The influence of the working alliance on the treatment and outcomes of patients with bipolar disorder: A systematic review

Journal of Affective Disorders 260 (2020) 263–271

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Review article

The influence of the working alliance on the treatment and outcomes of patients with bipolar disorder: A systematic review

T

Nelson Andrade-Gonzáleza, Alba Hernández-Gómezb, Sonia Álvarez-Sesmeroc, ⁎ Luis Gutiérrez-Rojasd, Eduard Vietae, María Reinarese, Guillermo Laheraf,g, a

Relational Processes and Psychotherapy Research Group, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain Faculty of Psychology, Complutense University of Madrid, Madrid, Spain c Department of Psychiatry, 12 de Octubre University Hospital, Madrid, Spain d Faculty of Medicine, University of Granada, Granada, Spain e Bipolar and Depressive Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain f Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain g IRyCIS, CIBERSAM, Madrid, Spain b

A R T I C LE I N FO

A B S T R A C T

Keywords: Bipolar disorder Working alliance Treatment Patient outcome Systematic review

Background: The working alliance plays an essential role in the treatment of patients with different diseases. However, this variable has received little attention in patients with bipolar disorder. Therefore, this systematic review aimed to examine the working alliance's influence on these patients’ treatment outcomes, analyze its role in the adherence to pharmacotherapy, and identify the variables that are related to a good working alliance. Methods: PubMed, PsycINFO, and Web of Science databases were searched until January 5, 2018 using a predetermined search strategy. Then, a formal process of study selection and data extraction was conducted. Results: Seven articles fulfilled the inclusion criteria and they included a total of 3,985 patients with bipolar disorder type I and II. Although the working alliance's ability to predict the duration and presence of manic and depressive symptoms is unclear, a good working alliance facilitates the adherence to pharmacological treatment. In addition, good social support for patients is associated with a strong working alliance. Limitations: The selected studies used different definitions and measures of the working alliance and adherence, and most used self-reports to assess the working alliance. Furthermore, the relationships found among the variables were correlational. Conclusions: The working alliance can play an important role in adjunctive psychological therapies and in pharmacological and somatic treatments for patients with bipolar disorder. However, the number of studies on working alliance in bipolar disorder is rather limited and there is methodological heterogeneity between the studies.

1. Introduction Bipolar disorder (BD) is a chronic severe illness that is characterized by manic, hypomanic, and depressive episodes (Grande et al., 2016). According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013), the diagnosis of bipolar I disorder requires the patient to have a manic episode (having psychosis or a major depressive episode is not required), and bipolar II disorder requires the patient to have at least one hypomanic episode and at least one major depressive episode. Regarding the prevalence and burden of the disease, Ferrari et al. (2016)

found that 48.8 million people had BD in 2013 and this disease is among the first 20 causes of disability worldwide. Moreover, patients with BD often have anxiety disorders (Merikangas et al., 2007), attention deficit hyperactivity disorder (American Psychiatric Association, 2013), and substance use disorders (Hunt et al., 2016) in addition to having a greater suicide risk than the general population (Pompili et al., 2013). Pharmacotherapy is the first line treatment for patients with BD. The pharmacological treatment of each phase of the illness (mania and depression), as well as maintenance treatment, need a specific and individual approach according to clinical variables of patients

⁎ Corresponding author at: Faculty of Medicine and Health Sciences, University of Alcalá, Campus Universitario, Carretera Madrid-Barcelona Km. 33,600, 28871, Alcalá de Henares, Madrid, Spain. E-mail address: [email protected] (G. Lahera).

https://doi.org/10.1016/j.jad.2019.09.014 Received 26 April 2019; Received in revised form 22 July 2019; Accepted 2 September 2019 Available online 03 September 2019 0165-0327/ © 2019 Elsevier B.V. All rights reserved.

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Furthermore, an adequate WA between the patient and clinician is associated with better adherence to antipsychotic medication in patients with BD and schizophrenia (García et al., 2016). Regarding this, Day et al. (2005) examined the role of the WA as perceived by acute patients at the time of hospital admission (139 of them suffered from schizophrenia and 89 had a schizoaffective disorder). They found that, among other factors, a good WA between the patients and prescribing psychiatrists promoted medication adherence. Moreover, BaloushKleinman et al. (2011) assessed the WA in 112 patients (84 with schizophrenia and 28 with schizoaffective disorder) up to 6 months after discharge. These authors found that, in combination with other factors, the patients’ trust in their clinicians (the bond of the WA) predicted the patients' attitudes toward medication, and these attitudes predicted the antipsychotic medication adherence. Finally, Montreuil et al. (2012) evaluated the influence of the WA, as rated by seven case managers (CM) that did not prescribe medication and by 81 patients with a psychotic disorder (affective or nonaffective), and found that, at the study baseline, only the scores of the CM for the total WA and the task domain of the WA significantly predicted the patients’ subsequent adherence to pharmacological treatment. Consequently, the WA is an important relational variable in the treatment outcomes of patients with different diseases. Knowing the influence of the WA on the treatment received by BD patients will allow clinicians to build an atmosphere of trust and cooperation with their patients that facilitates the achievement of better results in different phases of the treatment. Therefore, the primary goal of this systematic review was to examine the influence of the WA on the outcomes of pharmacologic and psychotherapeutic treatment received by patients with different types of BD. The secondary aims were to investigate the role of the WA in medication adherence and to identify the variables that are associated with a good WA.

