Treatment Adherence in Schizophrenia and Schizoaffective Disorder

Donald C. Goff, MD; Michele Hill, MRCPsych; and Oliver Freudenreich, MD

Schizophrenia Program, Massachusetts General Hospital and Harvard Medical School, Boston

As many as half of all patients in the United States do not take medications as prescribed, resulting in avoidable hospitalizations estimated to cost $100 billion annually.1 Cramer and Rosenheck2 found adherence with antipsychotics (58%) to be lower than with other medications, including nonpsychiatric treatments (76%) and antidepressants (65%). The true difference between adherence rates with antipsychotics compared with other medications may be even greater because adherence with antipsychotics was estimated primarily by patient self-report and clinician judgment, both of which tend to overstate adherence; rates in nonpsychiatric patients were obtained using microelectronic monitoring. As the new federal health care reform focuses the attention of policymakers upon improved outcomes and more efficient use of health care resources, enhancing adherence is a priority for clinical research and practice.1

Measuring Adherence

An accurate measurement of adherence is central to understanding the magnitude of the problem, identifying contributing factors, and assessing the effectiveness of interventions. Several methods of measuring and defining adherence exist, each with its own set of limitations.3 The special interaction between patients and clinicians may promote an exaggeration of compliance—most likely a reflection of patients’ fears of disappointing their physician. Therefore, patient self-report and clinician estimates of adherence increasingly are supplemented by more direct measures, such as pharmacy prescription refill rates, pill counts, and electronic monitoring with MEMS caps.4

Adherence rates often vary over time, and early studies of electronic monitoring in medical patients demonstrated the importance of using extended periods of measurement. For example, a long-term study5 of epilepsy patients demonstrated substantial improvement in adherence during the period before and after appointments with their doctors but a decline about 1 month after the visit. This pattern suggests that another common approach to evaluating adherence, ie, a single measurement of medication blood level, may be misleading, especially if the blood is drawn during a regularly scheduled doctor’s appointment. For clinicians who do not have access to electronic monitoring, pharmacy data on prescription refill rates can provide a useful screen for identifying patients with adherence problems.6 However, clinicians generally need to obtain as much information as possible from various sources to assess an individual patient’s adherence.

Adherence Patterns in Schizoaffective Disorder and Schizophrenia

Nonadherence in patients with schizoaffective disorder and schizophrenia is common and difficult for clinicians to detect. Furthermore, adherence status is not as simple as the categories of “adherent” and “nonadherent” suggest—the variability of an individual’s level of adherence over time often is best captured by the term “partial adherence.”

Using electronic monitoring with MEMS caps over a 3-month period, Byerly et al7 found that 48% of patients with schizophrenia or schizoaffective disorder were nonadherent, as defined by taking < 70% of daily doses. Clinicians failed to identify any of the nonadherent patients. In a subsequent 6-month study,8 MEMS caps data were compared with patient and clinician estimates of antipsychotic adherence as well as with data from research assistants’ interviews with patients using a 3-item questionnaire. Again defining nonadherence as taking < 70% of doses, the MEMS caps revealed a nonadherence rate of 57%, compared with 5% reported by patients and 7% by prescribers. Research assistants were more accurate, identifying 54% of participants as nonadherent, with a 36% evenly distributed error rate. A similar study9 found that adherence calculated by pill counts was strongly correlated with electronic monitoring, whereas both patient self-report and clinician estimates of adherence were weakly correlated. Notably, clinician estimates correlated with patients’ clinical status, suggesting that clinicians assume patients are compliant if they are doing well.

Studies using pharmacy fill rates have produced results similar to those using electronic monitoring. Dolder and colleagues10 found that outpatients with schizophrenia or schizoaffective disorder treated with first-generation agents for 1 year were without medication an average of 7 days per month compared with 4 days for second-generation agents. Subsequent studies11 have found similar rates of adherence but have not detected an advantage with second-generation versus first-generation antipsychotics.

