Although antipsychotic medications are the mainstay of treatment for schizophrenia, pharmacotherapy alone produces only limited improvement in negative symptoms, cognitive functions, social functioning, and quality of life [2]. Additionally, many patients continue to suffer from persistent positive symptoms and relapses particularly when they fail to adhere to prescribed medications. This underlines the need for multimodal care including psychosocial therapies as adjuncts to antipsychotic medications to help alleviate symptoms and to improve adherence, social functioning, and quality of life [21, 22].

Despite the growing acceptance that medication nonadherence is a significant public health issue associated with financial, social, and illness costs, there is a limited amount of rigorous research on the use of specific interventions to target the problem. The available literature describes interventions of various types that have been utilized in schizophrenia. Some studies have specifically measured medication adherence as a primary outcome (primary outcome studies), while others described psychosocial interventions not used directly to address medication nonadherence, but that reported the effect of the intervention on adherence as a secondary outcome measure or as incidental finding (secondary outcome studies). Although the former provide more robust evidence, both types of study will be reviewed to give as much information as possible for translation into clinical practice [23]. Given the magnitude and importance of poor adherence to medication regimens, the WHO has published an evidence-based guide for clinicians, health care managers, and policymakers to improve strategies of medication adherence [24].

Several nonpharmacological strategies to enhance adherence in schizophrenia have been investigated. They include education sessions, memory aids, motivational interviewing, and cognitive behavioral approaches such as adherence or compliance therapy. Other suggestions such as optimizing therapy, for example by simplifying the regimen and considering side effect profiles with respect to individual patient characteristics, as well as fostering a good relationship between the patient and the healthcare professional, have been repeatedly mentioned. Studies demonstrate that no single strategy is effective for all patients and that a multidisciplinary approach customized to the patient’s individual needs results in improved adherence rates [3, 8–10, 17, 23, 25–27].

Experts’ recommendations reflect also the importance of individually tailoring medication regimens to improve adherence. It is crucial to select interventions that are likely to help eliminate the barriers that are interfering with adherence in the specific patient. Likewise, clinicians should keep in mind that the ultimate goal of any intervention is not medication adherence per se, but achieving the best possible outcomes for the patient [10, 28].

This systematic literature review focuses on studies examining psychosocial interventions to improve adherence to antipsychotic medications in patients with schizophrenia as a primary or a secondary outcome. Electronic searches were performed in the PubMed database and all studies published until April 2012 were included, without any language restriction. We found many kinds of psychosocial and programmatic interventions strategies for addressing adherence problems in schizophrenia that could have promising implications for clinical practice.

All the interventions and the strategies to improve adherence to antipsychotic medication in schizophrenia reviewed in this chapter are listed in Tables 2 and 3.

Psychoeducational interventions provide information to patients and family members about the disorder, its treatment, and strategies to cope with schizophrenia [2]. An extensive body of literature has accumulated regarding the efficacy of these interventions.

Meta-analyses [29–32] suggest that these interventions reduce high EE among relatives, and decrease relapse and rehospitalization rates. In general, interventions that include family members are more effective [33, 34].

CBT seeks to help patients rationally appraise their experience of symptoms of disease and how they respond to them, thereby reducing symptoms and preventing relapse [53, 54]. Although CBT is recommended as a standard of care for persons with schizophrenia [55, 56], data from pragmatic studies suggest that its benefits are modest at best [57, 58]. We will analyze separately behavioral and cognitive-behavioral interventions (Table 4).

A number of studies have shown behavioral interventions to be successful in improving medication adherence.

Eckman et al. [59] investigated a behavioral program in improving adherence and medication management skills in 160 outpatients with schizophrenia. Patients followed a structured module in groups for about 3 h per week over 4 months. Adherence improved significantly from about 60 % preintervention to 80 % post-intervention.

Boczkowski et al. [60] randomly assigned 36 males with schizophrenia to behavioral training, didactic psychoeducation, or standard treatment. The behavioral intervention consisted of patients being told the importance of adhering to medication and each participant was helped to tailor the prescribed regimen so that it was better adapted to their personal habits and routines. This involved identifying a highly visible location for placement of medications and pairing the daily medication intake with specific routine behaviors. At a 3-month follow-up, there was a significant improvement in the behavioral intervention group compared with the other two groups. Totally, 8 out of 11 patients who had received behavioral therapy showed adherence with 80 % or more of their medication, whereas only three out of 11 in the psychoeducation intervention group showed such levels.