(Yatham et al., 2018). Furthermore, according to Bravo et al. (2013), Chatterton et al. (2017), and Yatham et al. (2018), psychological therapies are a recommended adjunctive treatment. Although more research is needed, cognitive-behavioral therapy (CBT), psychoeducation, family intervention, and interpersonal and social rhythm therapy are among the most commonly used in BD (Reinares et al., 2014). On the other hand, psychoeducation is considered the first line as a maintenance therapy (Yatham et al., 2018). In particular, group psychoeducation has been shown to prevent relapses not only in the shortterm but also in long-term follow-up (Colom et al., 2009). In addition, the combination of psychoeducation and CBT increases medication adherence, reduces manic symptoms, and improves patient functionality (Chatterton et al., 2017). The benefits of family intervention have also been proven (Reinares et al., 2016). International guidelines for the treatment of BD consider CBT and family-focused treatment to be second-line therapies, followed by interpersonal and social rhythm therapy as a third-line recommendation (Yatham et al., 2018). The working alliance (WA), sometimes termed therapeutic alliance or helping alliance, is one of the most investigated variables in psychotherapy; however, it has not been extensively studied in BD. In general terms, the WA includes different aspects related to the collaboration between the patient and the clinician (Flückiger et al., 2018). Two well-known alliance models are those of Luborsky (1994, 1976) and Bordin (1994, 1979). According to Luborsky (1994), there are two types of helping alliance: (1) the type I alliance, characterized by the patient's perception of the therapist as a person who can support him or her and (2) the type II alliance, characterized by teamwork between the patient and the therapist aimed at overcoming the difficulties and distress of the patient. Meanwhile, for Bordin (1994, 1979) the WA has three components: (1) the bond between the patient and therapist, which “is likely to be expressed and felt in terms of liking, trusting, respect for each other, and a sense of common commitment and shared understanding in the activity” (Bordin, 1994, p. 16), (2) agreement between the patient and therapist about the goals of psychotherapy, and (3) agreement between the patient and therapist about the tasks of psychotherapy. Two groups of relevant measurement instruments of the WA are the following. First, the Helping Alliance Questionnaire (HAq; Alexander and Luborsky, 1986) is a measure of 11 items only for patients, and the Revised Helping Alliance Questionnaire (HAq-II; Luborsky et al., 1996), is an improved version for patients and therapists consisting of 19 items each. Second, the Working Alliance Inventory (WAI; Horvath and Greenberg, 1989) is the most widely used measure of the WA (Doran, 2016) and is based on Bordin's model (1979). The long and short versions of the WAI (for patients, clinicians, and observers) measure the alliance with 36 items and 12 items, respectively, contain 3 subscales (Bond, Goal, and Task), have adequate psychometric properties, and are available in different languages (http://wai.profhorvath.com/). Regarding the influence of the WA on psychotherapeutic treatment outcomes, different meta-analyses have found that higher WA scores are moderately and significantly associated with higher symptomatology improvement in adults (Flückiger et al., 2018), couples and families (Friedlander et al., 2011), and children and adolescents (Shirk and Karver, 2011) who undergo different psychotherapy models. The examination of the relationship between the WA and the patient outcomes has crossed the borders of psychotherapy treatment. Krupnick et al. (1996) found that the total WA scores (assessed by independent observers) were significantly associated with the outcomes achieved by 225 outpatients with major depressive disorder that were randomized to four different treatments: CBT, interpersonal psychotherapy, imipramine plus clinical management, and placebo plus clinical management. Likewise, Clarke et al. (2013) found that a strong WA perceived at the end of treatment (CBT plus medication) by 117 inpatients with different disorders (depression, BD, eating disorders, schizophrenia, and anxiety disorders) was significantly associated with a substantial symptomatology reduction at the time of discharge.

2. Methods The recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement (Moher et al., 2009) were followed to achieve the aims of this review. Ethical approval was not required because this was a systematic review of published studies.

