Why do psychiatric patients stop antipsychotic medication? A systematic review of reasons for nonadherence to medication in patients with serious mental illness

Figures & data

Figure 1 Flow schema of study selection process.

Figure 2 Number of studies investigating specific reasons for nonadherence.

Table 1 Reasons for nonadherence to antipsychotic medication in patients with SMI: summary of methods used in prospective studies

References	Reason(s)	Design/patients	Measurement
			Adherence	Reasons
Novick et al^Citation19	• Insight • Therapeutic alliance	• Post hoc analysis, 1-year observational study, France, Germany, Greece • SZ (n=612) and BPD (n=291), consecutive outpatients	MARS	Functioning: GAF; insight: SUMD (first 3 items); symptom severity: CGI-SCH or CGI-BP; therapeutic alliance: physician-reported scale, WAI
Brain et al^Citation20	• Attitude toward medication • Insight	• 1 year, Sweden • SZ or SZ-like psychosis as part of the COAST study (N=112)	Electronic monitoring with a MEMS	Attitude toward medication: DAI-10; functioning: GAF and PSP; insight: 1 item from PANSS; side effects: UKU-SERS-Pat; symptom severity: PANSS, CGI-SCH
Lam et al^Citation21	• Attitude toward medication • Insight • Prospective memory	• 3 months, Hong Kong • SZ (N=82) clinically stable patients, ~50% inpatients	Composite mean score of 4 methods: clinical impressions of the physician, structured clinical interview, pill counts by nurses, and MPR	Attitude toward medication: DAI; insight: SUMD-A; prospective memory: MMAA, computer paradigm, and self-report CAPM; side effects: AIMS, BAS, ESRS; symptom severity: PANSS
Baloush-Kleinman et al^Citation22	• Attitude toward medication • Insight • Family support • Side effects • Therapeutic alliance	• 6 months, post-hospital discharge, naturalistic, Israel • Early-episode SZ or SZD (N=112), convenience patient sample	Patient-rated at admission, discharge, 3 and 6 months after discharge using VAS-ATA (0%–100%)	Attitude toward medication: DAI; family support: modified DAI; insight: SUMD; side effects: ESRS, LUNSERS, and a patient-based measure of subjective side effects; symptom severity: CGI, SAPS, SANS; therapeutic alliance: TPS
Novick et al^Citation12	• Therapeutic alliance (hostility) • Independent housing • Social functioning • Substance abuse	• Post hoc analysis, 3-year observational SOHO study of real-world patients, 10 European countries • SZ, outpatients initiating or changing antipsychotic medication (N=6,731)	Adherence in past 4 weeks: interview with the physician	Hostility, living conditions, social functioning, alcohol/drug dependence/abuse: study-specific data collection form Symptom severity: CGI Quality of life: EQ-5D
Gonzalez-Pinto et al^Citation23	• Insight • Substance abuse	• 2-year observational study (EMBLEM), 14 European countries • BPD with a manic/mixed episode (N=1,831)	Adherence in past 4 weeks: interview with the physician	Insight: 1 item in the YMRS; symptom severity: CGI-BP, YMRS
Lepage et al^Citation24	• Neurocognition	• 6 months, following treatment initiation, Canada • First episode psychosis (N=160; 35 healthy controls)	5-point scale based on patient interview, review by case managers at 6 months of prescriptions and amount consumed	Standardized cognitive battery testing 7 cognitive domains (verbal memory, visual memory, working memory, speed of processing, reasoning/problem solving, attention, and social cognition) at baseline and at patient stabilization; symptom severity: SAPS, SANS
Miller et al^Citation25	• Substance abuse (cannabis)	• 1-year RCT, United States • First-episode SZ, SZP, or SZD (N=112)	Patient, family, clinician weekly report and plasma levels 4 times/year	Cannabis use: SADS-C (monthly), SCID (every 6 months), urine toxicology, clinician report, family report
Rabinovitch et al^Citation26	• Attitude toward medication • Insight • Social and family support	• 6 months, Canada • First-episode psychosis, mostly SZ, SZP, or SZD, consecutive patients (N=100)	Interview CORS with a rater 4 times after baseline (% of total doses taken over the last 4 weeks); case manager weekly evaluation; Information combined into a 5-point measure	Attitude toward medication: initial adherence assessment at entry into the program served as a proxy; insight: 1 item on PANSS; social and family support: case manager and patient-rated using 1 item in the provider and patient versions of the WQOL scale; symptom severity: SAPS, SANS
Mohamed et al^Citation27	• Attitude toward medication • Insight	• Post hoc analysis, 18 months, CATIE trial, United States • SZ (N=1,432)	Composite of monthly pill counts, patient questionnaire, clinician, and family feedback	Attitude toward medication: DAI; functioning: a panel of tests; insight: ITAQ; side effects: BAS, AIMS; symptom severity: PANSS, CDRS
Morken et al^Citation28	• Family support	• 2-year RCT comparing effect of interventions on adherence, Norway • SZ, SZP, SZD, recent onset (past 2 years), consecutive patients (N=50)	Recorded bimonthly from patient, therapist, caregiver interviews, also from plasma assays and patient records	Expressed emotion of a key relative about a mentally ill family member: assessed by a 5-min speech sample based on the CFI; symptom severity: BPRS
Liu-Seifert et al^Citation29	• Attitude toward medication • Stigma	• Post hoc analysis, RCT, 1 year, pooled groups, United States • SZ, SZP, SZD (N=664)	Discontinuation before trial completion; switching medication was not counted as discontinuation	Negative aspects of medication; denial of illness, positive external influence, perceived medication benefit, stigma: modified ROMI; symptom severity: PANSS
de Haan et al^Citation30	• Attitudinal, behavioral factors • Insight • Substance abuse • Therapeutic alliance (hostility)	• 5 years, the Netherlands • First episode SZ, SZP, SZD, consecutive inpatients (N=119)	By psychiatrists and specialized nurses every 6 months (3 levels), average was calculated for the 5-year period	Attitudinal and behavioral factors: ROMI; insight: 1 item on PANSS; subjective experience past 7 days: SWN; symptom severity: PANSS
McEvoy et al^Citation31	• Insight	• Post hoc analysis, 2-year RCT comparing efficacy of antipsychotics, United States • First episode SZ, SZP, SZD (N=251)	Pill counts at each study visit; patient interview	Insight: ITAQ; symptom severity: CGI-SCH, PANSS
Kamali et al^Citation32	• Insight • Substance abuse	• 6 months, Ireland • First-episode SZ, SZP, consecutive patients (N=100)	Compliance interview 6 months after baseline	Alcohol and drug abuse within the past month: SCID; insight: 1 item on PANSS; symptom severity: PANSS
Yamada et al^Citation33	• Insight	• 2-year adherence follow-up, Japan • SZ, outpatients with good adherence for >3 months at baseline (N=90)	Method not described; Nonadherence defined as being nonadherent for ≥1 week during the 2-year follow-up	Functioning: GAF; insight: ROMI-J (37-item Japanese version of ROMI); side effects: UKU-SERS-Pat; symptom severity: BPRS
Ascher-Svanum et al^Citation34	• Prior antidepressant use • Side effects • Substance abuse	• Post hoc analysis, naturalistic, 3-year study (US-SCAP), United States • SZ (N=1,579)	Self-report and the annual MPR based on prescription information in medical records	39 previously reported risk factors for nonadherence (~20 were demographic and illness related); functioning: GAF; side effects: AIMS, SAS; substance abuse: SCAP-HQ; symptom severity: PANSS