Consequences of Nonadherence

Partial or nonadherence has been associated with a range of poor clinical outcomes in patients with schizophrenia and schizoaffective disorder, including higher rates of emergency room visits, hospitalizations, and suicide.11–14 In response to undetected partial compliance that has lessened treatment response, an attempt by the clinician to improve response by increasing medication dosage can result in an excessive dose when the patient resumes full adherence. Clinicians may also incorrectly attribute a patient’s relapse to a lack of efficacy of the current medication and switch antipsychotics or institute polypharmacy, whereas the more appropriate strategy would be to improve adherence and maintain monotherapy. This dilemma can often be resolved by the supervised administration of rapidly dissolving formulations or depot injections that allow the clinician to ascertain adherence with certainty.

Factors Contributing to Nonadherence

In an extensive review15 of studies of medical and psychiatric patients, adherence was related to patient satisfaction with treatment, continuity of care, and insight regarding the need for treatment; nonadherence was associated with chronicity of illness, complicated treatment regimens, medication side effects, and poor social functioning. Adherence in individuals with schizophrenia and schizoaffective disorder appears to reflect a similar constellation of factors, although the greater limitations in insight and psychosocial functioning may produce greater challenges. AV 1AV 1 outlines several factors associated with nonadherence in patients with schizophrenia and schizoaffective disorder.16–25

Increasing the complexity of medication schedules adversely affects adherence rates.24 Among 50 patients with schizophrenia and schizoaffective disorder monitored by MEMS caps for 3 months following discharge from the hospital, adherence rates were significantly higher (P=.001) for patients prescribed a once-daily dosage (62%) compared with a twice-daily (26%) or thrice-daily (22%) dosage.

Patient attitudes toward medication, which can be measured by the Drug Attitude Inventory,26 consistently predict nonadherence and drug discontinuation.27 Freudenreich and colleagues17 found that positive attitudes toward antipsychotics did not differ between first- and second-generation agents but did correlate with greater illness insight, the belief that medication lessens symptoms, and more awareness of the social consequences of schizophrenia. Negative attitudes reflected more severe psychopathology, medication-induced side effects, and lack of insight. Paradoxically, patients with higher levels of functioning as measured by the Quality of Life Scale had more negative attitudes toward medication. Ideally, patients who achieve recovery will attribute their functional success to treatment, but, as they re-enter society, they may be more likely to resent the need for medication and the stigma of continued psychiatric treatment; hence, close monitoring and support are critical during this period. In addition to poor insight, Day et al25 demonstrated that perceived coercion was associated with a negative attitude toward treatment, highlighting the importance of autonomy.

Concerning adverse events, individual patients differ substantially in their vulnerability to specific drug side effects and in the distress that they experience. Antipsychotic side effects that have been associated with poor adherence include parkinsonism, akathisia, sedation, weight gain, and sexual side effects.28–31


Interventions to Improve Adherence

Several strategies are available to aid clinicians in improving patients’ treatment adherence (AV 2AV 2). A review32 of interventions in patients with schizophrenia noted that education alone was least effective, whereas successful interventions combined educational, behavioral, and affective strategies; had a longer duration; and emphasized the therapeutic alliance. For clinicians working with patients who have schizoaffective disorder, the therapeutic alliance is pivotal in helping patients accept and adhere to antipsychotic treatment.

Medication selection should be individualized to minimize side effects and maximize perceived benefit, and the medication regimen should be as simple as possible, ideally with once-daily dosing. Using depot instead of oral antipsychotic formulations can help to improve adherence by providing clinicians with accurate information about missed doses, and the improved adherence with depot administration may reduce relapse.33

A patient with schizophrenia or schizoaffective disorder may derive a sense of well-being from medication, particularly if it helps alleviate insomnia, anxiety, or depression in addition to providing antipsychotic effects.34 Conversely, considerable time and effort may be required to help a patient recognize the delayed benefits of treatment such as the prevention of relapse or improvement in social and occupational functioning. Some patients may engage in multiple episodes of nonadherence that result in relapse before acquiring enough insight to acknowledge the benefits of medication.