2.1. Selection criteria of the articles The inclusion criteria of the studies were (1) quantitative or qualitative research that examined the influence of the WA on the outcomes of the pharmacological and/or psychotherapeutic treatment received by patients with BD, (2) English language articles, and (3) patients of all ages. The exclusion criteria were (1) review articles and meta-analyses, letters to the editor, opinions or commentaries, case reports, and short communications, (2) studies that included patients with other diagnoses in addition to BD and that did not separate the results according to the diagnosis, and (3) articles with patients that did not fulfill the DSM or International Classification of Diseases’ criteria for the diagnosis of BD.

2.2. Search strategy The PubMed, PsycINFO, and Web of Science databases were searched until January 5, 2018. The search strategy used in these databases was (“therapeutic alliance” OR “working alliance” OR “helping alliance”) AND (“psychotherapy” OR “psychosocial treatment” OR “medication” OR “pharmacological treatment”) AND (“bipolar disorder” OR “manic depressive illness.”) Filters were used in the three databases to meet the inclusion criteria. 264

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is the case in the studies of Novick et al. (2015), O’Connor et al. (2008), Sajatovic et al. (2006), Strauss and Johnson (2006), and Sylvia et al. (2013). In another study, two measures that were administered by the interviewers were combined with the number of months that the patients remained in treatment (Gaudiano and Miller, 2006). Finally, one study used only self-report measures (Lee et al., 2011). The most frequent measures were the Bech-Rafaelsen Mania Scale (BRMS; Bech et al., 1979) and Modified Hamilton Rating Scale for Depression (MHRSD; Miller et al., 1985).

2.3. Study selection process This process was conducted in four phases. First, in the identification phase, the results of the searches of the three databases were unified and duplicates articles were removed. Second, in the screening phase, four reviewers (NAG, AHG, SAS, and LGR) independently read the titles and abstracts of the articles that potentially met the inclusion criteria. A reasoned discussion with each other solved any disagreements; when there was no agreement, the full text of the doubtful articles was reviewed. Third, in the eligibility phase, the same reviewers examined and independently read the full-text articles that were preselected in the previous phase and the doubtful articles (including the reference lists of all these studies). Any disagreements were resolved through a reasoned discussion; when there was no agreement, two expert reviewers (MR and GL) decided whether the article did or did not meet the inclusion criteria. Finally, in the inclusion phase, the reviewers selected the articles included in this systematic review.

3.1. Influence of the WA on the treatment outcomes Two studies examined the influence of the WA on the manic symptomatology of the patients. In the study by Gaudiano and Miller (2006), 84% of patients were in a manic or mixed episode at baseline. After the baseline evaluations, 19 patients received only pharmacotherapy, 23 received pharmacotherapy and six sessions of family psychoeducation group therapy, and 19 received pharmacotherapy and family therapy (range = 6–10 sessions). The primary outcome measure was the number of months in treatment (up to 28 months). In addition, the percentage of time that the patients were fully symptomatic (mania or depression) for up to 28 months was calculated. Patients with more than 14 points on the BRMS or MHRSD were considered fully symptomatic. Using a correlation matrix, these authors did not find a significant association between the early WA as perceived by the patients and clinicians and the percentage of time that the patients had manic symptomatology during treatment. Then, using a hierarchical multiple regression analysis, Gaudiano and Miller (2006) found that the early WA as perceived by the patients and clinicians did not predict the percentage of time that the patients had manic symptoms during the 28 months of treatment, after controlling the patients' initial expectancies of the treatment. The longitudinal study by Strauss and Johnson (2006) investigated if the patients' alliance scores covaried with fluctuations in their mood states and examined the ability of the alliance to predict the symptomatologic change over a 6-month follow-up. By using random effect regression models, it was found that the WA as rated by the patients did not significantly change according to the changes in the manic symptomatology. Furthermore, Strauss and Johnson (2006) found through a hierarchical multiple regression analysis that, after controlling the early manic symptoms, the stronger early WA as rated by patients predicted less manic symptoms 6 months after the WA assessment. The influence of the WA on the depressive symptomatology of the patients was examined in three studies. First, Gaudiano and Miller (2006) found negative correlations between the early WA as assessed by the patients and clinicians and the percentage of time that the patients were depressed; that is, the greater the alliance, the lower the depressive symptomatology. Then, using a hierarchical multiple regression analysis, these authors found that the early WA as assessed by the patients (regardless of their initial expectations about the treatment) predicted the percentage of time that these patients had depressive symptoms during the 28 months of treatment. However, although the WA of the clinicians tended to predict the percentage of time that the patients were depressed (regardless of the patients’ initial expectations of the treatment), this prediction was not significant. Lee et al. (2011) used data from the initial assessment of the patients and caregivers and examined three patient and caregiver distress variables (depression, anxiety, and quality of life) and three variables that represented possible treatment targets (the WA, stigma, and knowledge of BD). Regarding the patients, these authors found that a low patient-rated WA was significantly associated with higher depressive symptomatology at the beginning of the treatment. However, when they performed a stepwise linear regression analysis, the WA, as evaluated by the patients, was not associated with their depressive symptomatology. Finally, Strauss and Johnson (2006) found that the strength of the patient WA decreased according to an increase in the

