just one, more likely remembered to take the medication.4 Authors propose
that, in these patients, one antipsychotic is not enough for symptom improvement, hence
patients taking more than one showed better compliance.4 The same probably applies
to patients on other psychiatric medications such as mood stabilizers, anticonvulsants,
anticholinergics and anxiolytics.32
14
3.5. First episode psychosis (FEP) and multiepisode schizophrenia
First episode and multiepisode schizophrenia patients seem to have different

motivations to adhere to antipsychotic therapy.40
FEP patients are peculiar in the way that their short disease course hasn’t allowed
them the time to reach a “cause and effect” conclusion about medication. Unable to
perceive symptom relief deriving from antipsychotics, they are prone to deem medication
unnecessary once free from symptoms.40 However, other authors have found opposite
results, with FEP patients whose positive symptoms were relieved by medication being
more likely to stay adherent.46 These patients consider the doctor-patient relationship as
the most relevant factor driving adherence.40 Hence, in the first-episode crisis, it is
essential to create a strong therapeutic alliance, within which patient’s beliefs, life goals
and insight into illness are taken into account.40
Multiepisode patients have different motivations, including the desire to prevent
relapse and the understanding of the treatment’s benefits.40 Non-adherence in this group
is highly related to changes in appearance due to medication, since their longer
treatment course allows these effects to stand out.40
The moment in which the first episode occurs is also relevant for compliance.20
In adolescent FEP patients it was found that a decreased symptom burden was
predictive of non-adherence, which may seem counterintuitive.20 47 However, in this age
group, the tighter parental supervision leads to greater adherence if symptomology is
severe.20 On the other hand, adult FEP patients are less likely to be supervised, and their
adherence more closely impacted by symptom severity.47
3.6. Persistent refusal
While most non-adherent patients may be partially non-adherent, there is an

understudied group which consistently denies medication, over a long period of time.39
Persistent refusers, when compared to fully adherent patients, were found to
have lower insight levels and more frequently considered previous medications unhelpful
and previous psychiatrists unsatisfactory.39 Moreover, they felt they had been less
informed about medication in the past.39
Although this group of patients was thought to be more severely impaired and
thus less able to make judicious decisions, they were also found to have been through
relatively long periods of medication in the past, making it likely that the decision to refuse
had been rational and deliberate.39
15
4. Discussion
Adherence is a complex topic mainly because benefits and disadvantages of

