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Introduction (Back to Top)

Schizophrenia is a chronic mental illness characterized by psychosis, negative symptoms, and cognitive impairment. It affects approximately 1% of the world ’s population¹ and has a devastating effect on patients’ lives and their families. Psychiatric management should be based on a long-term treatment plan designed to meet the goals of preventing relapse and rehospitalization, eliminating or reducing symptoms, improving patient functioning and quality of life, and eventually achieving recovery.
Great advances have been made in the treatment of schizophrenia, and by integrating antipsychotic pharmacotherapies with psychosocial interventions, physicians can help patients meet their goals. However, clinical interventions are only effective if patients adhere to the prescribed pharmacotherapy regimen. It is therefore important for physicians to recognize the problem of nonadherence and institute strategies to improve patient adherence to medications. This activity identifies the barriers to treatment adherence for patients with schizophrenia and offers an expert review of evidence-based practices that can improve patients’ adherence to treatment through continuity of care.

Barriers to Treatment Adherence for Patients with Schizophrenia
PREVALENCE OF NONADHERENCE (Back to Top)

Antipsychotics are the primary medication used to treat schizophrenia. They are highly effective in reducing positive symptoms and preventing acute episode relapse and symptom exacerbation. However, adherence to medication is essential for treatment to be effective.
Nonadherence to medications is a common problem with many chronic illnesses. Moreover, it becomes more frequent as the length, complexity, and cost of treatment increases.² It is especially challenging in the treatment of schizophrenia. Compared to other chronic conditions, schizophrenia is second only to weight reduction in terms of the degree of difficulty, as judged in a survey of 20 psychiatrists, in maintaining adherence at a level sufficient to produce a therapeutic effect (Figure 1).³
Reported rates of adherence to antipsychotic medications vary widely, depending on how nonadherence is defined and measured, the observation time of the study, and the characteristics of the studied population.3 A recent review of studies measuring adherence to antipsychotic medications used 2 different standards, “strict” and “stricter,” to derive a mean rate of nonadherence.4 Ten out of 39 papers were identified that used strict criteria, in which adherence is defined as “taking medication as prescribed” and trained personnel are used to measure adherence. The strict categorization excluded studies that calculated adherence based on patients’ “willingness” to take medications or based on patient self-reporting, unless reports could be verified through other sources. The weighted mean of nonadherence rates of the 10 studies that met the strict criteria was 41.2% with a range of 20.0% to 55.6%. The review also used “stricter” criteria, which included only the strict studies that defined adherence as taking medication 75% of the time. The weighted mean of nonadherence in the 5 stricter papers was 49.5% with a range of 37.7% to 55.6%.⁴

Figure 1. Degree of Difficulty to Produce Adherence Sufficient for Therapeutic Effect: Psychiatrists’ Assessment.3

IMPACT OF NONADHERENCE ON THE PATIENT (Back to Top)

Nonadherence represents a spectrum of behavior, from complete nonadherence (discontinuation) to partial adherence, in which patients take some, but not all, of their medication or take the prescribed dosage intermittently with discrete gaps in which no medication is taken.⁵ Partial and complete nonadherence are associated with relapse, psychiatric hospitalization, and other deleterious outcomes for the patient.
Nonadherence to antipsychotic medications is a major risk factor of psychotic relapse. A study of 104 patients with first-episode schizophrenia showed a cumulative relapse rate of 81.9% by the end of a 5 year follow up.⁶ The 63 patients who recovered from the first relapse had a 78.0% cumulative rate of a second relapse after 5 years. The risk for first and second relapses was shown to be 5 times greater when medication was discontinued as measured by a survival analysis of relapse using medication status (use to discontinuation of use) as a time-dependent covariate. Further examination suggested that discontinuing use of the antipsychotic was not just an early manifestation of a relapse, but had a causative effect.⁶
Nonadherence is also associated with the risk of hospitalization.^5,7-10 This further supports evidence of an association between nonadherence and relapse since hospitalization is often used as a measurement for relapse. A study of 2,801 person-years of refill records for antipsychotic medication prescribed to beneficiaries of the California Medicaid program found that patients who were nonadherent (having possession of medication less than 49% of the time they were eligible for benefits) were 2.5 times more likely to be hospitalized than those who were adherent (having possession of their medication 80% to 100% of the time). Those who were partially adherent (having possession of the medication 50% to 79% of the time) were 80% more likely to be hospitalized as those who were adherent.⁸ A separate study of 4,325 refill records of California Medicaid beneficiaries showed that even small gaps in taking medication were associated with a higher risk of hospitalization. As the number of consecutive days (maximum gap) in which no medication appeared to be available increased, the percentage of patients who were hospitalized also increased (Figure 2).⁵
Although it can be difficult to separate the effects of relapse on patient outcome, nonadherence is specifically associated with other harmful outcomes. These include exacerbation of symptoms,¹¹ lengthening of episodic hospital stays,^12,13 increased housing instability,¹¹ and increased risk of suicide.¹⁴

