Data on nonadherence include the following: only 45% of patients referred for psychotherapy from a general hospital psychiatry outpatient department showed up for one or more appointments ³; nonattendance rates for patients with scheduled medical appointments are high (19% to 28%); nonadherence with medical recommendations accounts for 5% to 40% of hospital readmissions; medication doses are delayed or omitted by 30% to 50% of patients; patients with chronic diseases take their medications as prescribed only half of the time; 20% of patients stop filling their prescriptions within 1 month of their issue; approximately one-fourth of patients do not inform their physician about having stopped their antidepressant medications⁴; and in a follow-up study of inpatients with suicidal ideation, 52% of patients were nonadherent with use of medications at 12 weeks.⁵

CLINICAL AND ECONOMIC IMPACT OF ADHERENCE AND NONADHERENCE

Clinical outcomes are directly related to treatment adherence, which in turn is related to resource utilization and to the economic burden of mental illness. Adherence with psychiatric treatments is associated with better outcomes, a lower relapse rate, improved adherence with treatment regimens for nonpsychiatric illness, and lower rates of hospitalization.⁶^–⁸ Nonadherence has been associated with a greater risk of psychiatric hospitalization, use of emergency services, arrests, violence, victimizations, lower mental function, lower life satisfaction, and more prevalent use of substances.⁹ Rates of suicidal ideation are significantly greater among patients who are treatment nonadherent following hospitalization.⁵

Given the clinical impact of treatment nonadherence, the economic burden incurred through nonadherence is significant. Data derived from the Global Burden of Disease Study conducted by the World Health Organization, the World Bank, and Harvard University revealed that mental illness, including suicide, accounts for over 15% of the burden of disease in countries such as the United States.¹⁰ Additionally, since major depression is the leading cause of disability worldwide among persons age 5 or older, adherence to treatment can reduce the economic burden of mental illness.

Although little studied, the negative impact (including feeling frustrated, underappreciated, helpless, ineffectual, and “burned out”) of treatment nonadherence on clinicians should also be considered. Treating clinicians are affected when their patients are nonadherent with treatment. Future studies will undoubtedly measure the dispiriting impact when clinicians feel underappreciated and disaffected.

RISK FACTORS AND PREDICTORS OF TREATMENT NONADHERENCE

The reasons for treatment nonadherence are incompletely understood; however, they are undoubtedly multiple, com-plex, and varied. Any effort to understand this multifactorial challenge must include consideration of the elements in Figure 4-1 and Table 4-1.

Figure 4-1 Multifactorial Aspects to an Understanding of Treatment Adherence.

Table 4-1 Factors That Affect Treatment Adherence

• The patient. The patient’s maturity, resilience, and experiences affect adherence. For example, an adolescent may find his or her illness a source of embarrassment, or a middle-aged person may have concerns about how disclosure of an illness might affect his or her work and health insurance premiums. Negative experiences with the health care system can create mental barriers to seeking necessary treatment.

• Co-morbid illnesses. Substance abuse, medical illnesses, and dementia also adversely affect adherence.

• The patient-clinician relationship. A lack of trust in a clinician or the medical system negatively affects adherence.

• Socioeconomic status. Many patients are impoverished and lack health insurance; therefore, they are unable to access timely and adequate care. Even small co-payments can result in medication nonadherence.

• Cultural and religious factors. Cultural beliefs affect all aspects of illness, from patients’ interpretations of symptoms to their beliefs about treatment. For example, a patient may choose prayer as the sole means of healing.

• Treatment. The structure or content of treatment itself may contribute to poor adherence. For example, a patient with paranoid schizophrenia is unlikely to continue in an unstructured psychodynamic therapy group, or a patient who does not have a car and who lives 45 miles away from a health center is unlikely to attend weekly appointments. Medication may directly cause nonadherence if it lacks efficacy or causes intolerable side effects.

Most studies of adherence focus on specific patient populations that are typically categorized by diagnosis.