pharmacological treatment vary between patients, according to different sets of goals,
beliefs and circumstances.26 Thus, a personalized and dynamic approach is needed.26
Although many factors have been shown to predict non-adherence, and
strategies aimed at correcting them are likely to retrieve positive results, there is a set of
patients in which medication intake is the only way to improve adherence on the short
and long-term. This includes decompensated patients with intense positive
symptomology, low insight, disorganized thoughts and dysfunctional behavior.
The establishment of a therapeutic alliance seems of upmost importance and
likely paves the way to address multiple non-adherence risk factors. There is a need for
longer consultations within a caring environment, in which there can be an assessment
of patients’ concerns, beliefs, positive and negative attitudes, symptomology, cognitive
ability, social functioning and family support.26 Providers should be clear, simple,
instructive and encourage patients to ask questions and be a part of the decision-making
process. Treatment should be tailored to patients’ hopes and expectations,26 taking into
account their economic resources.13 This should also prevent the search for alternative
treatments unsupported by scientific evidence.38
Besides a good therapeutic alliance, the involvement of family members or other
caregivers seems crucial, since these can better monitor and motivate the patient to
follow treatment.22 For those with strong negative attitudes, psychotherapy and
psychoeducation might be of particular importance, by challenging dysfunctional beliefs
both about the disorder and its treatment.21 For patients who feel ambivalent towards the
psychotic experience, cognitive behavioral therapy may help counter delusional
assumptions without invalidating the experience of the patient.21
Side-effects from medication should be searched for in every appointment and
medication switched if necessary. Drug and alcohol use should be prevented or reduced.
Although the association between cognitive dysfunction in schizophrenia and
poor adherence is uncertain, consensus guidelines indicate that it is a factor contributing
to non-adherence.48 For patients in which memory impairment is an important factor,22
the use of memory aids, such as alarms, calendars, behavior prompts associated with
everyday tasks and notes in visible places, may be a way of improving adherence.26
These patients could also benefit from LAI antipsychotics, that assure medication
delivery.22 Cognitive behavioral therapy integrating cognitive remediation has also been
proposed to surpass this barrier.14 48
Despite the controversy surrounding the impact of LAI antipsychotics on
adherence, these tend to be used to improve adherence in high risk individuals in clinical
practice, their higher cost being offset by less hospitalization costs on the long term.2 45
16
Both atypical and typical antipsychotics seem to yield similar efficacy in
schizophrenia’s symptoms and relapse risk.2 10 In this way, the choice of antipsychotic is
normally guided by side-effects or patient’s specific factors, such as comorbidities and
past experience with these drugs.2 Although there is conflicting evidence regarding which
type of antipsychotic is better in terms of adherence, most clinicians favor the use of
atypical antipsychotics, which are less likely to induce prominent extrapyramidal
symptoms and endocrinal side-effects.10
Simplifying the treatment regimen, both in terms of amount of medication and
frequency of administration, is a way of improving adherence. Depot antipsychotics are
also an effective way of simplifying the regimen while guaranteeing administration.26
The inconsistent results often found can be ascribed to several limitations unique
to adherence studies. In the first place, the definition of medication adherence varies
widely between studies10 and there are no universally established cut-off points. As
adherence can be evaluated in categorical, dichotomous and continuous ways,10 there
should be an effort to standardize its measurement and categorization.26
Moreover, medication adherence can be generally assessed in two ways:
objetively and subjetively.10 Objetive assessments, such as the measurement of urine or
serum antipsychotic concentrations, seem more reliable and take into account individual
pharmacokinetics, but are usually limited by financial constraints.8 10
Other examples
include the direct observation of medication intake, pill counts, electronic monitoring
systems (MEM) and pharmacy refill records.10 Subjective assessments are the most
commonly used in research, mostly because of their time and cost effectiveness, ease
of use and relative reliability.15 These include patient’s self-report, interviews, diaries or
provider reports.8 49
Although self-reporting questionnaires are patient-friendly, less
expensive and easier to conduct,23 they rely on patient recall, and overestimation is likely
to occur.10 9 It has been proposed that studies should include two measurements in their
adherence assessment where at least one is objetive.7
Most studies are also designed as cross-sectional.8 Limitations include failure to
assess patients over time, limiting cause-effect conclusions,31 especially since
adherence is a dynamic process.18
Adherence is a complex topic in schizophrenia, with current literature exhibiting
vast and heterogenous findings. Since the biology of the disease is itself an intervening
factor and variables strongly interplay with one another, it is often difficult to establish
predictive relations.
Taking into account the importance of this topic, and since patients’ behavior is
known to fluctuate over time, future research should focus on prospective study designs
over long periods of time, and in large samples, under naturalistic settings.
17
Acknowledgements
Not applicable.
Funding
This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.
Declaration of interest
None.
18
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21
Agradecimentos
Ao Sr. Prof. Doutor Manuel Esteves pela orientação, disponibilidade e dedicação na

realização deste trabalho, bem como por partilhar comigo o seu conhecimento e espírito
criativo.
Aos meus pais, por tudo.
Aos meus amigos, pelo ânimo que me deram nos momentos certos.
Obrigada.
22
ANEXOS
Normas da revista: Comprehensive Psychiatry
23
COMPREHENSIVE PSYCHIATRY
AUTHOR INFORMATION PACK
TABLE OF CONTENTS XXX

. .
• Description p.1
• Impact Factor p.1
• Abstracting and Indexing p.1
• Editorial Board p.1
• Guide for Authors p.3
ISSN: 0010-440X
DESCRIPTION
.
Comprehensive Psychiatry is an open access, peer-reviewed journal that publishes on all aspects of
psychiatry and mental health. The mission of this journal is to disseminate cutting edge knowledge in
order to improve patient care and advance the understanding of mental illness. With the support of an
expanded international team of editors and peer reviewers, we aim to publish high quality papers with
a particular emphasis on the clinical implications of the work including the improved understanding
of psychopathology. We encourage our authors to adopt an accessible approach to presenting their
findings, to promote the fullest engagement with clinicians and other interested parties. Through our
new open access policy, we expect our papers will deliver the widest global impact, opening up fruitful
scientific engagement with researchers outside the immediate circle, as well as with mental health
clinicians, interested policy-makers and the public.
IMPACT FACTOR
.
2018: 2.586 © Clarivate Analytics Journal Citation Reports 2019
ABSTRACTING AND INDEXING

.
PubMed Central
Web of Science
Scopus
Directory of Open Access Journals (DOAJ)
EDITORIAL BOARD
.
Editor-in-Chief
N. Fineberg, University of Hertfordshire, Hatfield, United Kingdom
Associate Editor
S. Chamberlain, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
E. Grünblatt, Psychiatric University Hospital Zurich, Zurich, Switzerland
R. Li, Capital University of Medical Sciences, Beijing, China
F. Schneier, Columbia University Irving Medical Center, New York, New York, United States
AUTHOR INFORMATION PACK 7 Feb 2020 www.elsevier.com/locate/comppsych 1