Cramer and Rosenheck [61] described a randomized controlled trial of 60 patients allocated to usual treatment or to the MUSE program that teaches simple techniques of how to remember daily medication doses to patients with severe mental disorders. The intervention consisted of an initial session of 15 min where the patient was taught to develop cues to remember the dose times. The intervention utilized electronic monitoring pill bottles with special caps that display the date and time of each bottle opening. Results showed significant improvement in the intervention group. The mean 1-month adherence rate was 81 % in the intervention group and 68 % in the control group, at 6 months the rate was 76 and 57 %, respectively.

Razali et al. [62] studied the effectiveness of culturally modified behavioral family therapy compared with a standard version of behavioral family therapy in 166 individuals. Post-randomization, there were 74 subjects in the culturally modified intervention group and 69 in the behavioral family therapy group. Adherence was measured globally as a percentage of the total prescribed dosages actually taken during the previous 6 months. At follow-up, 73 % in the group receiving culturally modified therapy as compared to 59 % in the control group were adherent with 90 % of their prescribed medication. At 1 year, rates were 85 and 55 %, respectively.

In schizophrenia, CBT to improve adherence often incorporates motivational interviewing techniques. First developed for use in addiction treatment, these techniques assess patients’ motivation to make changes in behavior related to adherence.

Lecompte and Pelc [64] tested a cognitive behavioral program targeted at changing adherence patterns through the use of five therapeutic strategies: engagement, psychoeducation, identifying prodromal symptoms, developing coping strategies and strategies for reinforcing adherence behavior, and correcting false beliefs about medication. There are 64 nonadherent patients with psychosis were randomly assigned to receive either the active intervention or a control treatment of unstructured conversation. The primary outcome measure was the duration of hospitalizations 1 year before and 1 year after the intervention, which the authors argued was a useful indirect measure of adherence. Patients receiving the cognitive behavioral intervention spent significantly less time in hospital in the year after as compared to the year before the intervention, but no significant difference was found relative to the control group. Although these findings suggest the intervention is beneficial, it is not certain that this improvement can be attributed solely to improved adherence.

Motivational Interviewing has been defined as “a directive client centered counseling style for eliciting behavior change by helping clients to explore and resolve ambivalence” [65]. Although behavioral analysis is used, motivational interviewing does not try to force the person into accepting the evidence of advantages of a new behavior but considers the value of letting persons progressively discover advantages and disadvantages of their behavior for themselves.

Hayward et al. [66] used an intervention of medication self-management based on motivational interviewing aiming to allow patients and clinicians to work collaboratively to examine medication issues. Twenty-one inpatients received three 30-min sessions of either medication self-management or nondirective discussion on any issue except medication. The pilot work showed trends in favor of the intervention group with regard to adherence and attitudes toward treatment but none reached statistical significance.

This led to the development of the longer, more structured intervention CT [67, 68] which modified motivational interviewing techniques to give particular attention to the therapeutic relationship and to make the approach useful with patients suffering from psychosis and combined this with cognitive behavioral techniques. CT is a CBT intervention that targets adherence issues and incorporates psychoeducation and motivational interviewing to help patients understand the connection between relapse and medication nonadherence to improve motivation for taking medication.

The therapy is described in detail in a treatment manual [69]. The key techniques are those of reflective listening, regular summarizing, inductive questioning, exploring ambivalence, developing discrepancy between present behavior and broader goals, and using normalizing rationales. The intervention is divided into three phases that acknowledge that readiness to change is on a continuum. Phase 1 deals with patients’ experiences of treatment by helping them review their illness history. In phase 2 the common concerns about treatment are discussed and the “good” and the “bad things” about treatment are explored. Phase 3 deals with long-term prevention and strategies for avoiding relapse. Despite its name, CT appears to fit with a concordance model, involving patients in making decisions that are right for them, rather than trying to get them to be obedient to professional advice.