Figure 2. Percentage of patients with schizophrenia who were rehospitalized, by maximum gap in therapy.5

IMPACT OF NONADHERENCE ON THE COMMUNITY (Back to Top)

Schizophrenia exacts significant economic and social effects on society and emotional tolls on families, friends, and caretakers. The total cost of schizophrenia in 1990 was estimated at $32.5 billion. Direct costs of medical expenditures accounted for 53.2% of the total, while indirect costs, including morbidity, mortality, and costs relating to crime, social welfare, and family caregiving, accounted for the remainder.¹⁵ These estimates do not include costs of treatment for common comorbid conditions that are associated with or can be exacerbated by schizophrenia, including an increased risk for substance use disorders,¹⁶ cardiovascular disease,¹⁷ diabetes,¹⁷ infectious diseases (e.g., HIV, hepatitis B and C),¹⁸ and depression.¹⁷
Nonadherence adds significantly to the cost burden of schizophrenia, as well. Studies of prescription refill data of California Medicaid beneficiaries showed that expenditures for hospitalization of nonadherent patients were 3 fold higher than costs of individuals who were adherent.⁸ Costs of individuals who were partially adherent were 2.5 times higher than the costs of those who were adherent. These costs are likely attributable to the costs associated with relapse, including hospitalization. A 2003 review of studies estimated a range of costs associated with relapse to be between $10,000 and $26,000 per episode.¹⁹ The indirect costs of nonadherence are inestimable.
Nonadherence and its consequences take an emotional toll on patients’ support networks. Through support and supervision, family members, friends, and other social contacts can improve medication adherence.²⁰ Relapses put an increased burden on family and caregivers, ultimately affecting the long-term success of a treatment plan. Nonadherence and relapse can put enormous strain on family relationships and support.

Evidence-Based Practices to Address Patient Adherence (Back to Top)
RISK FACTORS FOR NONADHERENCE

Side effects are also risk factors for nonadherence. Depending on the type of antipsychotic medication, dosage, and patient, these can include extrapyramidal side effects, anticholinergic side effects, sedation, cardiovascular effects, weight gain and metabolic abnormalities, and effects on sexual function (Table 1).¹⁷ Extrapyramidal side effects, weight gain, and sexual side effects are thought to be most commonly associated with nonadherence.²⁰ The CATIE study showed that side-effects were a contributing factor to discontinuation of treatment, although it comprised the lowest rated of the 3 possible categories of discontinuation (10% to 19% across treatment groups).²⁷

Table 1. Shared side effects and dosages of commonly used antipsychotic agents.17

0 = No risk or rarely causes side effects at therapeutic dose. + = Mild or occasionally causes side effects at therapeutic dose. ++ = Sometimes causes side effects at therapeutic dose. +++ = Frequently causes side effects at therapeutic dose. bPossible exception of akathisia cSide effects frequently caused at therapeutic dose (+++) dSide effects attributable to a specific antipsychotic