Abbreviations: AIMS, Abnormal Involuntary Movement Scale; BAS, Barnes Akathisia Scale; BPD, bipolar disorder; BPRS, Brief Psychiatric Rating Scale; CAPM, Comprehensive Assessment of Prospective Memory questionnaire; CDRS, Calgary Depression Rating Scale; CFI, Camberwell Family Interview; CGI, Clinical Global Impression; CGI-BP, CGI for Bipolar Disorder; CGI-SCH, CGI for Schizophrenia; COAST, Cognition, Adherence and Stigma in Schizophrenia; CORS, Circumstances of Onset and Relapse in Schizophrenia; DAI, Drug Attitude Inventory; DAI-10, Drug Attitude Inventory-10; EMBLEM, European Mania in Bipolar Longitudinal Evaluation of Medication; EQ-5D, EuroQol-5D quality of life instrument; ESRS, Extrapyramidal Symptom Rating Scale; GAF, Global Assessment of Functioning; ITAQ, Insight and Treatment Attitudes Questionnaire; LUNSERS, Liverpool University Neuroleptic Side Effect Rating Scale; MARS, Medication Adherence Rating Scale; MEMS, Medication Event Monitoring System; MMAA, Medication Management Ability Assessment; MPR, Medication Possession Ratio; PANSS, Positive and Negative Syndrome Scale; PSP, Personal and Social Performance scale; RCT, randomized controlled trial; ROMI, Rating of Medication Influences; ROMI-J, Rating of Medication Influences (Japanese version); SADS-C, Schedule for Affective Disorders and Schizophrenia-Change; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms; SAS, Simpson-Angus Scale; SCAP-HQ, Schizophrenia Care and Assessment Program-Health Questionnaire; SCID, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition for Axis I Disorders; SMI, serious mental illness; SOHO, Schizophrenia Outpatient Health Outcomes; SUMD, Scale to Assess Unawareness of Mental Disorder; SUMD-A, Scale to Assess Unawareness of Mental Disorder, abridged; SWN, Subjective Well-Being Under Neuroleptics; SZ, schizophrenia; SZD, schizoaffective disorder; SZP, schizophreniform disorder; TPS, Trust in Physician Scale; UKU-SERS-Pat, Udvalg for Kliniske Undersøgelser side effect self-rating scale; US-SCAP, US Schizophrenia Care and Assessment Program; VAS-ATA, Visual Analog Scale for Assessing Treatment Adherence; WAI, Working Alliance Inventory; WQOL, Wisconsin Quality of Life; YMRS, Young Mania Rating Scale.