2.4. Data extraction process Four reviewers (NAG, AHG, SAS, and LGR) independently analyzed all the selected articles and the following information was extracted: (1) the title of the study, author(s), and year of publication; (2) research design; (3) patients' sample size; (4) characteristics of the participants (socio-demographic data, diagnosis, and outpatient or inpatient status); (5) study's methodology; (6) treatment type; (7) measurement of the WA (measures, kind of rater, and the moment when the WA was measured); (8) outcome measurement (measures and rater); and (9) key findings. Regarding the phase of treatment in which the WA was assessed, three categories that are commonly employed in psychotherapy research were used: early WA (i.e., the beginning of the treatment, which comprised the first to fifth session), mid WA (i.e., the middle of the treatment, which comprised the sixth session and up to four sessions before the end of the treatment, and late WA (i.e., the end of the treatment, which included the last three sessions). Disagreements about the data extracted from the selected articles were resolved by two expert reviewers (MR and GL). 3. Results Seven original studies that met the inclusion criteria were selected (Gaudiano and Miller, 2006; Lee et al., 2011; Novick et al., 2015; O'Connor et al., 2008; Sajatovic et al., 2006; Strauss and Johnson, 2006; Sylvia et al., 2013). Fig. 1 shows the selection process of these articles. The main characteristics of the papers are shown in Table 1. The selected studies included a total of 3,985 patients. From the available data (six studies), the weighted average age of the patients was 44.69 years. Considering the data of five studies, the weighted average percentage of patients that had BD type I was 72.64%. Six studies assessed the WA with self-report measures. Among these, the 36-item WAI (Horvath and Greenberg, 1989) was used in four studies, and it was the most frequent measure. On the other hand, Sylvia et al. (2013) applied the HAq-II (Luborsky et al., 1996) and Lee et al. (2011) used a measure that they developed; however, they did not provide data on its validation; these two measures were used to examine the patient's perspective of the WA. Finally, semi-structured interviews were performed in the qualitative research of O'Connor et al. (2008) to obtain information about this construct. Regarding the number of times that the WA was assessed, in four studies this variable was measured only once while in one article it was measured at different times of the intervention (Strauss and Johnson, 2006). Lastly, in another study, the WA was examined at the beginning of the research and one year after the start of the study (Novick et al., 2015). The outcome and medication adherence measurements were heterogeneous. Five studies included measures that were administered by different kinds of interviewers (e.g., clinicians, research assistants). This 265

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Fig. 1. The Preferred Reporting Items for Systematic Reviews and Meta-analyses’ diagram that illustrates the process of selecting the articles for the systematic review. WA = working alliance.

3.2. Influence of the WA on the medication adherence

depressive symptoms. Later, using a hierarchical multiple regression analysis and after controlling the initial depressive symptoms, these authors found that the patient-rated WA did not predict their depressive symptomatology 6 months after the WA assessment. Lastly, two studies examined the relationship between the WA and other outcome variables. Lee et al. (2011) found that a lower early WA, as assessed by the patients, was correlated with more anxiety symptoms at the beginning of the treatment. Later, when they conducted a stepwise linear regression analysis, they found that the patient-rated WA was associated with their anxiety symptomatology. In the study by Novick et al. (2015), a post-hoc analysis was performed to examine the relationship between WA, insight, and medication adherence, and their influence on the outcomes of patients with schizophrenia or BD. Data were collected from a prospective study that compared medication adherence between two oral forms of olanzapine, and the patients were followed up for one year. Regarding the patients with BD, Novick et al. (2015), using a path analysis, found that a strong early WA as rated by the clinicians was positively related with the patients’ better global functioning when measured using the Global Assessment of Functioning scale (GAF) one year after the start of the study (but not at the baseline).