An even higher level of insight is required to link medication to the attainment of life goals; this is an appropriate focus for CBT, which has been shown to improve medication adherence in several controlled trials.35 Compliance therapy, a CBT approach, involves facilitating the patient’s acknowledgement of illness, making analogies with maintenance treatment for medical illness (eg, high blood pressure), exploring the patient’s life goals and emphasizing the role of medication in achieving those goals, encouraging the patient to express misgivings about medications, and guiding the process of weighing therapeutic benefits against side effects.36 In one trial,36 4 to 6 sessions of compliance therapy improved compliance and reduced relapse for patients with psychotic disorders, but a large multicenter trial37 failed to find greater benefit when comparing compliance therapy with health education.

Shared decision making has received growing support in all areas of medicine. This patient-centered approach emphasizes providing information about medications to the patient, understanding the patient’s values and beliefs about medication, and involving the patient in the decision-making process. The dialogue between clinician and patient should be revisited regularly during the course of long-term treatment.

Directly observed therapy (DOT) is widely used for patients with infectious disorders like tuberculosis or HIV in which adherence to medication is critical.38 In DOT, a trained health care worker delivers and verifies the medication, checks for side effects, watches the patient swallow the medication, and documents the visit. For psychotic patients who do not live in a supervised setting, DOT can be implemented by visiting nurses or outreach workers. Cognitive adaptation training (CAT), an intervention that uses environmental supports such as signs, checklists, and alarms to cue and sequence adaptive behaviors in the home, was more effective at improving functional outcome than treatment as usual in schizophrenia.39 A new approach, information technology–aided relapse prevention (ITAREPS), uses a cell phone–based telemonitoring system that allows clinicians to monitor adherence and early signs of relapse. In one study,40 weekly remote monitoring reduced hospitalizations by 60% compared with a historical control.

An additional potential approach is the use of financial incentives, which have been used successfully to improve adherence in patients with substance abuse and in nonpsychiatric disorders.41 Two small, uncontrolled trials42,43 of financial incentives have shown promise in patients with schizophrenia, but ethical concerns about this strategy must be addressed.44


Poor adherence is common in patients with schizophrenia and schizoaffective disorder, may vary considerably over time, and is difficult for clinicians to detect. In the event of incomplete adherence, clinicians’ attempts to titrate medication dose may be counterproductive and strategies to treat relapse may be misguided. Many factors contribute to nonadherence, including poor illness insight, a negative attitude toward medication, substance abuse, and disorganization. Clinicians need to understand the patient’s assessment of medication benefits and disadvantages and work in collaboration with the patient to select medication that will provide a sense of well-being while minimizing side effects. Ultimately, the challenge is to help patients appreciate the long-term benefits of medication, including relapse prevention, improved functioning, and attainment of the patient’s life goals.

For Clinical Use


  • Be aware that nonadherence in schizophrenia and schizoaffective disorder is common and is associated with poor clinical outcomes such as relapse and rehospitalization
  • Recognize factors that contribute to nonadherence, including a lack of illness insight, perceived lack of autonomy, a poor therapeutic alliance, and lack of family and financial support
  • Accurately assess patients’ treatment adherence as much as possible, using direct measures such as electronic monitoring, prescription refill rates, and pill counts
  • Implement strategies to improve patients’ medication adherence, such as individualizing and simplifying medication regimens and using psychotherapeutic interventions



CAT = cognitive adaptation training
CBT = cognitive-behavioral therapy
DOT = directly observed therapy
ITAREPS = information technology–aided relapse prevention
MEMS = Medication Event Monitoring System