In a small-scale study, Kemp et al. [68] found that CT significantly improved insight, attitudes toward treatment, and adherence in patients with schizophrenia. The same research group reported a randomized controlled trial of 74 patients with psychosis allocated to 4–6 sessions of CT versus 4–6 sessions of supportive counseling [70]. Results demonstrated a significant effect on adherence in the intervention group as compared to the control group immediately post-treatment and at an 18-month follow-up. The improvements in compliance did result in enhanced community tenure, with patients in the CT group taking longer to relapse than those receiving nonspecific counseling. CT is effective in enhancing concordance and reducing the risk of relapse. There is also emerging evidence that after training in medication management, mental health nurses are able to deliver compliance therapy to people with a diagnosis of schizophrenia [71].

In contrast to the above studies, O’Donnell et al. [72] conducted a randomized controlled trial comparing CT with nonspecific counseling in a 1-year study of 56 inpatients with schizophrenia. No effect of CT over a control group was identified. The study did show that attitudes to treatment at baseline predicted adherence at 1 year, thus suggesting early identification of attitudes toward medication may be useful in clinical practice. Noticeably, this study had a longer period of follow-up (1 year), while the two previous studies had shorter periods of follow-up assessment (3 and 6 months). Although the study by Kemp et al. had further assessments at 12 and 18 months, their booster doses of the intervention at 3, 6, and 12 months may have influenced its long-term outcome.

Byerly et al. [73] evaluated the efficacy of CT when delivered to outpatients with schizophrenia or schizoaffective disorder. Thirty patients with schizophrenia or schizoaffective disorder were recruited from urban psychiatric outpatient clinics in an open trial of CT. The primary outcome was electronically measured antipsychotic medication adherence. Adherence data were analyzed for effects during an initial treatment period (month −1 to +1) and a subsequent 5-month follow-up period. Secondary outcome measures included clinician and patient ratings of adherence, symptoms, insight, and attitudes toward medication treatment. Patient ratings of adherence improved during the month −1 to +1 period, but not in the subsequent 5-month follow-up. Authors found that CT was not associated with improvements in antipsychotic medication adherence and they concluded that outpatients with schizophrenia or schizoaffective disorder did not benefit from CT schizophrenia.

In a 2006 Cochrane review on CT, McIntosh et al. [74] assessed systematically the effects of this intervention on antipsychotic medication adherence in schizophrenia. Authors concluded that there is no clear evidence to suggest that CT is beneficial for people with schizophrenia and related syndromes, and that more randomized controlled studies were needed in order to fully examine this intervention.

CT was slightly modified into AT, a brief individual cognitive behavioral approach [75]. The AT manual (http://​www.​adherencetherapy​.​com) describes a collaborative, patient-centered phased approach to promote treatment adherence, patient choice, and shared decision-making in subjects affected by schizophrenia. Techniques derived from cognitive behavioral therapy (e.g., testing out beliefs about treatment) and motivational interviewing (e.g., exploring patient ambivalence toward treatment) are used to enhance adherence to a shared treatment plan focused on medication adherence and illness management. The key therapeutic techniques used are exchanging information, developing discrepancy, and effectively dealing with resistance. The phases of AT are engagement, assessment, rating of readiness to take medication, intervention, and evaluation working through in a flexible patient-centered way. The five key interventions from the core of the therapy phase include: (1) medication problem solving; (2) medication timeline; (3) exploring ambivalence; (4) discussing beliefs and concerns about medication; and (5) using medication in the future. The aim of the therapy process is to achieve a joint decision about medication between the patient and therapist.

A study in Thailand [76] found that AT delivered by nurses who received intensive training significantly improved psychotic symptoms and attitude toward and satisfaction with medication. Thirty two patients with schizophrenia were randomly allocated to receive eight weekly sessions of AT or continue with their TAU. Patients were assessed at baseline and after 9 weeks. The primary outcome was overall psychotic symptoms. Secondary outcomes were general functioning, attitude toward and satisfaction with antipsychotic medication, and medication side effects. The findings indicated that patients who received AT significantly improved in attitude toward and satisfaction with medication compared with TAU.

A large European 52-week, single-blind, multicentre randomized controlled trial, with a small increase in the number of sessions (two extra sessions) and a more individually tailored structure, including 409 patients in four countries, did not find any differences between AT and a control group receiving an individual intervention of health education, nor were quality of life, or rates of patient-reported medication adherence different between groups. This effectiveness trial did not confirm any effect of AT in improving treatment adherence in people affected by schizophrenia with recent clinical instability, treated in ordinary clinical settings [75].