Five studies assessed this relationship. Gaudiano and Miller (2006) found a positive relationship between the early WA as perceived by the patients and clinicians and the number of months that the patient stayed in pharmacologic treatment. In addition, after conducting a hierarchical multiple regression analysis, it was found that the early WA as rated by the patients predicted treatment dropout after controlling their initial treatment expectations. Strauss and Johnson (2006) found a negative relationship between the early WA as perceived by the patients and two subscales of the Treatment Attitudes Questionnaire (Negative Aspects of Medication and Stigma) after controlling the depressive symptoms of the patients at the time of the WA assessment. In other words, the patients that build a strong WA with their clinician at the beginning of treatment have fewer negative attitudes about medication and a lower sense of stigma related to suffering from BD. In the qualitative study of O'Connor et al. (2008), the patients were interviewed after eight psychoeducation group sessions. According to most patients, a good WA with the clinician was an essential part of the pharmacological treatment that facilitated their trust in the clinician and the medication. Within the framework of the Systematic Treatment 266

267

Longitudinal

Cross-sectional

Longitudinal

Descriptive

Cross-sectional

Longitudinal

Longitudinal

Gaudiano et al. (2006)

Lee et al. (2011)

Novick et al. (2015)

O'Connor et al. (2008)b

Sajatovic et al. (2006)

Strauss et al. (2006)

Sylvia et al. (2013)

3,337e outpatients. 71.1% of patients had BD I. The WA was assessed if the patients had the willingness and ability to complete a WA measure.

291 outpatients (40.2% male; mean age = 44.6 years [SD = 13.1]). The WA was evaluated when the outpatients who were treated with olanzapine visited clinics in different European health centers. 11 outpatients (36.4% male; mean age = 41.0 years). The WA was assessed if patients had not relapsed in the previous six months. 113 inpatientsc (90.0% male; mean age = 46.4 [SD = 9.7]); 88% of these patients had BD I. 71 inpatientsd (93.0% male; mean age = 46.1 [SD = 11.1]); 85% of these patients had BD I. The WA was measured when patients were not stabilized. 58 outpatients and inpatients (47.0% male; mean age = 44.0 years [SD = 9.3]); 100% of patients had BD I. The WA was evaluated when the acute symptoms of most patients had remitted.

43 outpatients (mean age = 44.0 years [SD = 13.4]); 55.8% of patients had BD I. The WA was measured during the initial visit to an outpatient clinic.

61 outpatients (43.0% male; mean age = 42.0 years [SD = 12.0]); 100% of patients had BD I. 84% were in a manic or mixed episode at baseline. The WA was assessed during outpatient pharmacotherapy.

Patient sample

HAq-II

WAI

Medication

Medication

WAI

Medication

WAI

Medication

Interview

PA

Medicationa Family treatment

Medication Group psychoeducation

P, C

WAI

Medication Medication plus family psychoeducation group therapy Medication plus family therapy

P

P

P, C

P

C

P

Rater

Measure

WA

Type

Treatment

E

E, M, L

E

n/a

E, L

E

E

Time

CMF

BRMS MHRSD TAQ

Ad hoc interview

Ad hoc interview

GAF

CES-D STAI Q-LES-Q

No. of months in treatment BRMS MHRSD

The stronger early WA of the patients predicted less manic symptoms but did not predict their depressive symptomatology. The patients that built a strong early WA had fewer negative attitudes about medication and a lower sense of stigma. The patients’ higher social support was associated with a stronger early WA, as assessed by the patients. Six positive items of the HAq-II-P were positively associated with medication adherence. Three negative items of the HAq-II-P were not associated with medication adherence.

I

I

There were no significant differences between the medication-adherent patients and medicationnonadherent patients when the early WA was assessed by the patients and clinicians.

A good WA of the patients facilitated their trust in the clinician and the medication.

The early WA of the patients and clinicians did not predict the percentage of time the patients had manic symptoms. The early WA of the patients predicted the percentage of time that these patients had depressive symptoms. The early WA of the clinicians tended to predict it. The early WA of the patients predicted treatment dropout. The early WA of the clinicians tended to predict the dropout. The early WA of the patients was not associated with their depressive symptomatology. The early WA of the patients was associated with their anxiety symptomatology. The patients’ better quality of life was associated with their rating of a better early WA. The early WA of the clinicians was positively related with the patients’ better global functioning. The patients' lower insight was associated with a worse early WA as assessed by the clinicians.

Key findings

I

I

I

P

I

Outcome/Medication adherence Measure Rater

Note. WA = working alliance; SD = standard deviation; BD I = Bipolar Disorder type I; WAI = Working Alliance Inventory; P = patient; C = clinician; E = Early (beginning of treatment); BRMS = Bech–Rafaelsen Mania Scale; MHRSD = Modified Hamilton Rating Scale for Depression; I = interviewer; a = 83.7% of the patients received medication; PA = Poor Alliance Scale; CES-D = Center for Epidemiologic Studies Depression Scale; STAI = Spielberger State Trait Anxiety Inventory, state version; Q-LES-Q = Quality of Life Enjoyment and Satisfaction Questionnaire, short form; L = Late (end of treatment); GAF = Global Assessment of Functioning Scale; b = qualitative methodology; c = adherent to pharmacological treatment; d = nonadherent to pharmacological treatment; M = Middle (middle of treatment); TAQ = Treatment Attitudes Questionnaire; e = 2,091 patients were included in the analysis of the relationship between the working alliance and medication adherence; HAq-II = Revised Helping Alliance Questionnaire; CMF = Clinical Monitoring Form.