Table 2 Reasons for nonadherence to antipsychotic medication in patients with SMI: results of prospective studies

References	Results
Novick et al^Citation19	• Higher baseline insight and therapeutic alliance were associated with better adherence (each P<0.0001)
	• After 1 year of follow-up, significant direct associations were found between an improvement in the patient’s insight or an improvement in the patient–physician relationship and improved medication adherence
	• Insight and therapeutic alliance co-vary during the course of the disorder and bidirectionally affect each other
Brain et al^Citation20	• Nonadherence rate was 27% (≤80% MEMS adherence)
	• Negative drug attitude (OR =0.71, P<0.001) and worse psychosocial function (OR =0.94, P=0.007) were significant predictors of nonadherence in a multivariable model
	• Poor insight into illness was a significant predictor of nonadherence (OR =1.61, 95% CI: 1.08–2.42) in a univariable model but was not included in the best-fitting multivariable model
Lam et al^Citation21	• 33% of patients were nonadherent (<80% on composite score)
	• At 3 months, nonadherent patients had significantly worse prospective memory, symptom severity, insight, and attitude toward medication
	• Poor insight (OR =1.26, P=0.03) and worse symptom severity (OR =1.94, P=0.03) were significant predictors of nonadherence at 3 months
	• Prospective memory moderated adherence-predictive effects of insight and psychopathology but was not an independent predictor in a regression model
	• Prospective memory accounted for only a small proportion of the variance of nonadherence; medication management ability was a better predictor of nonadherence than prospective memory
Baloush-Kleinman et al^Citation22	• Compared with non/partially adherent patients, adherent patients showed better attitude toward medication (P<0.0001), higher levels of insight into illness (P=0.009) and awareness of need for treatment (P=0.0003), better therapeutic alliance (P=0.012), greater family involvement in treatment (P=0.0001), more positive attitudes toward medication in family (P<0.0001), and greater severity of side effects (P=0.036)
	• In a model predicting adherence at 6 months, attitudes toward medication mediated the effects of negative symptoms, awareness of the illness, and awareness of the need for medication adherence
Novick et al^Citation12	• 28.8% of patients were nonadherent (≤50% of doses taken) during the 3-year follow-up
	• Prior adherence was the best predictor of adherence during follow-up (OR =4.01, P<0.001)
	• Baseline predictors of nonadherence (logistic regression): alcohol dependence (OR =0.63, P=0.013) and substance abuse (OR =0.67, P=0.043) in the previous month, independent housing (OR =0.8, P=0.001), presence of hostility (OR =0.85, P=0.02)
	• Good social functioning was a predictor of adherence (OR =1.26, P<0.001)
Gonzalez-Pinto et al^Citation23	• 23.4% of patients were nonadherent (answered “adherent about half of the time or almost never adherent” at ≥1 interview during maintenance phase)
	• During maintenance, patients were more likely to be adherent if they had good insight (OR =1.98, 95% CI: 1.44–2.72; P<0.001) and less likely to be adherent if they used cannabis during the treatment (OR =0.31, 95% CI: 0.18–0.54; P<0.001) and had greater disease severity (OR =0.91, 95% CI: 0.84–0.99; P=0.028)
Lepage et al^Citation24	• 62%, 17%, and 21% of patients were fully (>75% of doses taken), partially (51%–75%), and poorly adherent (≤50%), respectively
	• No significant associations were observed between global or domain-specific cognitive performance and adherence at 6 months
Miller et al^Citation25	• 18% of patients were nonadherent at the end of the study (<50% of the dose)
	• 15%–20% of patients used cannabis
	• Patients who used cannabis were 2.4-fold (95% CI: 1.5–3.9) more likely to be nonadherent and 6.4-fold (95% CI: 1.2–35.6) more likely to drop out of the study
Rabinovitch et al^Citation26	• 45.1% of patients were nonadherent (≤75% of doses taken) over 6 months of treatment