Affective Disorders

Symptoms of both mania and depression directly affect treatment adherence. In depression, persistent dysphoria and hopelessness may make a patient feel that his or her condition is irreparable and that treatment is futile. Psychomotor retardation, decreased energy, poor concentration, and diminished self-care lead to missed medications and appointments. With hypomania and mania comes an elevated mood and an invigorated energy level that most patients experience as positive; this makes many unmotivated to take medications that slow them down. When insight and judgment are impaired, some patients do not believe that they have an illness that requires treatment.

Studies of treatment adherence in those with depression demonstrate that adherence is highest when the perceived need for medication is greatest and the harmfulness of medication is low.¹¹ In addition, a patient’s skepticism about the efficacy of antidepressant medications predicts early discontinuation of them.¹² Reasons for nonadherence include discomfort about psychiatric diagnoses, denial of the illness, problematic side effects, fears of dependency, and the belief that medications were unhelpful following resolution of the acute phase of illness.¹³

In a study of African American and Caucasian patients with bipolar I disorder, more than half of all patients were either fully or partially nonadherent with medications, 4 months after an episode of acute mania.¹⁴ More than 20% denied having bipolar disorder, and they cited side effects of medications as contributing to their nonadherence. African Americans (more often than Caucasians) cited the fear of addiction and medication as a symbol of illness as reasons for nonadherence, which suggests that different cultures or ethnic groups may differ in their reasons for nonadherence.

Among patients with bipolar disorder, insight into treatment has been positively correlated with medication adherence, and adherence at the time of remission predicted adherence at one year.¹⁵

Anxiety Disorders

Anxiety disorders are associated with hypervigilance regarding both the psychological and physical environment; this affects adherence in a number of ways. Illness may be so severe that a patient is too anxious to leave his or her home to keep appointments. Or it may be difficult to titrate and to taper medications, as a patient with an anxiety disorder may attribute any physical symptom to a medication side effect. With obsessive-compulsive disorder (OCD), counting rituals and fears of contamination may make it impossible for a patient to take medications, or to comply with pharmacological or other therapeutic recommendations.

Psychotic Disorders

Patients with schizophrenia have been intensively studied regarding their adherence to treatment, in large part because of the risks associated with treatment nonadherence. One post-hoc, pooled analysis of 1,627 patients with psychosis treated with atypical antipsychotics reported that 53% of the patients discontinued their medication soon after treatment began because of their perceptions of poor response and worsening symptoms (36%), followed by poor medication tolerability (12%).¹⁶ Other reasons for nonadherence include a lack of insight, positive symptoms, younger age, male gender, a history of substance abuse, unemployment, and low social function.^1,¹⁷

For patients with first-episode psychosis, the likelihood of becoming medication nonadherent is greater in those who believe that treatment is not important or who believe that medications are of low benefit. High levels of positive symptoms at baseline, a lack of insight at baseline, and alcohol or drug misuse at baseline predict nonadherence.^18,¹⁹

Among patients with schizophrenia, patient-reported reasons for nonadherence include feeling stigmatized by taking medications, having adverse drug reactions, being forgetful, and having a lack of social rapport. Other barriers to adherence include use and abuse of drugs and alcohol, a higher Positive and Negative Syndrome Scale score, and a higher mean Barnes Akathisia Score.²⁰ Factors that predict or enhance treatment adherence include feelings that the drug improves the illness, appreciating the time and commitment of staff, developing social support and engagement without a focus on medication, and invoking a partnership model of the therapeutic relationship.^21,²²

Substance Abuse

Active substance abuse also affects treatment adherence. Substances can interfere with medication effects or render them ineffective. A patient who believes that “mixing” substances and medications is dangerous will eschew medications in favor of alcohol or drugs. Drug intoxication and withdrawal affect a patient’s cognitive status (e.g., attention and memory) and affective state, often in a way that decreases adherence. The cost of substances may also directly affect a patients’ ability to make co-payments on medications and for appointments.