Design

Authors and year

Study

Table 1. Characteristics of the studies selected in the systematic review to examine the influence of the working alliance on the treatment of patients with bipolar disorder.

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depressive symptomatology improvement. It is possible that this disparity in these few studies is due to (1) their methodological differences (different research designs, small sample sizes of the patients, and different WA and outcome measures) and (2) the different treatments received by the patients (i.e., medication vs. combined treatment). However, this is consistent with the role that the WA plays in patients with psychotic disorders. In a systematic review of 26 studies (Shattock et al., 2018), eight papers investigated the relationship between the WA and symptomatic outcomes in patients with schizophrenia and other psychotic disorders. These studies also found mixed results about the ability of the WA (assessed at different times of treatment) to predict the symptomatologic change throughout treatment (e.g., positive and negative symptoms). Likewise, Andrews et al. (2016) evaluated the role of the early WA in 104 patients and their clinicians in relation to the treatment outcomes aimed at promoting a healthy lifestyle. Of these patients, 57.9% had a schizophrenia spectrum disorder, 22.5% had BD with psychotic features, and 19.7% had another non-organic psychotic syndrome. Andrews et al. (2016) found that higher patient scores in the Confidence subscale of the WA measure, which was the Agnew Relationship Measure (ARM), were associated with less depressive symptomatology as measured with the Beck Depression Inventory-II (BDI-II) at 12 months of treatment; however, the ARM (the total score and the five subscales’ scores) did not predict the change in psychotic and affective symptoms that were assessed with the Brief Psychiatric Rating Scale (BPRS-24). Regarding the clinicians, their scores in the Bond subscale of the ARM predicted a reduction of the patients' symptoms measured with the BPRS-24 at 12 months; however, their scores in the ARM (total and subscales) were not associated with the change in the BDI-II (Andrews et al., 2016). On the other hand, the positive influence of a good early WA as assessed by the clinicians regarding the global functioning of the patients, after one year from the start of the study but not at baseline (Novick et al., 2015), agreed with the mixed results found in patients with psychotic disorders. In the review by Shattock et al. (2018), one result favored the WA; the study by Svensson and Hansson (1999) found that the early WA scores of the clinicians correlated with the residual change scores of the GAF scale in patients with schizophrenia. Nevertheless, two studies in the review by Shattock et al. (2018) did not favor the WA. Specifically, Berry et al. (2015) found that the early WA scores of the patients and clinicians did not predict the change in the patients' total GAF scores at 12 and 24 months of treatment, and Jung et al. (2014) proved that the early WA of the patients and clinicians did not predict the global functioning in the GAF at the end of treatment. In line with these studies, Andrews et al. (2016) found that the early WA as assessed by the patients and clinicians did not predict the change in the GAF at 12 months of treatment. Regarding medication adherence, among the five selected studies that assessed the influence of the WA on this variable, three studies showed that a good WA facilitated pharmacotherapy adherence (Gaudiano and Miller, 2006; O'Connor et al., 2008; Sylvia et al., 2013), and a fourth study revealed that a strong patient-rated WA was associated with fewer negative attitudes to medication and a lower sense of stigma related to suffering from BD (Strauss and Johnson, 2006). Adherence to medication is essential in patients with severe mental illness. In patients with schizophrenia, adherence to antipsychotic treatment has been associated with a greater likelihood of remission of symptoms, and non-adherence with a higher probability of relapses, hospitalizations, and suicide attempts (Novick et al., 2010). Non-adherence has also been associated with greater use of emergency services, more violent behaviors and arrests, greater substance use and more problems related to alcohol, and poorer mental functioning (AscherSvanum et al., 2006). In patients with BD, good adherence to lithium treatment is a modifiable factor that is associated with a lower risk of suicide and suicide attempts (González-Pinto et al., 2006). In addition, it has been found that BD patients who are non-adherent to