  1. Cutler DM, Everett W. Thinking outside the pillbox: medication adherence as a priority for health care reform. N Engl J Med. 2010;362(17):1553–1555.
  2. Cramer JA, Rosenheck R. Compliance with medication regimens for mental and physical disorders. Psychiatr Serv. 1998;49(2):196–201.
  3. Velligan DI, Lam YW, Glahn DC, et al. Defining and assessing adherence to oral antipsychotics: a review of the literature. Schizophr Bull. 2006;32(4):724–742.
  4. Farmer KC. Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice. Clin Ther. 1999;21(6):1074–1090.
  5. Cramer JA, Scheyer RD, Mattson RH. Compliance declines between clinic visits. Arch Intern Med. 1990;150(7):1509–1510.
  6. Woltmann EM, Valenstein M, Welsh DE, et al. Using pharmacy data on partial adherence to inform clinical care of patients with serious mental illness. Psychiatr Serv. 2007;58(6):864–867.
  7. Byerly M, Fisher R, Whatley K, et al. A comparison of electronic monitoring vs. clinician rating of antipsychotic adherence in outpatients with schizophrenia. Psychiatry Res. 2005;133(2–3):129–133.
  8. Byerly MJ, Thompson A, Carmody T, et al. Validity of electronically monitored medication adherence and conventional adherence measures in schizophrenia. Psychiatr Serv. 2007;58(6):844–847.
  9. Velligan DI, Wang M, Diamond P, et al. Relationships among subjective and objective measures of adherence to oral antipsychotic medications. Psychiatr Serv. 2007;58(9):1187–1192.
  10. Dolder CR, Lacro JP, Dunn LB, et al. Antipsychotic medication adherence: is there a difference between typical and atypical agents? Am J Psychiatry. 2002;159(1):103–108.
  11. Gilmer TP, Dolder CR, Lacro JP, et al. Adherence to treatment with antipsychotic medication and health care costs among Medicaid beneficiaries with schizophrenia. Am J Psychiatry. 2004;161(4):692–699.
  12. Valenstein M, Copeland LA, Blow FC, et al. Pharmacy data identify poorly adherent patients with schizophrenia at increased risk for admission. Med Care. 2002;40(8):630–639.
  13. Weiden PJ, Kozma C, Grogg A, et al. Partial compliance and risk of rehospitalization among California Medicaid patients with schizophrenia. Psychiatr Serv. 2004;55(8):886–891.
  14. Hawton K, Sutton L, Haw C, et al. Schizophrenia and suicide: systematic review of risk factors. Br J Psychiatry. 2005;187(1):9–20.
  15. Blackwell B. From compliance to alliance: a quarter century of research. Neth J Med. 1996;48(4):140–149.
  16. Ascher-Svanum H, Zhu B, Faries D, et al. A prospective study of risk for nonadherence with antipsychotic medication in the treatment of schizophrenia. J Clin Psychiatry. 2006;67(7):1114–1123.
  17. Freudenreich O, Cather C, Evins AE, et al. Attitudes of schizophrenia outpatients toward psychiatric medications: relationships to clinical variables and insight. J Clin Psychiatry. 2004;65(10):1372–1376.
  18. Perkins DO, Gu H, Weiden PJ, et al, for the Comparison of Atypicals in First Episode Study Group. Predictors of treatment discontinuation and medication nonadherence in patients recovering from a first episode of schizophrenia, schizophreniform disorder, or schizoaffective disorder: a randomized, double-blind, flexible-dose, multicenter study. J Clin Psychiatry. 2008;69(1):106–113.
  19. Jeste SD, Patterson TL, Palmer BW, et al. Cognitive predictors of medication adherence among middle-aged and older outpatients with schizophrenia. Schizophr Res. 2003;63(1–2):49–58.
  20. Lacro JP, Dunn LB, Dolder CR, et al. Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of the recent literature. J Clin Psychiatry. 2002;63(10):892–909.
  21. Nose M, Barbui C, Tansella M. How often do patients with psychosis fail to adhere to treatment programmes? a systematic review. Psychol Med. 2003;33(7):1149–1160.