	• Low level of social support rated by case manager and poor early medication acceptance were significant predictors of nonadherence by logistic regression (OR =3.5, P=0.03 and OR =11.1, P<0.001), respectively
	• The level of social support based on patient ratings was not correlated with the case managers’ ratings and was not significantly associated with adherence
	• Insight into illness did not differ between adherent and nonadherent groups
Mohamed et al^Citation27	• Nonadherence percentage not reported
	• ITAQ and DAI scores were significantly positively correlated (r=0.32, P<0.0001)
	• Attitude toward medication but not insight at baseline were significantly associated with medication adherence in prospective assessments (P<0.001 and P>0.05, respectively)
	• In a model not including attitude toward medication, insight was significantly associated with medication adherence
Morken et al^Citation28	• 44% of patients were nonadherent to oral antipsychotics over the study period (1 month or 4 separate week without medication)
	• Patients with relatives showing low expressed emotion at baseline were significantly less adherent over the study period than those with relatives showing high expressed emotion (OR =6.0, 95% CI: 1.07–34.13, P=0.042)
	• Low expressed emotion is a marker of nonsupportive families
Liu-Seifert et al^Citation29	• A higher level of perceived beneficial effect of medication was the only factor associated with significantly reduced likelihood of early treatment discontinuation (HR =0.56, 95% CI: 0.40–0.79, P=0.001); ie, a higher level of perceived medication benefit by 1 point, such as strong vs mild or mild vs none, was associated with 44% less risk of discontinuation from the study during the following visit
de Haan et al^Citation30	• The mean medication adherence score over 5 years was 2.6 (1%, <25%; 3%, >75%)
	• 67.5% had score 2.5–3.0, indicating high adherence
	• Multivariable analysis: hostility and uncooperativeness (P=0.007), involuntary admission (P=0.02) but not cannabis use, SWN and ROMI total scores, and insight were associated with adherence during 5-year follow-up
	• Therapeutic alliance during acute admission appears to be critical for long-term adherence
McEvoy et al^Citation31	• Nonadherence defined as not taking any medication for >7 consecutive days (% not reported)
	• Better insight treated as a time-dependent covariate was associated with longer time to nonadherence (P=0.0076) throughout the study
	• Baseline insight was not significantly related to the probability of early discontinuation
Kamali et al^Citation32	• 33% of patients were nonadherent (≤74% of doses taken) over the past 3 months of treatment
	• Significant predictors of nonadherence at 6 months were positive symptoms (OR =8.56, P<0.01), alcohol misuse (OR =7.80, P=0.01), drug misuse (OR =4.38, P=0.04), lack of insight (OR =4.22, P=0.04)
	• Positive symptoms (OR =7.5, P=0.01) and lack of insight (OR =4.98, P=0.03) were the most significant predictors of nonadherence in patients without substance/alcohol abuse
Yamada et al^Citation33	• 16.7% of patients were nonadherent during the follow-up
	• The score of “fulfillment of life goals” (good insight) was greater in the adherent compared with the nonadherent group (P=0.015)
	• The score of “no perceived daily benefit” (poor insight) was greater in the nonadherent compared with the adherent group (P=0.018)
	• No significant difference in patient characteristics or scores of BPRS, GAF, or other ROMI items
Ascher-Svanum et al^Citation34	• 18.8% of patients were nonadherent during the first year (MPR ≤80%)
	• The best predictors of nonadherence were prior nonadherence (OR =4.1, P<0.001), illicit drug use (OR =1.8, P=0.025), alcohol use (OR =1.6, P=0.008), prior antidepressant use (OR =1.4, P=0.02), cognitive impairment (OR =1.3, P<0.001)

Abbreviations: BPRS, Brief Psychiatric Rating Scale; CI, confidence interval; DAI, Drug Attitude Inventory; GAF, Global Assessment of Functioning; HR, hazard ratio; ITAQ, Insight and Treatment Attitudes Questionnaire; MEMS, Medication Event Monitoring System; MPR, Medication Possession Ratio; OR, odds ratio; ROMI, Rating of Medication Influences; SMI, serious mental illness; SWN, Subjective Well-Being Under Neuroleptics.

