Determinants of Medication Compliance in
Schizophrenia: Empirical and Clinical Findings
by Wayne S. Fenton, Crystal R. Blyler, and Robert K. Heinssen
Abstract
Advances in psychopharmacology have produced
medications with substantial efficacy in the treatment
of positive and negative symptoms of schizophrenia
and the prevention of relapse or symptom exacerba-
tion after an acute episode. In the clinical setting, the
individual patient's acceptance or rejection of pre-
scribed pharmacological regimens is often the single
greatest determinant of these treatments' effectiveness.
For this reason, an understanding of factors that
impede and promote patient collaboration with pre-
scribed acute and maintenance treatment should
inform both pharmacological and psychosocial treat-
ment planning. We review the substantive literature on
medication adherence in schizophrenia and describe a
modified health belief model within which empirical
findings can be understood. In addition to factors
intrinsic to schizophrenia psychopathology, medica-
tion-related factors, available social support, substance
abuse comorbidity, and the quality of the therapeutic
alliance each affect adherence and offer potential
points of intervention to improve the likelihood of col-
laboration. Because noncompliance as a clinical prob-
lem is multidetermined, an individualized approach to
assessment and treatment, which is often best devel-
oped in the context of an ongoing physician-patient
relationship, is optimal. The differential diagnosis of
noncompliance should lead to interventions that target
specific causal factors thought to be operative in the
individual patient
Schizophrenia Bulletin, 23(4):637-651,1997.
Although advances in psychopharmacology have vastly
improved the range of treatment options for schizophre-
nia, outcome variance explained by the choice of medica-
tion is likely small compared with that accounted for by
how and if the patient takes what is prescribed.
637
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Compliance is defined as "the extent to which a person's
behavior coincides with medical or health advice"
(Haynes 1979, p. 2). The term has been criticized for over
20 years as a reflection of an outmoded and paternalistic
conception of the physician-patient relationship (Stimson
1974; Holm 1993). Nonetheless, compliance is a word
often used in clinical settings where for clinicians,
patients, and families it remains one of the most vexing
challenges in psychopharmacology.
Compliance is difficult to quantify and study for sev-
eral reasons. Clinicians' ability to identify which patients
do not take medicine is limited (McClellan and Cowan
1970; Norell 1981). Other measures of adherence include
patient or relative self-report, prescription renewals and
pill counts, saliva and urine screens, or steady-state serum
determinations. Concordance across different measures of
compliance is often low, although self-reported noncom-
pliance is corroborated more often than is self-reported
adherence (Rickels and Briscoe 1970; Gordis 1976;
Boczkowski et al. 1985). Measurement is further compli-
cated because compliance is rarely an all-or-none phe-
nomenon, but may include errors of omission, mistakes in
dosage and timing, and taking medications that are not
prescribed (Blackwell 1976).
A 1986 review of 26 studies using a variety of defini-
tions and detection methods to assess medication use
among outpatients with schizophrenia reported a median
default rate of 41 percent (range, 10% to 76%) with oral
medications and 25 percent (range, 14% to 36%) with
depot injections over time periods up to 1 year (Young et
al. 1986). Fifteen subsequent studies using varying defini-
tions of noncompliance and many mixing patients taking
oral and depot medications reported a median 1-month to
2-year noncompliance rate of 55 percent (range, 24% to
88%) (Hogan et al. 1983; Ayers et al. 1984; Carman et al.
Reprint requests should be sent to Dr. W.S. Fenlon, Chestnut
Lodge Hospital, 500 West Montgomery Ave., Rockville, MD 20850.
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
1984; Boczkowski et al. 1985; Gaebel and Pietzcker
1985; Munetz and Roth 1985; Frank and Gunderson
1990; Kelly and Scott 1990; Pristach and Smith 1990;
Buchanan 1992; Adams and Howe 1993; Parker and
Hadzi-Pavlovic 1995; Razali and Yahya 1995;
Macpherson et al. 1996a, 19966; Owen et al. 1996).
The belief that noncompliance is a direct result of dis-
ease processes in schizophrenia dominates the clinical per-
ception of noncompliance for these patients. Reported
noncompliance rates for schizophrenia, however, are in the
middle range of those reported for other common medical
disorders. Medication noncompliance rates of 55 to 71
percent have been reported for patients with arthritis (Berg
et al. 1993), 54 to 82 percent for patients with seizure dis-
orders (Shope 1988), 20 to 57 percent for patients with
bipolar affective disorder (Elixhauser et al. 1990), and 19
to 80 percent for patients with diabetes (Friedman 1988).
Half of patients with hypertension drop out of care within
1 year, and only two-thirds of those who remain take ade-
quate medication (Eraker et al. 1984).
A review of compliance with maintenance regi-
mens—rheumatic fever prophylaxis, glaucoma, isoniazid
for tuberculosis, and self-administered insulin—found a
mean noncompliance rate for these long-term illnesses of
54 percent (Sacket 1976). Compliance is lowest when the
condition is prolonged, treatment is prophylactic or sup-
pressive, and the consequences of stopping treatment are
delayed. In disorders sharing these features, adherence
declines with time (Blackwell 1973).
Through 1994 at least 14,000 English-language arti-
cles have addressed compliance-related issues in medical
care (Donovan 1995). Recent reviews converge in con-
cluding that noncompliance is far better documented than
understood and that a focus on the patient's decisionmak-
ing process is often a key missing ingredient in extant
research (Trostle 1988; Morris and Schulz 1993; Donovan
1995). Health belief (Becker and Maiman 1975; Kirscht
and Rosenstock 1979) or health decision (Eraker et al.
1984) models that emphasize a patient's subjective assess-
ment of the risks and benefits of treatment in the context
of personal values and goals are advanced as best inte-
grating available data on compliance research. Although
these models may require modification in disorders like
schizophrenia in which cognition and motivation are
affected directly by illness processes (Babiker 1986;
Bebbington 1995), they do facilitate a shift in perspective:
rather than viewing noncompliance as the patient's prob-
lem, it is redefined as an indication that the therapeutic
regimen is not assisting the individual patient to achieve
his or her goals.