Physicians may affect adherence by overestimating adherence in their patients, reducing the opportunities in which they might intervene. Medication adherence was followed in 21 outpatients for 3 consecutive months using a Medication Event Monitoring System (MEMS) and as judged by physicians using the Clinician Rating Scale. Nonadherence was detected in 13 of the 21 patients using MEMS, while nonadherence was only detected in 1 of the 21 patients using the rating scale.²⁸
A positive therapeutic alliance, as described in more detail below, between physician and patient can enhance adherence.^4,22 A recent study of 213 patients evaluated at discharge and 3 months later found that patients who became nonadherent to medications after discharge were more likely to have formed a poor therapeutic alliance with inpatient physicians than patients who were adherent.¹¹
Patient-related factors associated with nonadherence include many aspects of a patient’s personal life. Personal conflicts can include economic or practical barriers (such as lack of insurance, transportation, or child care) to obtaining medication.^20,22 Personal conflicts can also include a conflict between treatment and religious or cultural beliefs. Stigma attached to the diagnosis of schizophrenia or the medication can affect adherence,^3,23 as can isolation or lack of social support from family or community-based services.^20,23
Personal health beliefs and attitudes towards medication can interfere with adherence. These may be attributed to lack of psychoeducation about the illness, negative attitudes toward treatments, or a perception that treatment is not relevant to patients’ goals. Examples of such beliefs include the ideas that medication should be taken only when one feels sick, that it is unnatural to take medication,or that patients are cured after remission of symptoms.³
Alcohol and drug use disorders are identified as a major risk factor of nonadherence.^13,22 Evaluation of 213 patients at hospital discharge and 3 months later showed that alcohol and drug use disorders in the 3 months prior to hospitalization and 3 months after were the strongest predictors of medical nonadherence.¹¹ Patients may become nonadherent while using drugs or alcohol because they have been told that mixing antipsychotic medications with drugs or alcohol is dangerous. In addition, drug or alcohol use can lead to unreliable behavior or self-neglect, and patients who have substance use disorders are more likely to be asked to leave psychiatric programs.²⁹ Results from the 1990 Epidemiologic Catchment Area study furthermore demonstrate the association between schizophrenia and alcohol and drug use disorders. Of the individuals interviewed with a diagnosis of schizophrenia or schizophreniform disorder, 47% met the criteria for some form of substance abuse or dependence, with odds of having a substance abuse diagnosis 4.6 times as high as for the rest of the population.¹⁶
Housing instability and homelessness are also associated with nonadherence. In an opinion piece that reported on very early findings of a study concerning adherence, researchers found through home visits that unstable living environment and daily schedules were acting as barriers to adherence. Some patients slept in different relatives’ homes each night or had irregular meal or hygiene routines, which interfered with linking medication to a daily schedule.³⁰ A study of California Medicaid beneficiary refill records found that individuals living with family members or in assisted living facilities were more likely to be adherent than those who lived independently. Homeless individuals had the lowest adherence rates.⁸

PSYCHIATRIC MANAGEMENT PRACTICES TO IMPROVE ADHERENCE (Back to Top)

Physicians have a variety of tools to measure adherence (Figure 5). While there are no “gold standards,” adherence may be assessed by patient self-reporting, family or caregiver reporting, monitoring therapeutic blood or urine levels, counting pills, using electronic monitoring devices (MEMS), or monitoring patient pharmacy refill records.^28,31 Each method has strengths and weaknesses, thus implementation should be considered in light of patients’ treatment regimen, level of functioning, and financial and social circumstances.