Enhancement Program for Bipolar Disorder project, Sylvia et al. (2013) examined the association between the patient-rated WA, their satisfaction with the care, and their pharmacological adherence over one year. In this study, taking less than 25% of the total dose of any medication was considered nonadherent. Regarding the WA, through logistic regression analyses, Sylvia et al. (2013) found that, at the beginning of the treatment, six positive items of the patient version of the HAq-II were positively associated with medication adherence; this was found after controlling the current symptom severity and five variables that are associated with poor adherence to pharmacology treatment. These items examined the patients' perceptions of (1) their trust in the clinician, (2) feeling understood by the professional, (3) their respect for the point of view of the clinician, (4) having meaningful exchanges with the clinician, (5) having similar points of view to the clinician about their problems, and (6) having a good relationship with the clinician. However, two positive items of the HAq-II-P (the wish of the patients to work on their problems and the patients' perception that the clinician appears to be experienced in helping people) were not associated with medication adherence. In addition, three negative items of the HAq-II-P were not associated with this adherence. These items examined the patients' perceptions of (1) their distrust of the clinician's judgment, (2) the existence of unprofitable exchanges, and (3) the distance shown by the clinician. Finally, Sajatovic et al. (2006) analyzed the patients' characteristics, features of the patient-clinician relationship (e.g., the WA), and barriers to care that related to medication adherence among veterans with BD. In this study, the adherent group comprised the patients that took 100% of their medication and the nonadherent group contained the patients that took less than half of the medication or stopped taking it. Sajatovic et al. (2006) did not find significant differences between the medication-adherent patients and medication-nonadherent patients when the early WA was assessed by the patients and clinicians. 3.3. Variables associated with a strong WA After controlling the baseline depressive symptoms of the patients, Strauss and Johnson (2006) found a positive significant relationship between the total score of the Interpersonal Support Evaluation List, the scores of three of its subscales (Tangible Assistance, Self-Esteem, and Belonging), and the early WA scores of the patients. In this study, the patients’ social support was examined when it had elapsed for at least 2 months of the patients’ recovery. Then, using a hierarchical multiple regression analysis, these authors found that the patients’ higher social support was associated with a stronger early WA as assessed by the patients. Moreover, Novick et al. (2015) found that, at the beginning of the treatment, the lower insight of the patients, as measured with item 1 of the Scale to Assess Unawareness of Mental Disorder was associated with a worse early WA as perceived by the clinicians. Lastly, Lee et al. (2011) found that the patients’ better quality of life at the beginning of treatment was associated with their rating of a better early WA. 4. Discussion This systematic review aimed to examine the influence of the WA on the treatment outcomes of patients with BD, to analyze the role of the WA in the adherence to pharmacological treatment, and to identify the variables that are associated with a good WA. The review of the seven selected articles revealed that, even though the influence of the WA on the treatment outcomes of the manic and depressive symptoms is unclear, the WA contributes to increased medication adherence. In addition, good social support for patients is associated with a strong WA. The results of the studies that examined the role of the WA in the treatment of BD episodes were mixed. Gaudiano and Miller (2006), Strauss and Johnson (2006), and Lee et al. (2011) found contradictory results regarding the influence of the early WA on the manic and 268

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consequently, the patients’ answers could have been distorted and/or influenced by the social desirability bias and by their symptomatology. Fourth, the studies that examined the influence of the WA on the medication adherence used different adherence definitions and different adherence measures. Fifth, the relationships found between the examined variables in the selected studies are correlational, which indicates a mere covariation between them and not a causal relationship.

pharmacological treatment have more hallucinations and delusions (González-Pinto et al., 2010), worse general functioning (Ragesh et al., 2016), and worse performance in verbal learning tasks, cued short recall tasks, and spatial working memory tasks (Martínez-Arán et al., 2009). Consequently, improving medication adherence of patients with BD is a challenge for researchers and clinicians. As found in this review, good WA is associated with good adherence. However, more research is needed in order to better clarify the relationship between these two variables (Chakrabarti, 2018) and to examine the influence of other variables on adherence (attitudes and beliefs of the patient and his/her family about medication, knowledge of the patient about the disease and the treatment, and stigma perceived by the patient [Chakrabarti, 2016]). As Chakrabarti (2018) states, the ingredients of a robust alliance which could have a positive impact on medication adherence of BD patients are trust and support, open communication, a collaborative relationship, shared decision-making, and stability and continuity of the relationship. In terms of the variables that are associated with a good WA, one selected study (Strauss and Johnson, 2006) found that good social support for patients with BD is associated with a strong WA. In an outpatient sample with different diseases that were treated with psychotherapy, Bankoff (1996) revealed that the strength of the relationship between different types of social support before treatment and a good therapeutic bond was higher at the beginning of treatment and that this varied depending on the patients’ significant others (father, mother, couple, and friends). In patients with substance-related disorders that received residential rehabilitation treatment, Meier et al. (2005) found that good social support at intake predicted a good early WA as perceived by the patients. According to Meier et al. (2005), patients with a history of successful interactions with others are more likely to form a good WA. On the other hand, insight is an essential variable in the course of BD (De Assis da Silva et al., 2015). In patients with BD, one selected article (Novick et al., 2015) evidenced that, the lower insight of the patients was associated with a worse early WA as perceived by the clinicians. However, in patients with psychotic disorders, there is more evidence of the association between both variables. In the review by Shattock et al. (2018), the relationship between insight and the WA was positive in six out of ten studies when the WA was assessed by the patients and in two out of eight articles when it was rated by the clinicians. In patients with BD, the lack of awareness of the disease and its repercussions (especially in manic and mixed episodes) will hinder their participation in the treatment, as they will probably think they do not need it or that it represents a detriment to them. Therefore, reaching a mutual understanding of the patient's disease should be an initial task in treatment, which will contribute to achieving agreement about the goals of treatment. Lastly, patients with BD have a lower physical and mental quality of life (Gutiérrez-Rojas et al., 2008). Only the study by Lee et al. (2011) examined the relationship between the quality of life and the WA; the positive association between these variables is promising as it could increase the number of WA predictors in BD patients. This is the first systematic review to investigate the relationship between the WA and the treatment outcomes of patients with BD and to provide an accurate picture of this relationship. This qualitative summary of the evidence was necessary considering the heterogeneity of the WA measures and outcomes measures used in the selected research studies and the methodological differences among these studies.