Table 3 Reasons for nonadherence to antipsychotic medication in patients with SMI: summary of methods used in cross-sectional observational studies

References	Reason(s)	Design/patients	Measurement
			Adherence	Reasons
Eticha et al^Citation35	• Attitude toward medication • Insight • Side effects • Substance abuse	• Ethiopia • SZ, consecutive patients (N=393)	Modified MARS	Attitude toward medication: DAI; insight: ISP; side effects: a list of 16 items rated by patients
Na et al^Citation36	• Cognition • Depression • Insight	• Korea • Chronic SZ (N=104)	MARS (Korean version)	Cognition: a panel of tests; depression: GDS; functioning: GAF; insight: SUMD; symptom severity: PANSS
Jonsdottir et al^Citation37	• Insight • Substance abuse	• Consecutive outpatients, Norway • SZ (n=166) or BPD (n=114)	Medication serum concentration at study entry; self-reported adherence during past week	Insight: BIS; substance abuse: a specific questionnaire; symptom severity: PANSS, YMRS
Dibonaventura et al^Citation38	• Side effects	• Survey (online or paper), United States • SZ, self-report (N=876)	4-item MMAS, adherence defined as responding “no” to all 4 items	Side effects: self-report
Alene et al^Citation39	• Forgetfulness • Side effects • Substance abuse	• Ethiopia • SZ, SZD, mood disorder with psychotic features, or unspecified psychosis, consecutive patients (N=336)	Patient self-report using a structured questionnaire and pharmacy refill record	Patient structured questionnaire (same as for adherence)
Adelufosi et al^Citation40	• Family and friend support	• Nigeria • SZ, outpatients (N=313)	4-item MMAS	Social support from family and friends: self-report SCPQ; symptom severity: BPRS
McCabe et al^Citation41	• Therapeutic alliance	• 6 European countries • SZ or related psychotic disorders, outpatients (n=507) and their clinicians (n=134)	Clinician-rated: good (≥75%), average (25%–75%), poor (<25%) based on knowledge of the patient during past 3 months	Symptom severity: PANSS; therapeutic alliance: HAS-P and HAS-C
Magura et al^Citation42	• Self-efficacy in drug avoidance • Side effects • Social support and stability	• United States • MDD, SZ, BPD, anxiety, and substance abuse history, outpatients (N=131)	Modified MARS	Friends’ support for abstinence: SNIS; readiness to change: RCQ; recovery support: SSRS; recovery-promoting behaviors: PCQ; self-efficacy for mental health recovery: MHCS; self-efficacy in drug avoidance: DASES; side effects: 16 items; symptom severity: CSI
Sajatovic et al^Citation43	• Forgetfulness • Personal, sociocultural, economic factors • Side effects	• United States • BPD I and II, poorly adherent outpatients (N=20)	Poor adherence defined as missing ≥30% of medication based on TRQ during past week or month; also assessed by pill counts	Patient factors, environmental/social factors, provider/system factors, health beliefs, costs/burdens associated with treatment: SEMI TAD BD; symptom severity: HAMD, YMRS, BPRS, CGI-BP
Zeber et al^Citation44	• Access to specialist • Attitude toward medication • Substance abuse • Therapeutic alliance	• United States • BPD or SZD-bipolar subtype, VA patients from CIVIC-MD study, N=435	Morisky 4-item scale and independent assessment of missed medication in the last 4 days	Access to specialist: 1 item from Cunningham survey; attitude toward medication: ITM; binge drinking: 1 item from AUDIT; therapeutic alliance: HCCQ
Wong et al^Citation45	• Attitude toward medication • Insight • Side effects (weight gain)	• China • First-episode SZ, schizotypal and delusional disorders (N=160)	Self-report CRS to assess adherence in the past 2 weeks; patient and caregiver interview	Attitude toward medication: DAI-30; insight: SRIS; objective weight measure: BMI; subjective weight perception: FRS and cognitive attitude toward body size; symptom severity: SAPS and SANS
Beck et al^Citation46	• Attitude toward medication • Insight	• Switzerland • SZ or SZD outpatients (N=150)	Subscale “medication adherence” of the SES; BARS	Attitude toward medication: BMQ; insight: SUMD (2 items only: awareness of illness and awareness of social consequences of illness); symptom severity: PANSS
Dassa et al^Citation47	• Duration of untreated psychosis • Insight • Therapeutic alliance	• France • SZ or SZD consecutive outpatients (N=291)	10-item DAI	Insight: SUMD; therapeutic alliance: self-report PSQ; symptom severity: CGI
Acosta et al^Citation48	• Insight	• Spain • SZ, consecutive outpatients (N=74)	Electronic monitoring with MEMS; estimates of adherence by psychiatrists, patients, and relatives	Insight: 3 items on AIS; symptom severity: PANSS
Baldessarini et al^Citation49	• Affective comorbidity • Side effects • Substance abuse	• Questionnaire of psychiatrists and their patients, United States • BPD, consecutive patients (n=429); prescribing psychiatrists (n=131)	Patient self-report: missed doses during past 10 days	Symptoms and severity of BPD and its personal impact, patients’ expectations of treatment: patient self-report and physician questionnaire
McCann et al^Citation50	• Access to psychiatrist • Side effects • Social support • Stigma	• Australia • SZ, nonprobability sample (N=81)	Adherence and reasons (insight, substance use, significant other support, stigma, side effects, HCP support, access to medication): self-report using a 68-item F INMTS
Rummel-Kluge et al^Citation51	• Insight • Stigma	• Survey of psychiatrists (n=699), Germany • SZ (n=5,729)	Adherence and reasons: 10-item physician survey questionnaire assessing 10 patients per physician
Pratt et al^Citation52	• Insight • Medication complexity • Social functioning	• Study within an RCT comparing intervention strategies, United States, United Kingdom • SZ, SZD, BPD, MDD, older outpatients (age >50 years; N=72)	Pill counts, self-reported adherence (0%−100%), MARS, 1-item informant rating, a composite of 4 method scores	Insight: SUMD; medication complexity: calculated as a complexity score; social functioning: ILSS-SR, Multnomah; symptom severity: EBPRS, SANS
Elbogen et al^Citation53	• Depression • Social stability and living conditions • Substance abuse	• Patient subset of a risk behavior study, United States • SZ and related disorders (N=528)	Self-report (questionnaire)	Depressive symptoms: self-report; functioning: GAS; living stability: changing residences in the past 30 days (excluding hospitalization and/or arrests); social environment: various domains, including financial stability, homelessness, and transportation; substance abuse: DALI