STRATEGIES TO ASSESS AND ENHANCE ADHERENCE

Numerous qualitative and quantitative studies have investigated adherence-enhancing strategies. In general, strategies that employ purely educational tactics are less successful, whereas studies with combined educational, behavioral, and affective components have moderate improvements in adherence and concurrent improvements in clinical outcome.^23,²⁴ The majority of studies indicate that a collaborative approach, with both patients and clinicians involved in the decision-making, is most effective.¹⁴

Strategies for the assessment of adherence are largely based on patient self-report. Other methods include reports by significant others, prescription refill records, pill counting, determination of blood levels, and a urine analysis of medication.²⁵ However, all of these assessment tools are flawed. For example, recall bias affects self-report and significant other report. A patient may exaggerate the degree of treatment adherence, and a report by a significant other can be compromised by how closely he or she monitors medication administration. Pill counts are often affected by free samples and by leftover pills from other prescriptions. Blood levels vary significantly from individual to individual; relying on pharmacokinetic profiles does not confirm daily administration.

While numerous strategies to increase adherence have been studied, it is difficult to compare such studies (given the absence of standards for the evaluation of adherence). For example, one study employed self-report and defined adherence as taking medications on 70% of days, whereas another study used prescription records and pill counts and defined adherence more stringently (as 90% adherence to medications and coming to 100% of appointments). Nonetheless, some strategies that enhance adherence include the following: educating patients with a focus on building insight, on the need for treatment and on the benefits of treatment ^16,²⁰; increasing the frequency of visits²⁶; using a depot injection of antipsychotic medications^27,²⁸; limiting the number of daily doses²⁹; choosing medications with tolerable side effects; and using actual risk percentages (in addition to semantic information) when discussing the risks of adverse events.³⁰

PRACTICAL ADVICE FOR TREATING CLINICIANS

Given the relative lack of evidence-based treatment strategies for the assessment and enhancement of treatment adherence, the following section provides practical advice for the treating clinician.

The Initial Adherence Assessment

In judging the treatment compliance status of their patients, clinicians underestimate the frequency and magnitude of nonadherence.³¹ Nonetheless, the clinician is advised to complement evidence-based knowledge with empiric experience.

It is essential to identify an individual’s particular risk factors for nonadherence. For example, one patient may have poor insight, first-episode psychosis, or concurrent substance abuse. This assessment must be done early in the treatment relationship, preferably as a part of the initial consultation and the diagnostic interview. Making adherence a core element of the diagnostic interview accomplishes several goals, including identification of risk factors for nonadherence; elucidation of a patient’s beliefs that will ultimately affect adherence; and determination of adherence-enhancing strategies and the degree of intervention needed.

During a routine evaluation, adherence can be assessed in a variety of ways (Table 4-2).

Table 4-2 Assessment of Adherence

Component of History	Comment/Inquiry
History of present illness	Has nonadherence contributed to the present problem?
Past psychiatric history	Explore and try to understand patients’ beliefs about their mental illness and their perspective on treatment. What are patients’ typical reasons for hospitalization? Is there a history of nonadherence that leads to hospitalization? What was the context of their suicide attempts?
Past medical history	What is their understanding of their diagnosis and treatment? This may suggest how they are likely to approach their psychiatric illness.
Family history	If other family members have been mentally ill, what is the pattern of seeking or not seeking treatment? This can help identify family-held beliefs about mental illness and treatment.
Medications	How do patients feel about their medications? Do they feel the medications are necessary? Are they fearful of medication side effects and adverse events? What will they do if they experience a side effect or an adverse event?
Substance abuse	Is the patient actively using alcohol or illicit drugs?
Social history	Inquire about cultural, social, religious, or family-held beliefs that will affect the treatment. What is the patient’s living situation? Is the patient living in a safe environment with supports nearby? What kind of insurance and income does the patient have? How much can the patient afford, or is able to spend, per month on treatment? Ask what the patient feels about the clinician. Does the patient need “deputies” (family/friends) to partner in treatment protocols?
Mental status examination	Are there cognitive impairments (of attention or memory)? How is the patient’s insight and judgment?

Establishing the Treatment Plan

Once an illness has been diagnosed, the clinician should present treatment options in an open, enthusiastic, and optimistic fashion. With the exception of a patient who is in danger or who meets commitment criteria, the clinician sends a powerful message by including the possibility that “no treatment” is an acceptable choice. The patient is not being asked to surrender autonomy, control, or free will. Thus, the patient is alerted that the authority to decide largely resides not with the clinician, but with the patient.