In this article, we review the substantive literature on
medication compliance in schizophrenia with an emphasis
638
W.S. Fenton et al.
on empirical studies that (1) identify current or predictive
correlates of adherence and noncompliance and (2) assess
interventions targeted to improve adherence. These find-
ings provide an empirical basis for the differential diagno-
sis and understanding of noncompliance within a modi-
fied health belief or health decision model.
Methods
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This review is limited to studies of medication adherence
in schizophrenia: studies focused on psychiatric patients
without specifying diagnosis and those focused on adher-
ence to other aspects of treatment, such as aftercare
appointments, were not included. Clinical correlates of
compliance that have been studied include patient socio-
demographic features; illness characteristics, including
comorbidity and insight; medication features, including
side effects and route and frequency of administration;
family and social support; and treatment system charac-
teristics, including quality of the physician-patient rela-
tionship. Interventions studied include reinforcement,
education, skills training, and memory enhancement.
Potentially relevant English-language articles were
identified from the English language psychiatric and psy-
chological literature with the aid of computer searches
using such key words as compliance, adherence, psy-
chopharmacology, and schizophrenia. Bibliographies
from primary sources and reviews were then reviewed to
identify earlier relevant works. In addition to empirical
studies (those including some measure of compliance or
intention to comply), clinical reports were included for
review if they presented useful perspectives on social or
psychodynamic issues that would generally be inaccessi-
ble to empirical study. In selecting studies for review, reli-
ability testing and corroboration of patient self-report
were not required criteria; had they been, very few studies
would be left for review.
Correlates of Adherence and
Noncompliance
Patient-Related Factors.
Patient demographic characteristics. As in other
medical disorders, demographic variables are not consist-
ently associated with compliance in schizophrenia. Eleven
studies assessed the relationship between one or more
patient demographic characteristics and compliance (Leff
and Wing 1971; Hoffman et al. 1974; Soskis 1978; Hogan
et al. 1983; Pan and Tantam 1989; Buchanan 1992;
Draine and Solomon 1994; Sellwood and Tamer 1994;
Parker and Hadzi-Pavlovic 1995; Razali and Yahya 1995;
Determinants of Medication Compliance
Owen et al. 1996). Eight of ten found no association with
age, six of nine found no association with gender, four of
five found no association with ethnicity, and four of four
no association with education or income. In contrast, two
studies found noncompliance associated with youth, three
with male gender, one with single marital status, and one
with African-Caribbean ethnicity.
Illness Characteristics.
Illness history. Studies have failed to reveal an
association between compliance and age at onset and
duration of illness (Buchanan 1992), age at first hospital-
ization (McEvoy et al. 1984), and premorbid functioning
(Adams and Howe 1993). Data relating the number of
prior hospitalizations to compliance are contradictory:
Three studies indicated more prior hospitalizations
(Nelson et al. 1975; Pan and Tantam 1989; Sellwood and
Tarrier 1994); two studies, fewer prior hospitalizations
(Reilly et al. 1967; McEvoy et al. 1984); and one study,
no difference in prior hospitalizations (Hogan et al. 1983)
among patients judged to be noncompliant at an index
assessment. Although these data do not strongly support
the contention that patients learn to adhere to medications
after repeated relapses, hospitalization may improve com-
pliance in the period immediately after discharge: Two
studies assessing compliance among patients before and
after an index admission showed significant decreases in
noncompliance rates at followup (Christensen 1974;
Owen et al. 1996).
The association between compliance and future hos-
pitalization risk is far less equivocal: Seven studies indi-
cated that patients rated as noncompliant have a 6-month
to 2-year risk of relapse that is an average of 3.7 times
greater than patients rated as compliant (Leff and Wing
1971; Linn et al. 1982; Gaebel and Pietzcker 1985;
Munetz and Roth 1985; Kashner et al. 1991; McFarlane et
al. 1995; Parker and Hadzi-Pavlovic 1995). Two addi-
tional studies did not allow calculation of relative risk, but
identified irregular medication adherence as a significant
predictor of relapse (Falloon et al. 1978; Verghese et al.
1989). The magnitude of elevated risk associated with
noncompliance seems comparable with that conveyed by
randomization to placebo in maintenance trials
(Baldessarini et al. 1990). Consistent with these data is
the finding of recent medication noncompliance in the his-
tory of 38 to 68 percent of relapsed patients (Reilly et al.
1967; Christensen 1974; Herz and Melville 1980; del
Campo et al. 1983; Parker and Hadzi-Pavlovic 1995;
Owen et al. 1996). Because relapse typically occurs
weeks to months after the discontinuation of medication,
however, patients only rarely attribute it to noncompliance
(Chien 1975; Herz and Melville 1980).
639
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
Although the association between noncompliance and
relapse is robust, causality is likely bidirectional:
Crawford and Forrest (1974) found erratic pill-taking
associated with worsening symptoms for patients taking
placebo tablets while maintained on depot phenothiazine
injections. Likewise, in a study that randomized schizo-
phrenia patients to drug or placebo groups 2 months after
hospital discharge, Hogarty et al. (1973) found that about
50 percent of the relapsers from either group were non-
compliant compared with only 15 percent of patients from
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either group who had not relapsed within 6 months.
Illness severity and subtype. Both inpatient drug
refusal and outpatient noncompliance are consistently asso-
ciated with more severe ratings of psychopathology. Eight
studies assessed the relationship between symptom severity
or global functioning and inpatient medication refusal,
future outpatient medication compliance, or attitude toward
medication. Marder et al. (1983) found more severe psy-
chopathology, including disorganization, hostility, and sus-
piciousness, associated with inpatient drug refusal. Five
investigations reported a positive association between
symptom severity at or after discharge and poor outpatient
compliance (Renton et al. 1963; Van Putten et al. 1976;
Kelly et al. 1987; Pan and Tantam 1989) or poor attitude
toward compliance (Draine and Solomon 1994). One study
found only the Brief Psychiatric Rating Scale (Overall and
Gorham 1962) grandiosity score to be associated with poor
compliance (Bartko et al. 1988), and one study reported no
relationship between symptom severity at discharge and
future outpatient compliance (Ayers et al. 1984).