Abbreviations: AIS, Amador Insight Scale; AUDIT, Alcohol Use Disorders Identification Test; BARS, Brief Adherence Rating Scale; BIS, Birchwood Insight Scale; BMI, body mass index; BMQ, Beliefs about Medication Questionnaire; BPD, bipolar disorder; BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; CGI-BP, CGI for Bipolar Disorder; CIVIC-MD, Continuous Improvement for Veterans in Care-Mood Disorders; CRS, Compliance Rating Scale; CSI, Colorado Symptoms Index; DAI, Drug Attitude Inventory; DALI, Dartmouth Assessment of Lifestyle Instrument; DASES, Drug Avoidance Self Efficacy Scale; EBPRS, Expanded Brief Psychiatric Rating Scale; FINMTS, Factors Influencing Neuroleptic Medication Taking Scale; FRS, Figure Rating Scale; GAF, Global Assessment of Functioning; GAS, Global Assessment Scale; GDS, Geriatric Depression Scale; HAMD, Hamilton Depression rating scale; HAS, Helping Alliance Scale (C, clinician, P, patient); HCCQ, Health Care Climate Questionnaire; HCP, health care professional; ILSS-SR, Independent Living Skills Survey-Self Report; ISP, Insight Scale for Psychosis; ITM, Insight To Medication; MARS, Medication Adherence Rating Scale; MDD, major depressive disorder; MEMS, Medication Event Monitoring System; MHCS, Mental Health Confidence Scale; MMAS, Morisky Medication Adherence Scale; PANSS, Positive and Negative Syndrome Scale; PCQ, Processes of Change Questionnaire; PSQ, Patient Session Questionnaire; RCQ, Readiness to Change Questionnaire; RCT, randomized controlled trial; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms; SCPQ, Sociodemographic and Clinical Profile Questionnaire; SEMI TAD BD, Subjective Experience of Medication Interview Treatment Adherence Bipolar Disorder; SES, Service Engagement Scale; SMI, serious mental illness; SNIS, Social Network Influence Scale; SRIS, Self-Rated Insight Scale; SSRS, Social Support for Recovery Scale; SUMD, Scale to Assess Unawareness of Mental Disorder; SZ, schizophrenia; SZD, schizoaffective disorder; TRQ, tablets routine questionnaire; VA, Veterans Health Administration; YMRS, Young Mania Rating Scale.