  22. Freudenreich O, Deckershach T, Goff DC. Insight into current symptoms of schizophrenia: association with frontal cortical function and affect. Acta Psychiatr Scand. 2004;110(1):14–20.
  23. Perkins DO. Predictors of noncompliance in patients with schizophrenia. J Clin Psychiatry. 2002;63(12):1121–1128.
  24. Diaz E, Neuse E, Sullivan MC, et al. Adherence to conventional and atypical antipsychotics after hospital discharge. J Clin Psychiatry. 2004;65(3):354–360.
  25. Day JC, Bentall RP, Roberts C, et al. Attitudes toward antipsychotic medication: the impact of clinical variables and relationships with health professionals. Arch Gen Psychiatry. 2005;62(7):717–724.
  26. Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative ability. Psychol Med. 1983;13(1):177-183.
  27. Gaebel W, Riesbeck M, von Wilmsdorff M, et al. Drug attitude as predictor for effectiveness in first-episode schizophrenia: results of an open randomized trial (EUFEST). Eur Neuropsychopharmacol. 2010;20(5):310–316.
  28. Fleischhacker WW, Meise U, Gunther V, et al. Compliance with antipsychotic drug treatment: influence of side effects. Acta Psychiatr Scand Suppl. 1994;382:11–15.
  29. Weiden PJ, Mackell JA, McDonnell DD. Obesity as a risk factor for antipsychotic noncompliance. Schizophr Res. 2004;66(1):51–57.
  30. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–1223.
  31. Robinson DG, Woerner MG, Alvir JM, et al. Predictors of medication discontinuation by patients with first-episode schizophrenia and schizoaffective disorder. Schizophr Res. 2002;57(2–3):209–219.
  32. Keith SJ, Kane JM, Turner M, et al. Guidelines for the use of long-acting injectable atypical antipsychotics [academic highlights]. J Clin Psychiatry. 2004;65(1):120–131.
  33. Schooler NR. Relapse and rehospitalization: comparing oral and depot antipsychotics. J Clin Psychiatry. 2003;64(suppl 16):14–17.
  34. Naber D, Moritz S, Lambert M, et al. Improvement of schizophrenia patients' subjective well-being under atypical antipsychotic drugs. Schizophr Res. 2001;50(1–2):79–88.
  35. Turkington D, Kingdon D, Weiden PJ. Cognitive behavior therapy for schizophrenia. Am J Psychiatry. 2006;163(3):365–373.
  36. Kemp R, Kirov G, Everitt B, et al. Randomised controlled trial of compliance therapy: 18-month follow-up. Br J Psychiatry. 1998;172(5):413–419.
  37. Gray R, Leese M, Bindman J, et al. Adherence therapy for people with schizophrenia: European multicentre randomised controlled trial. Br J Psychiatry. 2006;189(6):508–514.
  38. Hart JE, Jeon CY, Ivers LC, et al. Effect of directly observed therapy for highly active antiretroviral therapy on virologic, immunologic, and adherence outcomes: a meta-analysis and systematic review. J Acquir Immune Defic Syndr. 2010;54(2):167–179.
  39. Velligan DI, Diamond PM, Mintz J, et al. The use of individually tailored environmental supports to improve medication adherence and outcomes in schizophrenia. Schizophr Bull. 2008;34(3):483–493.
  40. Spaniel F, Vohlidka P, Hrdlicka J, et al. ITAREPS: information technology aided relapse prevention programme in schizophrenia. Schizophr Res. 2008;98(1–3):312–317.
  41. Giuffrida A, Torgerson DJ. Should we pay the patient? review of financial incentives to enhance patient compliance. BMJ. 1997;315(7110):703–707.
  42. Staring AB, Mulder CL, Priebe S. Financial incentives to improve adherence to medication in five patients with schizophrenia in the Netherlands. Psychopharmacol Bull. 2010;43(1):5–10.
  43. Claassen D. Financial incentives for antipsychotic depot medication: ethical issues. J Med Ethics. 2007;33(4):189–193.
  44. Szmukler G. Financial incentives for patients in the treatment of psychosis. J Med Ethics. 2009;35(4):224–228.