Seven studies investigating the relationship between
paranoid suspiciousness, persecutory delusions, or schizo-
phrenia subtype and medication adherence yielded mixed
results. Two studies reported that noncompliance preced-
ing a hospitalization is more common among patients
with paranoid schizophrenia subtype (Reilly et al. 1967;
Pristach and Smith 1990). An additional investigation
reported greater noncompliance as measured with urine
screens among inpatients with paranoid delusions (Wilson
and Enoch 1967). In contrast, one investigation found no
association between paranoid schizophrenia subtype and
the expressed willingness to take medications (Soskis
1978), one study found no association between subtype
and self-reported outpatient compliance (Hoffman et al.
1974), and another study reported no association between
paranoid ratings and missed depot appointments (Bartko
et al. 1988). In a study that may reconcile these discrepant
findings, Van Putten et al. (1976) found no association
between compliance and paranoid schizophrenia subtype,
but noted that 85 percent of paranoid schizophrenia
patients with delusions of persecution or influence habitu-
ally complied with medications, whereas 92 percent of
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
paranoid patients with grandiose delusions habitually
refused medications.
Cognition/memory. Neither overall intelligence
(Adams and Howe 1993), discharge Mini-Mental State
Exam score (Folstein et al. 1975; Buchanan 1992), nor
Neurobehavioral Cognitive Status Exam results (Northern
California Neurobehavioral Group 1988; Cuffel et al.
1996) has been associated with compliance. The potential
association between specific neuropsychological deficits
and compliance has not been explored. A significant per-
centage of outpatients, however, attribute noncompliance
to forgetting (Hoffman et al. 1974) or indicate that they
believe reminders to take their medicine would be helpful
(Serban and Thomas 1974).
Insight. The concept of insight has undergone con-
siderable elaboration in recent years, coincident with a
shift in explanatory focus from psychological to neurolog-
ically based formulations of self-awareness deficits
(Amador et al. 1993, 1994). A review emphasized the
multidimensional nature of insight and its relative inde-
pendence from symptom severity (Amador et al. 1991).
Using a variety of self-report measures of illness aware-
ness, nine studies assessed the relationship between
insight and adherence with prescribed pharmacological
regimens. Poor insight was consistently associated with
noncompliance. Three studies reported an association
between poor insight assessed at admission or during hos-
pitalization and medication noncompliance among inpa-
tients (Lin et al. 1979; Marder et al. 1983; McEvoy et al.
1989). Four studies reported an association between a
lack of insight at hospital admission, discharge, or post-
discharge assessment and poor outpatient compliance
(Nelson et al. 1975; Van Putten et al. 1976; Bartko et al.
1988; Macpherson et al. 1996a, 1996b). Perhaps reflect-
ing the fact that both insight and compliance can fluctuate
with clinical state, one study found that an awareness of
illness and medication compliance were related only
when measured concurrently (Cuffel et al. 1996). One
study reported an association between involuntary admis-
sion status (an indirect index of insight) and poor 2-year
postdischarge medication compliance, but no association
between ratings from attitude questionnaires and compli-
ance (Buchanan 1992). Although a statistical relationship
between insight and adherence has been replicated in a
variety of settings, several investigators noted that a siz-
able subgroup of patients who do not believe they are ill
or require medication nonetheless are regularly compliant.
Other Health Beliefs. Except for the consistent rela-
tionship between awareness of the presence of a psychi-
atric illness and medication compliance, the association
between specific health beliefs and medication compli-
ance among patients with schizophrenia is more ambigu-
640
W.S. Fenton et al.
ous. Kelly et al. (1987) found that greater perceived sus-
ceptibility to rehospitalization was associated with
increased compliance among a population made up
largely of patients with schizophrenia. Hogan et al. (1983)
also found that schizophrenia outpatients rated by their
therapists as generally compliant with medication were
more likely than noncompliant patients to believe that
staying on medication would prevent relapse.
Noncompliant patients were more likely to believe that
medication should only be taken when one feels sick, that
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it would harm them physically, and that it is unnatural to
take medication. In contrast, Pan and Tantam (1989)
found no difference in beliefs about the possibility of
relapse if maintenance treatment were stopped between
regular attenders and outpatients who had missed two or
more appointments over 12 months at a depot neuroleptic
clinic. Buchanan (1992) found no association between
compliance and self-appraisal of the likelihood of becom-
ing ill again. Serban and Thomas (1974) found that most
hospitalized schizophrenia patients who reported that they
did not use prescribed medications between hospitaliza-
tions failed to do so despite their expressed belief that reg-
ular medication would be helpful. It should be noted that
this disjunction between health beliefs and behaviors is by
no means unique to schizophrenia.
Subjective Weil-Being. Perceived immediate benefit
and a subjective sense of well-being derived from medica-
tions seem to be associated more consistently with com-
pliance than are expressed beliefs concerning susceptibil-
ity to relapse. Patients who do not comply are likely to
feel that their medications do not help, are of no benefit,
or are ineffective and unnecessary (Nelson et al. 1975;
Soskis 1978; Lin et al. 1979; Herz and Melville 1980).
Patients who consent to and comply with neuroleptics are
more likely to report feeling better (Marder et al. 1983),
getting help (Buchanan 1992), and endorsing a direct
(Hogan et al. 1983; Razali and Yahya 1995) or indirect
(Adams and Howe 1993) beneficial effect of medication
on their well-being. After resolution of an acute episode,
however, some patients stop medications because they
feel well and therefore no longer in need of treatment
(Reilly et al. 1967; Hoffman et al. 1974). As described
below in the section on side effects, to the extent that sub-
jective well-being is associated with initial and long-term
adherence, subjective discomfort is associated with med-
ication refusal or noncompliance.