Figure 5. Methods of measuring adherence.3,31

When nonadherence is detected, it is appropriate to engage in both general and patient-tailored interventions. Motivational interviewing is a general technique used for prevention and intervention that has shown to be effective in increasing adherence.³² During motivational interviewing, patients identify and relate their goals to the treatment plan and are provided psychoeducation about medication that helps link health beliefs and behaviors to outcomes. As an additional general measure, physicians can engage in assertive outreach to patients who become nonadherent. This could include telephone calls or home visits if a patient misses an appointment.¹⁷
Physicians can tailor other interventions to illness-related factors, treatment-related factors, or patient-related factors that are contributing to nonadherence. For example, cognitive impairment is an illness-related factor that can act as a barrier to adherence. Physicians can simplify the dosing, assist in establishing a routine with use of a pill box or a daily alarm, or engage in psychosocial interventions focused on increasing cognitive functioning to improve adherence.¹⁷
Patients should be encouraged to share their feelings about medication, report their side effects, and describe if they feel the treatment is not effective so that physicians can quickly identify when a patient is at risk of becoming nonadherent.¹⁷ Physicians can respond to treatment-related factors such as lack of efficacy or presence of side effects by changing dosages of medication, switching medications, adding another medication, or delivering medications through a different route.²⁴ Physicians should also consider whether nonadherence is contributing to treatment resistance.¹⁷
Patient-related factors that act as a barrier to adherence can be addressed by reaching out to family or community groups to provide practical assistance, such as transportation or child care.¹⁷ Through a strong therapeutic alliance, physicians should discuss effects of health beliefs, cultural or religious beliefs, feelings of stigma, living arrangements, as well as work, social, and family life.²⁹ More complicated issues such as comorbid substance use disorders and homelessness or housing instability need to be monitored and addressed, as well.
While adherence interventions within the 8 practices of psychiatric management apply to all stages of schizophrenia (Figure 4), some adherence intervention techniques may be more appropriate for certain stages of schizophrenia than others. For example, the goals of treatment in the acute phase of schizophrenia include to prevent harm, reduce the severity of psychotic symptoms, determine the factors that lead to the acute episode (which include nonadherence), and affect a rapid return to functioning.¹⁷ It would be appropriate in this stage to introduce behavior therapies, such as motivational interviewing, to improve adherence. Physicians can also consider changing the route of administration to quick-dissolving oral medications or depot medications in order to improve adherence at this stage.¹⁷
During the stabilization phase, in which patients are transitioned from inpatient to outpatient care, medication efficacy and side effects should be closely monitored to prevent nonadherence. Initiation of psychosocial education programs during this phase would be appropriate.¹⁷ Inpatient and outpatient providers should coordinate to assure that there is no gap in delivery, as this can result in inadvertent nonadherence. As an example, patients who were visited at home by clinical staff to monitor medication adherence were found with 2 different dosages of medication prescribed by inpatient and outpatient providers. They planned on taking both medications despite the fact that the one medication was intended to replace the other.³⁰
Treatment during the stable phase of schizophrenia is focused on maintaining symptom stability, reducing relapse, and improving patient functioning. Given the relationship between relapse and nonadherence, adherence monitoring and interventions should continue throughout the stable phase. The APA guidelines report that most patients will generally benefit from psychosocial interventions, which should be tailored to the needs of the patients.¹⁷ Many of these programs are initiated during the stable phase.

PSYCHOSOCIAL INTERVENTIONS TO ADDRESS ADHERENCE (Back to Top)

Although pharmacotherapy is the cornerstone of treatment for schizophrenia, psychosocial interventions are part of a comprehensive approach to treatment that improves the outcome of schizophrenia.^33,34 The goals of psychosocial interventions are to prevent relapse, help patients cope with symptoms, and increase social and vocational functioning.¹⁷ This activity focuses on the evidence-based psychosocial interventions that improve adherence to medications.
Compliance therapy, also referred to as adherence therapy,³⁵ is a combination of cognitive approaches and motivational interviewing aimed at focusing patients on the importance of being well and connecting the benefits of medication to adherence.^34,36 It is usually time-limited and nonconfrontational.³⁴ In a randomized controlled trial with 74 inpatients assigned to compliance therapy or control therapy (supportive counseling), the group undergoing compliance therapy measured significantly higher on positive attitudes toward treatment and adherence with antipsychotic medications. The group receiving compliance therapy also showed improvement on measures of insight, global social functioning, and had a significantly longer time to rehospitalization than the control group.³²
Family psychoeducation provides knowledge, guidance, and support to family members so that they can be effective caretakers. Education programs provide information about the illness, its course, and the medical regimen and can involve families in planning treatment and setting treatment goals with the patient and clinician. Some programs provide coping and stress management strategies to help family members care for the patient and for themselves.¹⁷ Integration of the family, with the patient’s consent, should begin as early as possible in the acute phase.¹⁷ A systematic review of randomized controlled trials showed that family-oriented therapies have been successful in increasing adherence and clinical outcomes in some studies and less successful in others.²
Program for Assertive Community Treatment (PACT) involves case management, active interventions, and outreach provided 24 hours a day, 7 days a week in patients’ homes, neighborhoods, and places of employment. It coordinates involvement with the patients’ support networks (e.g., family, friends, and employers), community groups, and physicians.17 This program is meant for outpatients in the stabilization and stable phases.¹⁷ Medication adherence is emphasized, although evidence supporting effectiveness in improving adherence is modest. Of 10 studies examining treatment models akin to PACT reviewed by Zygmunt and colleagues, 4 studies showed positive results in improving adherence.³⁶

PHARMACOLOGICAL TREATMENTS TO IMPROVE ADHERENCE (Back to Top)