A further pragmatic, exploratory, single-masked trial, to explore the efficacy, acceptability, and satisfaction with AT was conducted in the USA, in a sample of people with schizophrenia [77]. Twenty six patients (12 experimental and 14 controls) were randomly allocated to receive eight weekly sessions of AT or continue with TAU. Patients were assessed at baseline and after therapy completion, while the primary outcome was psychiatric symptoms and the secondary outcome medication adherence. Patients receiving AT did not significantly improve in overall psychiatric symptomatology or in medication adherence compared with the TAU group at follow-up. The results indicated no significant difference between the AT and TAU groups on measures of severity of symptomatology and subjective evaluation of treatment, including medication adherence from baseline to follow-up after the completion of the intervention.

Another adaptation of CT is called ACE, which aims at enhancing insight and at promoting treatment adherence in patients with early psychosis. In a pilot study this intervention, consisting of 14 individual sessions, was tested against supportive therapy [78]. In a sample of 19 participants, perceived need for treatment and benefits of medication appeared to be better in patients with ACE shortly after intervention, compared to controls. However, no direct adherence rates were available and follow-up results are awaited.

Staring et al. [79] developed another treatment, TAT, whose intervention modules are tailored to the reasons for an individual’s nonadherence. In a recent randomized controlled trial therapy they measured the effectiveness of TAT with regard to service engagement and medication adherence in 109 outpatients with psychotic disorders. TAT is an intervention based on an empirical–theoretical model, in which patient’s determinants of nonadherence are taken into account. According to the clusters of determinants of nonadherence, therapists choose the intervention tailored to each patient. The duration and number of sessions therefore varied according to the needs of the individual patient, in general, it took no more than 6 months. Most of the TAT therapists were trained psychiatric nurses. The study found that TAT may enhance service engagement (Cohen’s d = 0.48) and medication adherence (Cohen’s d = 0.43) more than TAU. The effects were smaller at 6-month follow-up, yet still statistically significant for medication adherence.

It is proposed that individuals are more likely to adhere to medication if the perceived threat of the illness (susceptibility and severity) is high and the perceived benefits of treatment exceed the perceived barriers.

Compliant patients consider the medication to be helpful in treating their illness and have a positive attitude toward medication [84–86]. Conversely, noncompliant patients see no reason for taking medication because they may not consider themselves to be ill, or they may see taking the medication as the wrong way to solve their problems [87–91].

The beliefs described are influenced by a number of modifying factors [92] such as:

The model also states that individuals need a prompt (a reminder either of the threat of the illness or the action that must be taken against it) before they will engage in health-related behaviors [93]. These “cues to action” may be internal, such as recognition of prodromal symptoms, alternatively, the cues may be external, such as statements made by others, or media references to illness or medication (Fig. 1).

This model emphasizes the collaboration between physician and patient in treatment decisions. The critical factor for successful management of adherence is creating an atmosphere where a nonadherent or potentially nonadherent patient does not feel disapproved and so he will be able to talk honestly about his concerns related to drug treatments and pattern of adherence [82].

The clinician needs to have a clear picture of the patient’s cognitive representation of the illness. If patients acknowledge partial or total nonadherence, it is useful to try to decide whether this is unintentional or intentional. Un-intentional nonadherers tend to identify a higher number of perceived barriers to treatment. Most of these are practical rather than psychological. Intentional nonadherers often demonstrate more ambivalence about the perceived threat of the disorder and are probably less likely to acknowledge their nonadherence without prompting. In practice, it is likely that both groups will benefit from the behavioral interventions, but that the cognitive techniques will have a more obvious role with intentional nonadherers. The primary goal with unintentional nonadherers is to enhance cues to action and to minimize any real or perceived barriers to adherence [13].

The HBM posits that health behavior is a product of an implicit and subjective assessment of the relative costs and benefits of compliance in relation to personal goals and the constraints of everyday life. HBM has proven helpful in addressing adherence in medical illness, however, it must be used cautiously in patients with schizophrenia. Disease-related symptoms such as cognitive impairment and poor reality testing may limit a patient’s ability to perceive the benefits of antipsychotic therapy. Since schizophrenia may disrupt illness perception and the capacity to plan and act, consideration of the cognitive and motivational resources available to assess risk, and formulate action should be additional elements to take into account when dealing with patients suffering from schizophrenia [13, 84–91].