Co-Occurring Alcohol and Drug Use. Comorbid alco-
hol or other substance abuse is common among individu-
als with schizophrenia (Regier et al. 1990) and is a strong
predictor of neuroleptic noncompliance. Drake et al.
(1989) studied 115 outpatients with schizophrenia and
Determinants of Medication Compliance
found that 45 percent were occasional and 23 percent
heavy alcohol users. More severe alcohol use and abuse
were associated with medication noncompliance, psy-
chosocial problems (including homelessness), disorga-
nized and hostile behavior, medical problems, and fre-
quent rehospitalizations over a 1-year followup. In a
second group of outpatients, Kashner et al. (1991) found
that substance-abusing patients with schizophrenia were
13 times more likely than non-substance-abusing patients
to be noncompliant with antipsychotic medication. In a
group of schizophrenia inpatients with a rate of self-
reported noncompliance (72%) before admission that was
too high to find an overall association with their substance
abuse history, Pristach and Smith (1990) reported that 62
percent stopped taking medications while drinking.
Patients often cited their physicians' advice not to mix
medicine and alcohol as a reason for intermittent noncom-
pliance. Among inpatients assessed for substance abuse
and followed after discharge for 6 months, Owen et al.
(1996) reported that substance abuse in the 30 days before
index assessment was the strongest predictor of noncom-
pliance at followup assessment. Substance abuse
increased the risk of noncompliance eightfold and seemed
to interact with decreased outpatient contact to result in
poor clinical outcome. Of potential relevance to compli-
ance are reports that tardive dyskinesia and akathisia may
be more prevalent among patients who abuse alcohol
(Lutz 1976; Olivera et al. 1990; Dixon et al. 1992).
Medication-Related Factors.
Side effects. Neuroleptic side effects that may be
particularly unpleasant include sedation, anticholinergic
effects, cognitive blunting, depression, sexual dysfunc-
tion, and extrapyramidal syndromes—dystonia, akinesia,
Parkinsonian effects, akathisia, and tardive dyskinesia
(Weiden et al. 1986). Between one-quarter and two-thirds
of patients who unilaterally discontinue prescribed neu-
roleptic medicines cite side effects as their primary reason
for noncompliance (Renton et al. 1963; Reilly et al. 1967;
Hoffman et al. 1974; del Campo et al. 1983). Among out-
patients, both self (Falloon et al. 1978; Hogan et al. 1983;
Kelly et al. 1987) and physician (Nelson et al. 1975; Pan
and Tantam 1989; Buchanan 1992) ratings of side effects
are associated with or predictive of noncompliance.
Although side effects are consistently associated with
poor maintenance adherence among outpatients, inpa-
tients may not reliably report a history of side effects.
Pristach and Smith (1990) did not find self-reported his-
tory of neuroleptic side effects to be related to noncompli-
ance among inpatients before admission. Marder et al.
(1983) found no overall association between the self-
reported history of side effects and inpatient drug refusal:
641
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
Inpatient drug refusers were described as including a sub-
group of patients with severe side effects and a second
group in whom illness-related factors, such as denial, hos-
tility, and grandiosity, were major determinants of refusal.
Fleischhacker et al. (1994) attributed their failure to find
an association between side effects during the first 4
weeks of treatment and subsequent compliance among
patients on haloperidol and clozapine to an aggressive
approach to detect and treat adverse effects by changing
medications, lowering dosages, and prescribing concomi-
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tant medications.
In an important series of studies based on the obser-
vation that normal volunteers differed in their reactions to
a test dose of phenothiazines (Heninger et al. 1965), Van
Putten et al. (1974) described a subgroup of schizophrenia
patients who experienced a dysphoric response to a vari-
ety of conventional neuroleptics available at that time.
These patients felt miserable on neuroleptics, complained
about drug effects, and pleaded to have their medications
stopped or dosages reduced. In contrast, nondysphoric
responders reported that they "liked" medications and
"felt better" on them. Akathisia was found to be the most
significant factor underlying a dysphoric neuroleptic
response and was highly associated with medication
refusal or outpatient noncompliance or both. In some
patients, akathisia was experienced as a catastrophic sense
of terror and impending annihilation that was phenomeno-
logically similar to an exacerbation of psychosis (Van
Putten 1974). More frequently, patients reported a subtle
inner restlessness, anxiety, and inability to feel comfort-
able in any position, a phenomenon that was incompatible
with any productive activities and could not be tolerated
for any period of time. However, much of the akathisia
responsible for outpatient noncompliance was described
as sufficiently mild as to remain undetected by an
observer who lacked a close and continuous relationship
with the patient (Van Putten 1974). Two subsequent stud-
ies replicated the finding of a significant association
between an initial dysphoric response to a test dose of
thiothixene or haloperidol, akathisia, and subsequent med-
ication noncompliance (Van Putten et al. 1981, 1984). In a
third independent sample, a greater proportion of patients
with a dysphoric than a syntonic response to a chlor-
promazine test dose were noncompliant over a 9-month
followup period (Ayers et al. 1984). Together, these
results point to a strong association among a dysphoric
response to medication, akathisia, and medication refusal
or noncompliance or both.
Dosage and agent Higher (Pan and Tantam 1989),
lower (Nelson et al. 1975), and no different (Hogan et al.
1983) neuroleptic dosages have been reported among out-
patients rated as less compliant with maintenance treat-
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
ment. A curvilinear relationship between dosage and com-
pliance, with very low doses associated with lack of effi-
cacy and very high doses with excessive side effects,
seems likely. However, few data are available that assess
differential compliance rates to different agents. Carman
et al. (1984) found noncompliance rates as measured by
serum and urine assays to be significantly higher among
patients taking high-potency compared with low-potency
agents (65% vs. 13%). Among outpatients receiving phe-
nothiazine injections, Carney and Sheffield (1976)
reported a higher noncompliance rate (43%) among those
receiving fluphenazine enanthate than among patients
receiving fluphenazine decanoate or flupenthixol
decanoate (23%). The difference was attributed to a
higher rate of extrapyramidal side effects among those
prescribed fluphenazine enanthate. We were unable to
locate any randomized controlled study assessing compli-
ance with different agents.