Editorial Office
Editors Emeriti
D.L. Dunner, Mercer Island, WA, USA
J.C. Markowitz, New York State Psychiatric Institute, New York, New York, United States
R.A. O'Connell
Editorial Board
M. van Ameringen, McMaster University, Hamilton, Ontario, Canada
B. Boland, Hertfordshire Partnership University NHS Foundation Trust, St Albans, United Kingdom
C.R. Cloninger, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, United States
W.H. Coryell, University of Iowa, Iowa City, Iowa, United States
J.R. DePaulo, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
B.M. Dell'Osso, University of Milan, Milano, Italy
J. Du, Shanghai Mental Health Center Drug Abuse Treatment Center, Shanghai, China
E. Fernandez-Egea, University of Cambridge, Cambridge, United Kingdom
L.F. Fontenelle, Monash University, Clayton, Victoria, Australia
D.A. Geller, Massachusetts General Hospital - Harvard Medical School Center for Nervous System Repair, Boston,
Massachusetts, United States
J. E. Grant, University of Chicago, Chicago, Illinois, United States
G. Grassi
E. Hollander, Yeshiva University Albert Einstein College of Medicine, Bronx, New York, United States
K. Ioannidis, University of Cambridge, Cambridge, United Kingdom
S. Kasper, University of Vienna, Wien, Austria
K.R. Laws, University of Hertfordshire, Hatfield, United Kingdom
B. Lerer, Hadassah Medical Center, Jerusalem, Israel
M. Mohler-Kuo
S.A. Montgomery, Imperial College London, London, United Kingdom
S. Morein
Z. Nemoda, Semmelweis University of Medicine, Budapest, Hungary
A. Ozerdem, Dokuz Eylül University, İzmir, Turkey
S. Pallanti, Stanford University Department of Psychiatry and Behavioral Sciences, Palo Alto, California, United
States
K. A. Phillips, Cornell University, New York, New York, USA
A. J. Rothschild, University of Massachusetts Medical School, Worcester, Massachusetts, United States
N. Sartorius, Association for the Improvement of Mental Health Programmes, Geneva, Switzerland
L. J. Siever, Icahn School of Medicine at Mount Sinai, New York, New York, United States
D. J. Stein, University of Cape Town Department of Psychiatry and Mental Health, Cape Town, South Africa
J. Stochl, University of Cambridge, Cambridge, United Kingdom
M. Zimmerman, Rhode Island Hospital, Providence, Rhode Island, United States

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Treatment in Schizophrenia: Factors For Adherence: Francisca Caiado de Bragança

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Treatment in Schizophrenia: Factors For Adherence: Francisca Caiado de Bragança

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2019/2020

Francisca Caiado de Bragança

Mestrado Integrado em Medicina

Área: Psiquiatria e Saúde Mental

Trabalho efetuado sob a Orientação de:

Trabalho organizado de acordo com as normas da revista:

Francisca Caiado de Bragança1, Manuel António Fernandez Esteves2

Keywords: schizophrenia; adherence; antipsychotics.

Schizophrenia is a disabling chronic illness that affects aproximatelly 0,5%-0,7%

3.1. Disease-related factors

3.1.1. Illness duration

A shorter illness duration was found to be significantly associated with higher

The efficacy of antipsychotics in decreasing symptom burden is consistently

Some patients describe psychosis as fascinating, with an undisputable risk of attachment

3.1.3. Neurocognitive dysfunction

Cognitive dysfunction is a robust feature of schizophrenia and has been pointed

3.1.4. Insight level

Patients exhibiting high hostility were found to be less adherent to treatment.30 25

There are conflicting results regarding the relationship between demographic

3.2.2. Adherence background

Previous non-adherence to medication is also an important factor impacting

3.2.3. Alcohol and drug use

3.2.4. Social functioning

In the context of schizophrenia, being socially active relates to better adherence

3.2.6. Attitudes toward medication

3.3.1. Living area

Improved medication adherence has been observed in schizophrenic patients

3.3.3. Stigma and support from others

3.4. Hospitalizations and medication-related factors

Non-adherence is more frequent in patients with multiple past and short-duration

3.4.2. Medication side-effects

3.4.3. First- and second-generation antipsychotics

adherence was reported to be significantly higher when using typical antipsychotics,23

3.4.4. Oral and long-acting injectable (LAI) antipsychotics

3.4.5. Medication scheme

First episode and multiepisode schizophrenia patients seem to have different

3.6. Persistent refusal

While most non-adherent patients may be partially non-adherent, there is an

Adherence is a complex topic mainly because benefits and disadvantages of

1. American Psychiatry Association Apa. DSM-V-TR - Manual Diagnóstico e Estatístico de

Ao Sr. Prof. Doutor Manuel Esteves pela orientação, disponibilidade e dedicação na

Aos meus pais, por tudo.

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