Patients affected by schizophrenia weigh the benefits of antipsychotic treatment such as symptom reduction with the associated costs of antipsychotic treatment such as side effects. Benefits of antipsychotic treatment are largely dependent on the patient’s knowledge about illness and belief that the treatment may has a positive effect on the severity of their symptoms. The HBM emphasizes the patient’s as opposed to the physician’s understanding of illness and treatment [94]. Perceived benefits of treatment are largely dependent on the patient’s illness awareness and insight. Insight has been one of the most common predictors of adherence problems [94, 95] and it is not necessarily found in all patients who are adherent with antipsychotics [96]. Most patients have some ambivalence about taking antipsychotic medications, all of which can be associated with unpleasant and, rarely, dangerous side effects. On the other hand, patients with good insight into their symptoms or illness may not perceive their prescribed medication as potentially or actually helpful. Patients who do experience troublesome or serious side effects may decide that these effects outweigh the benefits of medication. If a patient stops taking medication during the stable phase, he may feel better, with less sedation or other side effects. As a result, the patient may come to the false conclusion that the medication is not necessary or does not have benefits. Finally, people significant to the patient, including family and friends, may discourage the patient from taking medication or participating in other aspects of treatment.

HBM may help clinicians to develop methods to improve adherence. To help clinicians learn how to adapt CBT for assessing adherence attitudes, Velligan et al. [97] have developed a method called the HBD. The underlying concept of this interview approach is very simple. The authors believe that attitudes or beliefs cannot be changed before the clinician understands those attitudes and beliefs. Too often patients’ perspective is interrupted by a well-meaning but ineffective lecture about the benefits of medication and the importance of adherence. In contrast, a major goal of the HBD approach is forcing the clinician to withhold any intervention or comment on adherence attitudes until those attitudes are fully understood [97].

Perkins [94] has modified the HBM in the context of schizophrenia and underlined the relevance of improving patient’s assessment of the costs and benefits of treatment. This may require targeting a diverse area of risk factors for nonadherence such as poor insight, negative attitudes toward medications, substance abuse, and alliance with therapist. When clinicians detect the presence of any of these risk factors for nonadherence, strategies to address these issues and interventions to improve adherence should be implemented. Successful aspects of the interventions reviewed can be easily incorporated by clinicians to improve adherence with antipsychotic therapy such as, providing information about the purpose and potential side effects of medications (psychoeducation); helping patients to cognitively reframe negative attitudes and learn to become more effective consumers (behavioral and affective); and simplifying regimens, teaching skills, and providing external cues such as medication reminder devices (behavioral) [8].

Perceived benefits of treatment also include the therapeutic relationship. The quality of the therapeutic relationship is related to medication adherence [98, 99]. In a cross-sectional and longitudinal adherence study with 162 patients, working alliance was most consistently related to medication adherence [100]. Patient satisfaction in the physician–patient relationship may lead to a greater willingness to follow the physician’s advice independent of the level of insight of the patient.

Costs of treatment include the patient’s perception of medication side effects. When patients perceive adverse effects as problematic or unacceptable they may lead to poor adherence. On the contrary patients will often continue to take medication despite unpleasant side effects if they perceive the benefits of medication as outweighing the disadvantages caused by side effects [101].

There are studies suggesting a correlation between dimensions of the HBM and adherence in schizophrenia.

Budd et al. [102] found an association between beliefs around susceptibility and adherence status, that is, those who did adhere to medication perceived themselves to be more susceptible to relapse than nonadherers. They conducted a study of the impact of the HBM in schizophrenia patients in Wales comparing 20 patients who had presented for, and accepted, depot antipsychotic medication at all scheduled appointments over the year prior to the study (compliers) with 20 patients who had failed to attend and/or accept medication for one-third or more of all scheduled appointments over the same period (noncompliers). The constructs of the HBM were evaluated using a HBQ [103, 104]. The authors found that scores on the susceptibility subscale had the greatest discriminatory power in distinguishing compliers from noncompliers. Scores on the severity and benefits subscales were significant in distinguishing between the two groups when tested in separate analyses, but were not significant when added to a model that already contained the susceptibility subscale.