The correlation between greater psychopathology at
index assessment and noncompliance likely reflects an
association between the efficacy of prescribed treatment
and compliance. The finding that noncompliance rates for
chlorpromazine were substantially higher than those for
imipramine among depressed (70% vs. 44%) but not
schizophrenia (32% vs. 25%) outpatients provides addi-
tional support for a relationship between efficacy and
compliance (Willcox et al. 1965).
Route. A 1986 review of 26 studies reporting non-
compliance rates indicated a lower mean default rate
(25%) in studies of depot compared with oral (41%) neu-
roleptics (Young et al. 1986). Based on the hypothesized
advantage of depot preparations in improving compliance,
six controlled studies comparing relapse rates among
patients randomized to oral versus depot neuroleptics
were reviewed more recently (Davis et al. 1993). These
studies suggest a modest advantage for the depot route in
reducing relapse rates that may be greater in nonresearch
samples (Dixon et al. 1995). Changing patients to depot
preparations does not, however, seem to be an effective
global strategy to eliminate noncompliance: Van Putten et
al. (1976) found that 83 percent of habitually noncompli-
ant schizophrenia outpatients who were switched to
decanoate did not return with any regularity for bimonthly
injections. Likewise, Falloon et al. (1978) reported that 73
percent of schizophrenia patients returned to the commu-
nity after hospital treatment who were irregular in their
tablet taking also missed at least one injection in 12
months. Buchanan (1992) found no difference in compli-
ance rates over 2 years postdischarge for patients taking
oral and depot neuroleptics.
Although long-acting phenothiazine injections do not
ensure medication compliance because they must be
642
W.S. Fenton et al.
administered by a treatment provider, noncompliance with
this type of treatment can be detected quickly and with
certainty. Such noncompliance allows an assessment of
clinical impact for the individual patient and may trigger
assertive interventions. For this reason, the major advan-
tage of depot neuroleptics may be the ability to eliminate
covert noncompliance as a cause of clinical decompensa-
tion (Schooler and Keith 1993).
Complexity of regimen. Although the complexity
of a medication regimen is associated with compliance
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across a broad range of medical disorders (Haynes 1976),
only one (Razali and Yahya 1995) of four empirical stud-
ies that focused exclusively on schizophrenia identified a
statistically significant association between complexity of
regimen and compliance. Hoffman et al. (1974), Hogan et
al. (1983), and Buchanan (1992) found no such associa-
tion.
Environmental Factors.
Family and social support. Social support, in gen-
eral, and the availability of family or friends to assist or
supervise medications, in particular, are consistently asso-
ciated with outpatient adherence. Eight studies indicated
that patients living with relatives or whose medications
are supervised by relatives are more likely than those
lacking such support to maintain adherence to prescribed
antipsychotic medication (Parkes et al. 1962; Renton et al.
1963; Reilly et al. 1967; Hoffman et al. 1974; Nelson et
al. 1975; Van Putten et al. 1976; Buchanan 1992; Razali
and Yahya 1995). An additional study found a nonsignifi-
cant association between stability of living arrangements
and compliance (Owen et al. 1996). Causality is likely
bidirectional in determining the association between fam-
ily or social support and compliance. In a group of mostly
schizophrenia outpatients, Draine and Solomon (1994)
found that better social functioning and more extensive
social networks were related to positive attitudes toward
medication compliance. In addition, negative or stressful
social interactions may counteract the positive effect on
compliance of living with others (Reilly et al. 1967).
Practical barriers. In one investigation, 28 percent
of patients who had reduced or stopped taking medica-
tions before an inpatient admission cited financial burden
as the principal reason for discontinuation (Reilly et al.
1967). Sullivan et al. (1995) found that family informants
reported that 7 percent of previously hospitalized patients
lacked money for medication and 19 percent had missed
medication because of a lack of transportation to the phar-
macy. Practical barriers or lack of access to care may be
particularly salient for homeless individuals, who are
often viewed as noncompliant (Interagency Council on
the Homeless 1992).
Determinants of Medication Compliance
Physician-patient relationship. The clinical sup-
position that a positive therapeutic alliance facilitates
medication compliance finds empirical support in three
studies. Nelson et al. (1975) found that the single best pre-
dictor of medication compliance among discharged schiz-
ophrenia patients was the patient's perception of the
physician's interest in him or her as a person. Marder et
al. (1983) found that, compared with patients who refused
medications, schizophrenia inpatients who consented to
neuroleptic treatment rated themselves as more satisfied
with ward staff and their own physicians and felt that their
physicians understood them, had their best interests in
mind, and had explained the reasons for taking medica-
tions and their potential side effects. Illness severity or
treatment response may partially explain these associa-
tions. Frank and Gunderson (1990) found that 74 percent
of patients with fair or poor therapeutic alliances (rated at
6 months) failed to comply fully with prescribed medica-
tion regimens during the next year and a half. In contrast,
only 26 percent of schizophrenia patients with a good
alliance with their therapist (rated at 6 months) were non-
compliant. In this study, the association between therapeu-
tic alliance and medication compliance was independent
of the patient's severity of psychopathology, type or
dosage of medication, or inpatient/outpatient status.
Attitude of staff. Irwin et al. (1971) reported a
nonsignificantly higher noncompliance rate as determined
by urine screen (39% vs. 25%) among outpatients treated
by physicians who viewed medication as having question-
able value, compared with patients of physicians who
viewed medication as an essential aspect of treatment.
Interventions. Psychosocial treatments for schizophre-
nia often include promotion of medication compliance as
an implicit or explicit goal. Data bearing on the efficacy of
individual psychotherapy, social skills training, case man-
agement, family psychoeducation, and assertive commu-
nity treatment programs have been reviewed recently
(Lehman et al. 1995). Here we review a more narrow set
of interventions that specifically target medication compli-
ance: reinforcement, education, and memory enhancement.