Table 4 Reasons for nonadherence to antipsychotic medication in patients with SMI: results of cross-sectional observational studies

References	Results
Eticha et al^Citation35	• Nonadherence rate was 26.5%
	• Better adherence was significantly associated with positive attitude toward medication (OR =1.40, 95% CI: 1.26–1.55); fewer medication side effects (OR =0.97, 95% CI: 0.94–0.99); less khat chewing (OR =0.24, 95% CI: 0.09–0.68); and 2 dimensions of insight: better ability to relabel symptoms (OR =1.57, 95% CI: 1.19–2.07) and better awareness of illness (OR =1.44, 95% CI: 1.12–1.85)
Na et al^Citation36	• Nonadherence rate was 15.4%
	• Nonadherence was significantly associated with poor insight into need for treatment (P=0.0005), depression (P=0.03), and 1 of the cognitive measures: number of errors in word reading (P=0.0008)
Jonsdottir et al^Citation37	• Adherence in SZ: 33.8% partial adherence, 11% nonadherence
	• Adherence in BPD: 26.2% partial adherence, 16.5% nonadherence
	• Patients with SZ from a full-adherence group showed a significantly higher mean level of insight compared with those from a nonadherent group
	• The difference was not significant for patients with BPD
	• The use of illicit substances and alcohol was greater in nonadherent and partially adherent groups in both SZ and BPD compared with that in the adherent groups
Dibonaventura et al^Citation38	• 57.5% of patients were nonadherent
	• 71.7% of patients were taking atypical antipsychotics
	• ~80% of respondents reported ≥1 medication side effect
	• Agitation/EPS (OR =0.57, P=0.0007), sedation/cognition (OR =0.70, P=0.033), prolactin/endocrine effects (OR =0.69, P=0.034), metabolic effects, including weight gain (OR =0.64, P=0.008) were associated with nonadherence
Alene et al^Citation39	• 52.1% of patients were fully adherent (self-report) but only 19.6% based on refill data
	• Forgetfulness was stated as the main reason for missing medication (36.2%)
	• Experiencing side effects, exposure to social drugs, and number of medications taken concurrently were associated with worse adherence
Adelufosi et al^Citation40	• 40.3% of patients were nonadherent
	• Adherence was significantly better among respondents with good level of perceived social support from families and friends, respondents satisfied with their outpatient care, and among employed vs unemployed respondents (univariate analysis)
	• Poor outpatient clinic attendance (OR =4.97, P=0.001), moderate satisfaction with outpatient care (OR =2.78, P=0.002), and symptom severity (OR =1.08, P=0.001) were independent predictors of nonadherence (multivariable analysis)
McCabe et al^Citation41	• 24.3% of patients had average or poor adherence
	• Patient and clinician ratings of therapeutic alliance weakly correlated (rs =0.13, P=0.004; ie, the perspectives differ)
	• For each unit increase in clinician-rated therapeutic alliance score, the OR of good adherence was increased by 65.9% (95% CI: 34.6%–104.5%)
	• For each unit increase in patient-rated therapeutic alliance score, the OR of good adherence was increased by 20.8% (95% CI: 4.4%–39.8%)
Magura et al^Citation42	• 71% of patients were at least partially nonadherent
	• 3 factors were significantly associated with adherence: self-efficacy for drug avoidance, medication side effects, and recovery support (multivariable analysis)
	• The final model explained 21% of the variance in adherence, indicating that other factors were not accounted for
	• Intensity of substance use was not associated with adherence
Sajatovic et al^Citation43	• 41%–43% of patients were nonadherent
	• Forgetting to take medication and side effects were the most common self-reported reasons for nonadherence (55% and 20%, respectively)
	• Difficulty with medication routine, denial of illness severity, and fear of medication side effects ranked highest among negative attitudes toward medication
	• 95% of participants reported good relationship with their HCP
	• The results may reflect adherence problems independent of therapeutic alliance
Zeber et al^Citation44	• 46% of patients had adherence problems
	• Multivariable analysis: OR of reasons most influencing poor adherence (95% CI): attitude toward medication, 2.41 (1.17–3.91); binge drinking, 1.95 (1.04–2.93); limited access to mental health specialist, 1.73 (1.08–2.69)
	• Therapeutic alliance did not show statistical significance in the same model (OR =1.55, 95% CI: 0.94–2.13, P=0.09)