Antipsychotic medication includes first-generation (or conventional) agents and second-generation (or atypical) agents. (Table 1) Both classes of medication have therapeutic effects on reducing positive symptoms of schizophrenia and preventing relapse. There is evidence suggesting that atypical antipsychotics are more effective in treating negative symptoms.¹⁷ However, there is ongoing debate as to whether one class of antipsychotic is more efficacious than the other.
Two 2003 meta-analyses of randomized, controlled trials showed superior efficacy of second-generation antipsychotics. One analysis concluded that as a class, atypical antipsychotics were more effective than conventionals in preventing overall treatment failure.³⁷ The other concluded that 4 types of atypical antipyschotics were more efficacious than the conventionals.³⁸ In contrast, another meta-analysis of randomized controlled trials comparing conventional and atypical antipsychotics concluded that there was no clear evidence that atypical antipsychotics were more effective than conventionals when researchers controlled for the higher than recommended dosages of conventional antipsychotics used in some trials.³⁹
As discussed earlier, the 2005 CATIE phase 1 study, in which 1,460 patients were randomly assigned to 1 of 4 atypical agents or 1 conventional agent, showed the atypical agent, olanzapine, was more effective than the others when measured by time to all-cause discontinuation.²⁷ However, when measured by time to discontinuation due to tolerability, risperidone was the most effective drug.²⁷ Seventy-four percent of patients in the CATIE phase 1 trial did not stay on their first drug.²⁷ In a second phase of the trial, patients were allowed to choose a treatment pathway based on efficacy or tolerability. In those patients who chose the regimen for improved efficacy, olanzapine was again the most efficacious drug. Accordingly, in those patients who chose a new regimen based on tolerability, risperidone was the most effective antipsychotic overall.²⁷ These trials demonstrate how patients’ response to conventional and atypical antipsychotics varies and how medication continuation can be affected by several variables, including efficacy and tolerability.
Selection of antipsychotics is often based on a patient’s history or risk of side effects. Atypical antipsychotics have a decreased risk of extrapyramidal side effects and tardive dyskinesia (Table 1), thus they are often used as first-line medications for patients in the acute phase of schizophrenia.¹⁷ Since atypical antipsychotics have a lower extrapyramidal side effect profile than conventionals, it has been suggested that patients would be more willing to adhere to atypical antipsychotic medications. Unfortunately, there is not a consensus whether atypical antipsychotics are associated with a higher rate of adherence. Some studies have shown an increase in adherence associated with atypical antipsychotics,40 whereas others show no significant difference in adherence between the 2 classes of antipsychotics.^4,8,37,39
Barring more robust evidence showing superior efficacy or adherence of one antipsychotic class over the other, selection of antipsychotic medication should be based on patient needs. The APA guidelines provide general guidance in this context by recommending physicians choose antipsychotic medications based on patients’ past experience with antipsychotics, in terms of efficacy and tolerability, as well as their own preferences of medication, including a preference for route of administration.¹⁷
Physicians may want to consider whether changing the route of administration of the prescribed antipsychotic could improve adherence. The APA guidelines suggest that physicians should consider using long-acting injectable antipsychotic medication in patients with recurring relapses related to nonadherence.¹⁷ In a national survey, psychiatrists rated long-acting injectable medication as the most effective intervention in addressing nonadherence in both patients who were aware and unaware of their illness.²⁴

Long-Acting Injectable (LAI) Medication (Back to Top)