Reinforcement. When characterized by institu-
tional surroundings, long waits, and impersonal or
bureaucratic treatment, mental health clinics can be
uninviting in a way that discourages attendance and com-
pliance (Talbott et al. 1986; Chen 1991; Dencker and
Liberman 1995). Making the setting more appealing by
providing reinforcement has improved adherence.
Liberman and Davis (1975) designed a program to rein-
force compliance by serving lunch at a monthly medica-
tion clinic and allowing patients who tested positive for
neuroleptics to select among several rewards, including
643
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
toiletries and personal items. Compared with patients ran-
domly assigned to a control medication group, the experi-
mental group showed better attendance, higher compli-
ance levels, and more positive attitudes toward
medication. Cassino et al. (1987) successfully increased
attendance among schizophrenia patients at a decanoate
clinic from 58 to 76 percent over a 17-week period by
offering brunch at morning sessions of the clinic. Offering
lunch-type food at an afternoon session, however, had lit-
tle effect on attendance.
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Education. Circumscribed educational interven-
tions aimed at providing information about schizophrenia
and its treatment have been ineffective at increasing com-
pliance. Boczkowski et al. (1985) found no difference in
compliance between an experimental group of outpatients
provided a 30- to 50-minute information session and a
control group for whom no specific attempt to focus on
medication or diagnosis was made. Macpherson et al.
(1996a) randomly assigned patients to one of three
groups: one receiving three educational sessions at
weekly intervals, one receiving a single educational ses-
sion, and one having no educational intervention.
Although participants in the group receiving the three ses-
sions did have fewer knowledge errors at 1-month fol-
lowup, their scores on a medication compliance scale did
not change. Similarly, Brown et al. (1987) documented an
increase in knowledge among schizophrenia outpatients
who received two instructional sessions 1 month apart,
but noted that instruction did not affect independently
rated compliance.
Skills training in areas related to medication seems to
be more effective than providing factual information.
Eckman et al. (1990) designed a medication management
module that trained patients in four skill areas: obtaining
information about medications, administering medication
and evaluating its benefits, identifying side effects, and
negotiating medication with health care providers. The
module was delivered to patients in a variety of settings
for 3 hours per week over 15 to 20 weeks. Upon comple-
tion of the module and over a 3-month followup, knowl-
edge about medication, skill utilization, and compliance
improved over baseline. Compliance assessed by the
patients' psychiatrists increased from 67 percent before
training to 82 percent after training, and compliance
assessed by designated caregivers increased from 60 to 79
percent.
Based on a randomized trial of individual and family
education, Kelly and Scott (1990) described two circum-
scribed interventions that each reduced noncompliance at
6-month followup. The individual intervention was deliv-
ered by a health educator before the first two postdis-
charge aftercare appointments and focused on increasing
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
the patient's ability to communicate with providers by
expressing concerns and asking questions. The family
intervention included up to three home visits that focused
on the development of an individualized behaviorally ori-
ented compliance plan that, if necessary, included family
involvement in aftercare. The authors believed that the
critical ingredients in each of these effective interventions
were frequent repetition and behavioral modeling, rather
than appealing to attitudes and beliefs. Skills training of
this sort was described as least effective for patients with
comorbid alcoholism, who frequently dropped out of
treatment. Nelson et al. (1975) reported that a basic form
of skills training—allowing schizophrenia patients to self-
administer medications while hospitalized—increased
outpatient compliance over a 6- to 24-week followup. The
intervention was effective, however, only for patients
who, based on Rorschach test data, accepted that they
were psychiatrically disturbed.
In a study of the impact of psychoeducationally ori-
ented family therapy on medication compliance, Strang et
al. (1981) randomly assigned to individual supportive or
family therapy recently discharged schizophrenia patients
living with a relative who exhibited high expressed emo-
tion. Patients receiving family therapy that included spe-
cific behavioral compliance strategies worked out
between patient and family (Falloon et al. 1984) were
more likely to take their prescribed tablets, less likely to
require a change to depot neuroleptics, and showed higher
and more stable neuroleptic plasma levels, despite identi-
cal mean daily doses for the two groups.
Memory enhancement. Boczkowski et al. (1985)
described a "behavioral tailoring" intervention that
included identifying a highly visible location for storing
medication, pairing medication intake with specific rou-
tine behaviors, and prescribing a self-monitoring calendar
with tear-off slips. In a randomized trial, behavioral train-
ing participants were more compliant at 1- and 3-month
followup than patients receiving a didactic educational
session or control intervention.
Psychodynamic Considerations. Data concerning the
role of psychodynamic factors in medication compliance
derive from the observations of clinicians prescribing
medication to patients with schizophrenia over time.
Three areas are consistently identified as pertinent: the
psychological meaning of medication to the individual
patient, the role of psychotic symptoms in maintaining
self-esteem or personality organization, and issues related
to transference and countertransference.
Psychological meaning. Clinicians have reported a
wide range of psychological meanings ascribed to med-
ications. Patients who are preoccupied with issues of
authority and control may be particularly prone to engage
644
W.S. Fenton et al.
in struggles over medication (Amdur 1979). In view of
the significant loss of personal control associated with
psychosis, Diamond (1984) described noncompliance as
an effort to regain control over one's life and feel better.
Gutheil (1977) noted that individual patients may con-
cretely equate medication with sickness ("/// need drugs
I must be sick. The higher the dose the sicker I am. I'll
stop being sick if I stop taking drugs"). Book (1987)
described several dynamic issues affecting compliance:
paranoid patients' experience of being controlled, poi-
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soned, or invaded by medication; the painful reminder of
a defective, "about to fall apart" self among patients who
make extensive use of denial; and the possibility that
patients' attitudes toward medication are influenced by
identification with relatives who received similar medica-
tion and experienced poor outcomes, such as suicide.