Wong et al^Citation45	• Multivariable analysis: perception of being overweight was associated with significantly worse adherence (P<0.01); better attitude toward medication (P<0.01) and insight into illness (P=0.006) were associated with significantly better adherence
	• Attitude toward medication was the most influential factor
	• 72% of patients who believed that antipsychotics led to weight gain had reduced/omitted the drug dosages (P<0.001)
	• The concerns of weight gain occurred in those who perceived themselves as overweight and contributed significantly to poor adherence
Beck et al^Citation46	• Attitude toward antipsychotic medication impacts adherence over and above insight into illness; it differs from attitude toward medication in general in association with adherence
	• Attitude toward antipsychotic medication has 2 dimensions interacting with each other: necessity and concerns
	• Awareness of illness influences adherence indirectly through perceived necessity of medication
Dassa et al^Citation47	• 30% of patients were nonadherent
	• Multivariable analysis: nonadherence increased with increasing lack of insight into effect of medication (OR =3.23, 95% CI: 1.05–9.89), a lower level of therapeutic alliance (OR =0.45, 95% CI: 0.32–0.64), and duration of untreated psychosis (OR =1.12, 95% CI: 1.03–1.22)
	• Awareness of effect of medication was more important than awareness of illness for adherence
Acosta et al^Citation48	• 24.3% of patients were nonadherent (≤75% MEMS adherence)
	• Subjective assessments of adherence were in agreement with the MEMS in 77%–78% of cases when rated by psychiatrists, patients, and relatives
	• Multivariable analysis: nonadherence was associated with poor insight (OR =1.22, P=0.04) and higher scores on the PANSS items indicating conceptual disorganization (OR =1.74, P=0.07)
Baldessarini et al^Citation49	• 33.8% of patients were nonadherent (≥1 missed dose in last 10 days, patient self-report)
	• Multivariable analysis: factors significantly (P<0.05) and independently associated with nonadherence: alcohol dependence (OR =4.89) > cognitive side effects (OR =2.59) > affective comorbidity (OR =1.10)
	• Major adverse effects associated with nonadherence in patients with self-reported nonadherence: weight gain (58.5%), excessive sedation (54.2%), physical awkwardness or tremor (33.1%)
McCann et al^Citation50	• 19.7% of patients were nonadherent (≥1 missed dose over the past week)
	• Multivariable analysis: independent predictors of nonadherence were self-rated poor access to psychiatrists (OR =25.0; 95% CI: 1.85–333) and side effects (OR =12.8, 95% CI: 1.35–120.9)
	• Stigma was not associated with nonadherence
Rummel-Kluge et al^Citation51	• 68%–69% of patients were considered partially nonadherent (for unintentional partial nonadherence: missing 1 dose in last month)
	• The most common reasons for partial adherence were lack of insight into the need for prophylactic medication (68%), lack of insight/denial of illness (63%–66%), and stigma (embarrassment about taking daily medication, 62%)
Pratt et al^Citation52	• Mean nonadherence rate was ~40% based on pill count, but only 9%–17% based on self-report and MARS score
	• Significantly better adherence, expressed as a composite score, was correlated with SZ-spectrum disorders relative to BPD or MDD, higher level of medication supervision, greater level of insight, more prescribed medications, fewer negative symptoms, and better community functioning
Elbogen et al^Citation53	• 22% of patients were nonadherent (doses taken never or sometimes during past 30 days)
	• Multivariable analysis: 6 factors significantly associated with nonadherence: substance abuse (OR =1.72; P=0.0177), functional impairment (OR =1.94; P=0.0023), having moved in the past 30 days (OR =1.92; P=0.0028), feeling emotionally numb (OR =2.18; P=0.0006), loss of interest in daily activities (OR =1.81; P=0.0075), and reporting recent suicidal ideation (OR =1.98; P=0.0047)
	• Substance abuse, living instability, and depressive symptoms increased the probability of nonadherence from 0.14 to 0.66
	• The relationship between substance abuse and adherence was not mediated by depression or living instability – the effect is independent for all 3 factors

Abbreviations: BPD, bipolar disorder; CI, confidence interval; EPS, extrapyramidal symptoms; HCP, health care professional; MARS, Medication Adherence Rating Scale; MDD, major depressive disorder; MEMS, Medication Event Monitoring System; OR, odds ratio; PANSS, Positive and Negative Syndrome Scale; SZ, schizophrenia.

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