Long-acting injectable (LAI) medication formulations of fluphenazine and haloperidol have been available for many years. More recently, a long-acting injectable formulation of the second generation antipsychotic risperidone has become available. It is accepted that LAI conventional antipsychotics confer greater benefit on global outcome than oral antipsychotics.⁴¹ Studies summarizing a comparison of conventional oral and depot medication demonstrate that depot medication reduces relapse rates and the length of hospitalization.³⁵
It is likely that at least part of the benefits conferred by LAI antipsychotics can be attributed to increased adherence. A review of studies reports an association between increased adherence and the use of depot medications.²² LAI antipsychotics are given as an injection in an outpatient setting usually once every 2 weeks; thus the patient does not have the burden of remembering to take the medication daily. One of the major advantages of LAI medications is that they eliminate covert nonadherence. Physicians know immediately if a patient misses a scheduled injection. Accordingly, it is beneficial for the patient if physicians have a plan of outreach and intervention if a patient misses an injection.⁴¹ An additional benefit of LAI medication is the regular contact between the patient and clinician and clinical staff, which can strengthen the therapeutic alliance and provide psychosocial support for the patient.⁴² This exemplifies how pharmacological, as well as psychosocial, interventions can create a continuum of improvement in treatment adherence.
Long-acting injectables have been shown to have improved bioavailability over oral medications. Oral medications are metabolized in the liver, with considerable inter-individual variability in resulting blood levels. Injected medications avoid first-pass metabolism, thus blood levels are more predictable. This results in a more controllable and stable plasma level of the long-acting injectable medication and a reduction in the daily peak to trough ratio, allowing a lower effective dose to be used.^35,41 Lower doses are associated with the occurrence of fewer side effects.³⁵ If a patient does miss an injection, there is no abrupt discontinuation of medication because the elimination half-life of the conventional LAIs are 14 and 21 days and steady-state levels of the atypical LAI are maintained for 4 to 6 weeks after the last injection.^35,41
Despite the advantages of LAI medications, some believe they are not used as often as they should be.³⁵ This may be attributable to patients’ fears of discomfort or pain with the injections or frequently the doctor’s hesitancy to work through these fears. Conventional LAIs are dissolved in solutions such as vegetable oil, and large volumes of injections have been associated with redness, swelling, and palpable masses at the injection site.⁴¹ The atypical risperidone LAI formulation is suspended in a water-based solution and has shown to result in less pain or inflammation and limited or no redness, swelling, or irritation.⁴¹ In spite of perceived fears, a systematic review of patient attitudes to depot medications showed that a majority of the patients who had experienced both preferred depot medications over oral medications.43
Lack of use may also be attributed to physicians’ fears of an inability to rapidly withdraw medication upon emergence of adverse effects. A summary of current research indicates that equivalent dosages of long-acting injectable drugs have no greater risk for adverse events than oral antipsychotics. In fact, the lower dosage that can be used for LAI antipsychotics may actually lower the rate of extrapyramidal side effects.⁴¹
Physicians might also continue to associate LAI medications with conventional antipsychotics, which were the only formulations available prior to 2003. Physicians who were concerned about the extrapyramidal side effects of conventional antipsychotics reserved use of conventional depot medications for the most refractory or noncooperative patients.35 With the development of a LAI atypical antipsychotic, LAI risperidone, physicians have an opportunity to offer patients an atypical antipsychotic in a long-acting form.

Treatments in Development (Back to Top)

In June of 2006, it was estimated that at least 40 new or reformulated antipsychotic medications were under development.⁴⁴ Researchers are experimenting with new delivery routes of existing approved medications and new chemical entities, which may give physicians additional tools to improve adherence. A long-acting injectable formulation of the atypical antipsychotic medication olanzapine is currently being tested in a phase 3 trial.⁴⁵ If approved, long-acting olanzapine would be administered once a month via an intramuscular injection.⁴⁴ Extended-release and sustained-release formulations of oral drugs are also being developed. Taken once daily in oral form, they have some of the advantages of LAI medications because they do not cause the plasma-level peaks and troughs associated with short-acting oral medications and therefore result in a more stable drug delivery throughout the day.⁴⁶ The Food and Drug Administration approved an extended-release formulation of paliperidone in late 2006.⁴⁶ A phase 3 trial to test the efficacy and safety of switching patients from an oral, short-acting formulation of quetiapine to a developmental sustained-release formulation is currently recruiting patients.⁴⁷
It is too early to know whether long-acting injectable medications and extended/sustained release formulations will have a dramatic effect on adherence. However, researchers are hopeful that new medications will be used to help address the critical issue of nonadherence in schizophrenia.

CONCLUSIONS (Back to Top)

Nonadherence to medication is a significant barrier to the successful treatment of patients with schizophrenia, and thus, is an important determinant of clinical outcomes. It is associated with an increased risk of psychotic relapse, hospitalization, suicide, violent and aggressive behavior, increased family or caregiver burden, and has an impact on health care resource utilization. Risk factors of nonadherence are associated with the psychopathology of schizophrenia, the treatment of the disease, and the patients’ personal circumstances. By identifying these risk factors and assessing the level of medication adherence using various clinical tools, physicians can implement a comprehensive plan that improves patient adherence to medications and facilitates continuity of care.
Effective psychiatric management of patients incorporates various prevention and intervention practices. A strong therapeutic alliance between physician and patient and active outreach by the physician to the patient, family, and other health professionals are effective in increasing adherence. Psychosocial interventions effective in increasing adherence, such as compliance therapy, family psychoeducation, and programs for assertive community treatment, should be integrated into a comprehensive treatment plan. It is evident that patients must be managed individually, according to the several variables affecting their disease and treatment. Individualized management, however, includes the need for various choices of antipsychotic medication formulations and delivery systems in order to help physicians and patients address barriers to adherence.