6. Conclusion In conclusion, the influence of the WA on the treatment outcomes of the manic and depressive episodes of patients with BD is inconclusive. However, the WA does facilitate medication adherence and it is associated with fewer negative attitudes toward medication. Finally, good social support for the patients is associated with a good WA, while the patients' insight and quality of life are promising factors in the formation of the WA. The fact that the number of studies of the WA in BD is low and that they used different methodologies suggests that we should be cautious when drawing conclusions. The establishment and maintenance of a good WA is a modifiable treatment factor that should not only be present in adjunctive psychological therapies but also in the pharmacological and somatic treatments that the patients with BD receive. Due to the interest in evaluating the influence of the WA in patients with other pathologies (Flückiger et al., 2018; Shattock et al., 2018), it is necessary to perform more studies in the future that examine the role of the WA in patients with BD. These studies should clearly specify the clinical state of the patients at the time of WA evaluation and measure the patients’ and clinicians’ perception of this variable. This will help to determine up to what point the WA predicts the symptomatologic change and the global functioning of these patients, and to understand how it contributes to this change in patients treated with only medication or with medication plus psychotherapy. In addition, future research studies should determine if the WA has a direct effect on medication adherence or if its role is mediated by other variables (e.g., patients' attitudes toward the medication). In addition, as social support is essential in the recovery process of the patients with BD (Dunne et al., 2019), more studies that analyze its role in the WA are needed (the same can be said about insight and quality of life). In any case, according to what has been found in this review, it is suggested that clinicians should create an atmosphere of confidence and respect in their relationship with the patients and involve them in the treatment plan; as it has been seen, this will probably influence the treatment outcomes and facilitate the medication adherence in patients with BD. 7. Statement of authors’ contributions NAG and AHG designed the study. NAG, AHG, SAS, and LGR carried out the search, screening, data extraction, and quality assessment. GL and MR supervised the search strategy and checked the inclusion/exclusion criteria. NAG prepared table 1 and prepared the first draft for review. GL and MR provided input into the development of the manuscripts, including the final one. EV critically revised the manuscript for intellectual content and reviewed the first and second draft. All authors contributed significantly to the discussion of the findings and approved the final draft. Role of the funding source

5. Limitations This work was supported by the Health Department of Catalonia, Spain (project SLT006/17/00357).

This review has a few limitations. First, four of the seven selected studies assessed the WA early on in the treatment (early WA), which does not reflect the role that the WA can play in other phases of the treatment. Second, some studies did not clearly specify the clinical state of the patients at the time of WA evaluation. Third, the use of selfreports to assess the WA was usual in the selected articles;

Declaration of Competing Interest Dr. Andrade-González. Declarations of interest: none. Miss Hernández-Gómez. Declarations of interest: none. 269

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Miss Álvarez-Sesmero. Declarations of interest: none. Dr. María Reinares. Declarations of interest: none. Dr. Gutiérrez-Rojas has been a consultant to or has received honoraria or grants from Janssen-Cilag, Otsuka-Lundbeck, Pfizer, Servier, and Novartis. Dr. Lahera has been a consultant to or has received honoraria or grants from Janssen-Cilag, Otsuka-Lundbeck, Lilly, Astra-Zeneca, CIBERSAM, and Instituto de Salud Carlos III. Dr. Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmaindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SanofiAventis, Servier, Shire, Sunovion, Takeda, the Brain and Behavior Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Program (ENBREC), and the Stanley Medical Research Institute.

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