It is also helpful to inform the patient that treatments can be discontinued if they do not help, if they have intolerable side effects, or even if they are helpful and have no side effects. Paradoxically, the best way for some patients to decide on, and to commit to, a treatment course is to empower them with a sense of agency and the ability to otherwise say “no.”

Once mutually acceptable goals are decided on, they should be made explicit. Clear and open communication of recommended goals and adherence expectations is crucial. Providing both verbal and written instructions helps, because many patients do not recall verbal instructions even when delivered in an optimal fashion.

The concept of treatment adherence should be discussed in advance of treatment. With such an approach, a patient will feel more comfortable reporting his or her difficulties with adherence. This strategy removes the negative, demeaning, and at times scolding tone from the subject of nonadherence, and prepares the patient for ongoing assessment.

ONGOING ASSESSMENT

Once adherence has been assessed in the initial consultation with the patient, adherence should be assessed routinely at subsequent visits. These follow-up assessments will be guided by the initial evaluation, with more or less attention paid depending on the patient’s profile. For example, if a patient has few risk factors and has a demonstrated history of being conscientious and adherent with treatment, less time will be spent on the issue.

In general, questions should be asked in an empathic, nonthreatening way with a tone of genuine curiosity. For example, starting with open-ended questions (e.g., “How is it going with the medication?”) is more likely to be positively received than starting with closed-ended ones (e.g., “Do you take your medications as prescribed?”). After beginning with an open-ended question, asking specifically about which medications patients are taking and how they are taking them allows the clinician to assess patients’ understanding of the treatment recommendations. Ask, “Let me confirm that my records are accurate. What medications are you taking?” To specifically address adherence, disarming inquiries (e.g., “Sometimes it is difficult to remember to take medication. Have you ever noticed that you occasionally forget to take your pills?”) are less likely to be experienced as shaming or punitive. The goal is to foster a treatment relationship where patients feel comfortable truthfully reporting their behaviors.

THE DISCOVERY OF NONADHERENCE

During the course of treatment the majority of patients have issues with nonadherence. Effort should be invested in trying to determine the specific behavior patterns involved in medication nonadherence. This allows for the information to be incorporated into the individual’s treatment plan. Table 4-3 outlines examples of nonadherence, what questions should be raised, and what interventions may help.

Table 4-3 Examples of Nonadherence

Examples of Nonadherence	Questions to Raise	Possible Interventions
Missing a single dose per week.	Should the dose be skipped or the next dose doubled?	Use pill boxes or medication reminders.
Taking a lower dose than recommended.	Are there bothersome side effects at the higher dose? Has the desired effect been achieved at this lower dose, or is the patient worried about dependence on the medication and tries to minimize “need?”

Adjust the dose or switch the medication to address the side effects.

Educate about the illness and treatment.

Taking medications sporadically. Does the patient have an insufficient understanding or acceptance of the illness being treated, or the treatment’s mechanism of action?

Educate about the illness and treatment.

Enlist a partner to help with medication administration.

Use medication reminders.

Taking pills every other day.

Among many possibilities, this may indicate an inability to afford medications. Is there a cheaper alternative?

Are samples available? Is the patient eligible for more services or greater services?

Switch to a cheaper alternative.

Refer to a social worker or to financial services for help.

Taking more medication than prescribed. Are symptoms adequately managed? Are treatment recommendations understood? Is the patient is misusing (e.g., selling drugs on the street) or abusing the medication?

Educate about the illness and treatment.

Have the patient keep a medication diary.

Enlist a partner to monitor dosing.

Once discovered, the solution may be simple. Often an empathic discussion enables the patient to feel heard and allows a reestablishment of adherence. However, some patients will continue to have significant barriers to adherence and will be difficult to manage (see Table 4-4 for strategies to enhance adherence).

Table 4-4 Strategies to Enhance Adherence

• Keep a daily medication diary.

• Use a pill box.

• Enlist a family member or friend to attend sessions and to help administer medications.

• Increase the frequency of appointments.

• Use PACT teams.

• Review prescriptions and refill records.

• Provide medication reminders. Examples include placing a sticker on the bathroom mirror that reminds the patient to take his or her pills, or statements such as “When I drink my orange juice, I take my meds,” or “When I feed the dog, I take my meds.”