References (Back to Top)
1. Mueser KT, McGurk SR. Schizophrenia. Lancet. 2004;363:2063-2072.
2. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions [published correction appears in JAMA. 2003;289:3242.] JAMA. 2002;288:2868-2879.
3. Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: our patients can do better. J Clin Psychiatry. 2003; 64:1308-1315.
4. Lacro JP, Dunn LB, Dolder CR, Leckband SG, Jeste DV. Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry. 2002;63:892-909.
5. Weiden PJ, Kozma C, Grogg A, Locklear J. Partial compliance and risk of rehospitalization among California Medicaid patients with Schizophrenia. Psych Serv. 2004;55:886-891.
6. Robinson D, Woerner MG, Alvir JMJ, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999:56:241-247.
7. Rittmannsberger H, Pachinger T, Keppelmuller P, Wancata J. Medication adherence among psychotic patients before admission to inpatient treatment. Psychtr Serv. 2004;55:174-179.
8. 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;161:692-699.
9. McEvoy JP, Howe AC, Hogarty GE. Differences in the nature of relapse and subsequent inpatient course between medication-compliant and noncompliant schizophrenic patients. J Nerv Men Dis. 1984;172:412-416.
10. Valenstein M, Copeland LA, Blow FC, et al. Pharmacy data identify poorly adherent patients with schizophrenia at increased risk for admission. Med Care. 2002;40:630-639.
11. Olfson M, Mechanic D, Hansell S, Boyer CA, Walkup J, Weiden PJ. Predicting medication noncompliance after hospital discharge among patients with schizophrenia. Psychtr Serv. 2000;51:216-222.
12. Leucht S, Heres S. Epidemiology, clinical consequences, and psychosocial treatment of nonadherence in schizophrenia. J Clin Psychiatry. 2006;67(suppl 5):3
13. Hunt GE, Bergen J, Bashir M. Medication compliance and comorbid substance abuse in schizophrenia: impact on community survival 4 years after a relapse. Schizophr Res. 2002;54:253-264.
14. Herings RMC, Erkens JA. Increased suicide attempt rate among patients interrupting use of atypical antipsychotics. Pharmaoepidem Drug Saf. 2003;12:423-424.
15. Rice DP. The economic impact of schizophrenia. J Clin Psychiatry. 1999;60(suppl 1):4-6.
16. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of metal disorders with alcohol and other drug abuse. JAMA. 1990;264:2511-2518.
17. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guidelines for the treatment of patients with schizophrenia, second edition. American Psychiatric Association web site. Available at: http://www.psych.org/psych_pract/treatg/pg/Schizophrenia2ePG_05-15-06.pdf. Accessed February 13, 2007.
18. Rosenberg SD, Goodman LA, Osher FC, et al. Prevalence of HIV, Hepatitis B and Hepatitis C in people with severe mental illness. Am J Pub Health. 2001;91:31-37.
19. Thieda P, Beard S, Richter A, Kane J. An economic review of compliance with medication therapy in the treatment of schizophrenia. Psychiatr Serv. 54:508-516.
20. Oehl M, Hummer M, Fleischhacker WW. Compliance with antipsychotic treatment. Acta Psychiatr Scand. 2000;102 (suppl 407): 83-86.
21. Novak-Grubic V, Tavcar R. Predictors of noncompliance in males with first-episode schizophrenia, schizophreniform and schizoaffective disorder. Eur Psychiatry. 2002;17:148-154.
22. Fenton WS, Blyler CR, Heinssen RK. Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr Bull. 1997;23:637-651.
23. Kane JM. Problems of compliance in the outpatient treatment of schizophrenia. J Clin Psychiatry. 1983;44:3-6.
24. Olfson M, Marcus SC, Wilk J, West JC. Awareness of illness and nonadherence to antipsychotic medications among persons with schizophrenia. Psychiatr Serv. 2006;57:205-211.
25. Jeste SD, Patterson TL, Palmer BW, Dolder CR, Goldman S, Jeste DV. Cognitive predictors of medication adherence among middle-aged and older outpatients with schizophrenia. Schizophr Res. 2003;63:49-58.