While viewing compliance primarily as a learned
behavioral response, Falloon (1984) noted that some
patients fear that prolonged medication may lead to
dependence and addiction or equate the need for medica-
tion with having a weak character. Taking medication may
also be equated with physical or psychological weakness
so that the recovering patient who feels strong enough
will stop taking medicine (Amdur 1979). Noncompliance
in this context may be a test or gamble designed to deter-
mine if the illness is still present (Morris and Schulz
1993).
Medication may be be an area around which family
or interpersonal conflicts are enacted, so patients stop
medication to express anger toward a relative or mental
health professional (Kane 1983). Similarly, patients may
discontinue medications in the face of increased pressure
to improve functioning or on the verge of hospital dis-
charge or beginning a new job, school, or rehabilitation
program. In these circumstances noncompliance can be
understood as an unconscious expression of the fear of
autonomy or as a communication that expectations have
been set too high (Fenton and McGlashan 1995).
Psychological homeostasis. Psychotic symptoms
may be syntonic or serve to support an individual against
further personality disintegration or the collapse of self-
esteem. Grandiose delusions cast the self as powerful, and
persecutory delusions mark the sufferer as worthy of spe-
cial persecution. When psychosis provides a more posi-
tive self-image than can be provided by reality, patients
will cling tenaciously to delusions and resist efforts to
ameliorate them (Van Putten et al. 1976; Corrigan et al.
1990). Under these circumstances a frontal attack on psy-
chotic symptoms is rarely effective and may precipitate a
catastrophic collapse in self-esteem that leads to self-
destructive behavior (Drake and Sederer 1986). Some
patients, particularly young men, who organize a sense of
self-cohesion around body well-being and activity may
Determinants of Medication Compliance
experience the physical effect of neuroleptics as a threat
to self-organization (Heninger et al. 1965). Other patients
may adapt to impending personality disorganization by
globally organizing in opposition to the will of others and
may resist medications as part of an overall effort to
maintain a tenuous sense of effectiveness or control.
Transference/countertransference. Clinicians
have noted that patients' views of medications arise in
relation to their attitude toward the prescriber and may be
distorted by these attitudes. In the context of a relation-
ship perceived as authoritarian, the physical effects of
medication may be perceived as rejecting, hostile, or
threatening (Sarwer-Foner 1960) or as a bodily attack or
invasion (Gutheil 1977). Other interpretations may cast
the prescription as a negative dismissal of the patient, or
the patient may fear that the reduction of symptoms will
be accompanied by a parallel reduction in the physician's
interest and attention. Positive transference toward the
prescriber may spill over to the medication, which can be
viewed as a "relationship equivalent" or gift (Gutheil
1978).
Countertransference, or feelings and attitudes evoked
in the physician by the patient, has also been described as
potentially undermining pharmacotherapy. Hopelessness
and frustration in the face of patient noncompliance and a
desire to see the patient taught a lesson by suffering a
relapse have been described as common countertransfer-
ence reactions (Weiden et al. 1986; Book 1987). The urge
to abandon or humiliate the noncompliant patient may
also be felt. In this respect, allowing the noncompliant
patient who leaves treatment against medical advice to do
so with dignity can at least set the stage for more collabo-
rative interactions should the patient return in the future
(Diamond 1983; Frances and Weiden 1987).
Discussion
Major difficulties in empirical studies of noncompliance
include both ascertainment and the fact that the most
severely noncompliant individuals leave treatment alto-
gether. Those who remain are the "curiously ambivalent"
individuals who continue in care, but do not adhere to
prescriptions (Blackwell 1972). In view of these limita-
tions it is perhaps surprising that available empirical stud-
ies yield a relatively consistent set of correlates of non-
compliance in schizophrenia, as outlined in table 1.
In evaluating these findings, it is important to note
that data suggest multiple possible causes of noncompli-
ance. Because noncompliance can have many causes, its
statistical association with any single factor is diluted by
the presence of patients in the sample for whom other fac-
tors are causal. Similarly, the potential impact of interven-
645
Schizophrenia Bulletin, Vol. 23, No. 4,1997
Table 1. Empirical correlates of noncompliance
in schizophrenia
Patient-related factors
Greater illness symptom severity or grandiosity or both
Lack of insight
Substance abuse comorbidity
Medication-related factors
Dysphoric medication side effects
Subtherapeutic or excessively high dosages
Environmental factors
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Inadequate support or supervision
Practical barriers, such as lack of money or transportation
Clinician-related factors
Poor therapeutic alliance
tions that focus on a single cause of noncompliance—
inadequate knowledge or skills, for example—is limited
to those in the sample whose noncompliance derives from
that cause.
Based on the empirical and clinical literature
reviewed here, a general set of treatment recommenda-
tions to maximize the likelihood of compliance are out-
lined in table 2. Given noncompliance in an individual
patient, however, a process of differential diagnosis
should lead to specific hypotheses regarding underlying
causes that allow the design of focal and targeted clinical
interventions.
Health Belief Model and Differential Diagnosis of
Noncompliance. The health belief model posits that
health behavior is a product of an implicit and subjective
assessment of the relative costs and benefits of compli-
ance in relation to personal goals and the constraints of
everyday life. Elements of this model include (1) individ-
ual goals and priorities; (2) an evaluation of the perceived
adverse effects of illness and the personal risk of suffering
these effects; (3) the individual's perception of the advo-
cated health behavior's likely effectiveness and feasibility
(the patient's subjective assessment of benefits weighed
against the costs of treatment, including physical, psycho-
logical, and practical disadvantages and barriers to
action); and (4) the availability of internal or external cues
to action that trigger health behavior (Becker and Maiman
1975; Bebbington 1995). Because schizophrenia may dis-
rupt illness perception and the capacity to plan and act,
consideration of the cognitive and motivational resources
available to assess risk and formulate action should be an
additional element of a health belief model applicable to
schizophrenia.
Elements of this modified health belief model outline
areas of assessment pertinent to the differential diagnosis
of noncompliance. A structured interview that explores
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
Table 2. General interventions to maximize the
likelihood of compliance
• Conduct an assessment of compliance history and
risk factors, including substance abuse and financial or
other practical barriers, as part of the evaluation of every
patient.