26. Liu-Seifert H, Adams DH, Kinon BJ. Discontinuation of treatment of schizophrenia patients is driven by poor symptom response: a pooled post-hoc analysis of four atypical antipsychotic drugs. BMC Medicine. 2005;3:21-30.
27. Lieberman JA, Stroup TS, McEvoy JP et al, for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1222.
28. Byerly M, Fisher R, Rush AJ, Holland R, Varghese F. A comparison on clinical versus electronic monitoring of antipsychotic adherence in schizophrenia [poster]. Presented at the 41st annual meeting of the American College of Neuropsychopharmacology; Dec 8-12, 2002. San Juan, Puerto Rico.
29. Weiden P, Zygmunt A. The road back: working with the severely mentally ill. J Prac Psych Behav Health. 1997;3:106-110.
30. Velligan DI, Lam F, Ereshefsky L, Miller AL. Perspectives on medication adherence and atypical antipsychotic medications. Psychiatr Serv. 2003;54:665-667.
31. Vitolins MZ, Rand CS, Rapp SR, Ribisl PM, Sevick MA. Measuring adherence to behavioral and medical interventions. Contr Clin Trials. 2000;21:188S-194S.
32. Kemp R, Kirov G, Everitt B, Hayward P, David A. Randomised controlled trial of compliance therapy. 18-month follow up. Br J Psychiatry. 1998; 1772:413-419.
33. Hogarty GE. Prevention of relapse in chronic schizophrenia patients. J Clin Psychiatry. 1993;54 (suppl):18-23.
34. Lenroot R, Bustillo JR, Lauriello J, Keith SJ. Integrated treatment of schizophrenia. Psychiatr Serv. 2003;54:1499-1507.
35. Kane JM. Review of treatments that can ameliorate nonadherence in patients with schizophrenia. J Clin Psychiatry. 2006;67 (suppl 5):9-14.
36. Zygmunt A, Olfson M, Boyer CA, Mechanic D. Interventions to improve medication adherence in schizophrenia. Am J Psychiatry. 2002;159:1653-1664.
37. Leucht S, Barnes TRE, Kissling W, Engel RR, Correll C, Kane JM. Relapse prevention in schizophrenia with new generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry. 2003;160:1209-1222.
38. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60:553-564.
39. Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipyschotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ. 2000;321:1371-1376.
40. Dolder CR, Lacro JP, Dunn LB, Jeste DV. Antipsychotic medication adherence: is there a difference between typical and atypical agents? Am J Psychiatry. 2002;159:103-108.
41. McEvoy JP. Risk versus benefits of different types of long-acting injectable antipsychotics. J Clin Psychiatry. 2006;67 (suppl 5):15-18.
42. Parellada E. Clinical experience and management considerations with long-acting risperidone. Curr Med Res Opinion. 2006;22:241-255.
43. Walburn J, Gray R, Gournay K, Quraishi S, David AS. Systematic review of patient and nurse attitudes to depot antipsychotic medication. Br J Psychiatry. 2001;179:300-307.
44. Rosack, J. Drug firms vie to develop more effective antipsychotics. Psychiatr News. 2006;41:25-29.
45. Comparison of Intramuscular Olanzapine Depot to Oral Olanzapine and Low-Dose Depot in Patients With Schizophrenia. U.S. National Institutes of Health website, Clinicaltrials.gov Available at: http://clinicaltrials.gov/show/NCT00088491. Accessed March 6, 2007.
46. Bryant, B. FDA approves medication for schizophrenia treatment. Psychiatr News. 2007;42:30.
47. Immediate Release (IR) to Sustained Release (SR) Switching Study: Study of Switching From IR Seroquel to SR Seroquel in Outpatients With Schizophrenia. U.S. National Institutes of Health website, ClinicalTrials.gov. Available at:
http://clinicaltrials.gov/ct/show/NCT00206128. Accessed March 6, 2007.
48. Treating Schizophrenia, A Quick Reference Guide. American Psychiatric Association web site. Available at: http://www.psych.org/psych_pract/treatg/quick_ref_guide/Schizophrenia_QRG.pdf. Accessed February 13, 2007.