• Allow sufficient time to know the patient as a person
and to understand his or her personal goals, concerns,
and psychodynamic issues. Place assisting the patient in
meeting self-defined goals at the center of treatment.
• Use a negotiated approach to medication. Create a
therapeutic environment where deviation from recommen-
dations can be discussed openly, rather than concealed.
Show an interest in medication by asking in a nonauthori-
tarian manner how much is being taken and the effects.
Involve the patient in medication treatment by allowing
self-regulation of dosage, if possible.
• Maximize efficacy and minimize side effects in
choosing agents and dosages. Attend seriously to all side
effects and actively elicit and respond to concerns.
• Educate patient and family regarding the biological
underpinnings of illness, relapse prevention, and medica-
tion side effects.
• Enlist support in the community, including family,
friends, and employers. If needed, arrange for supervised
medication administration.
• Employ cognitive and memory-enhancing strategies
if disorganization or forgetfulness is a problem.
• When the patient is rendered incompetent because
of illness, be prepared to recommend judicial intervention.
• If the patient will not comply and is competent, man-
age countertransference to allow for a continued relation-
ship and the possibility of future treatment.
• Promote the patient's participation in activities that
can compete with psychosis as sources of gratification
and serf-esteem.
many of these areas has been developed to facilitate
patient evaluation (Weiden et al. 1994).
Noncompliance may signal that patient and physician
goals and priorities differ (Weiden et al. 1986). Main-
taining sexual functioning, avoiding obesity, or not miss-
ing work for a doctor's appointment, for example, may be
of primary importance to the patient, whereas relapse
reduction is the physician's priority. An assessment of
patient goals forms the basis of a negotiated approach to
prescription that is likely to enhance compliance
(Eisenthal et al. 1979; Wilson 1995).
Since pursuing strategies designed to remedy inad-
vertent noncompliance will fail when noncompliance is
purposeful, the differential diagnosis should attempt to
separate intentional from inadvertent noncompliance.
Empirical studies suggest that from the patient's perspec-
tive an immediate subjective dysphoria or other side
646
W.S. Fenton et al.
effects are the most significant costs of compliance.
Psychological reports suggest that stigma, loss of the sick
role, or disturbed psychic homeostasis may be less dis-
cernible costs. These costs may weigh heavily, particu-
larly when accompanied by a low perceived benefit of
medication that derives from a lack of knowledge, poor
insight, denial, or grandiosity. Interventions under such
circumstances should target potentially modifiable ele-
ments thought to be operative for the individual patient.
Neuroleptic dosage reductions, use of adjunctive agents,
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or a change to an atypical neuroleptic with fewer side
effects may reduce the cost side of the equation.
Promoting participation in self-esteem-enhancing activi-
ties may diminish the need to maintain delusional sources
of self-esteem. Change to an agent with greater efficacy
may reduce denial and grandiosity and create the potential
for greater insight and perceived medication benefits.
Inadvertent noncompliance is associated whh severe
psychopathology, including cognitive disorganization,
memory impairment, or motivational deficits. The chaotic
life circumstances associated with substance abuse
comorbidity, as well as such practical considerations as
finances and transportation, may also be operative. Here
behavioral skill and memory-enhancing interventions,
assertive outreach efforts, and recruiting the assistance of
family or other supports to supervise medication are
major treatment considerations.
New Neuroleptics Versus Depot Preparations. Be-
cause of their reduced extrapyramidal side effects and
greater efficacy against positive and negative symptoms,
new neuroleptics, such as clozapine, risperidone, olanza-
pine, and sertindole, should provide greater patient bene-
fits at a reduced perceived cost. Depot preparations have
the advantage of eliminating covert noncompliance and
maximizing the likelihood of steady-state neuroleptic
blood levels in patients with cognitive disorganization,
memory disturbance, or motivational deficits. Although
an empirical basis for choosing among these two pharma-
cological interventions is not available, the full range of
factors associated with noncompliance might be consid-
ered clinically relevant. Patients with good insight and a
good therapeutic alliance but who report intolerable side
effects are likely the best candidates for a trial of a new
agent. Patients with poor insight, grandiosity, or other
psychotic symptoms or those with memory, motivational,
or cognitive deficits might also benefit from a trial of a
new agent in the absence of comorbid substance abuse
and the presence of either a good therapeutic alliance or
adequate family or other supervision to ensure regular
adherence. Poor insight and severe psychopathology in
the absence of sufficient supervision favor the use of
depot agents. Weiden (1995) has suggested that family
Determinants of Medication Compliance
factors may also have a bearing on the decision between
atypical depot agents: Family concern over akinesia or
other side effects favors a trial of a new agent, whereas
chronic family conflict over taking oral medications
favors depot preparations.
It is useful to reassess the decision between depot and
new neuroleptics periodically. Some patients, for example,
may require a considerable period of depot treatment to
attain a level of clinical stability, therapeutic alliance, and
insight sufficient to render a trial of a new agent feasible.
Conclusion
The prevention and treatment of noncompliance are of
major importance in the care of patients with schizophre-
nia. Although noncompliance has multiple causes, the
empirical literature identifies a circumscribed set of fac-
tors that alone or in varying combinations are likely to be
operative in individual cases. Exploring each of these fac-
tors within a modified health belief model should allow
for differential diagnosis and an individualized approach
to reducing noncompliance. A comprehensive understand-
ing and integration of patient, illness, treatment, and envi-
ronmental factors are needed to manage noncompliance
(Kane 1986). This integrated approach can best be accom-
plished within an ongoing physician-patient relationship
that allows sufficient time for doctor and patient to know
each other and maintain a collaborative therapeutic asso-
ciation over time (Fenton and McGlashan 1995).
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The Authors
Wayne S. Fenton, M.D., is Medical Director, Chestnut
Lodge Hospital, and Director, Chestnut Lodge Research
Institute; Crystal R. Blyler, Ph.D., is Research
Psychologist, Chestnut Lodge Research Institute; and
Robert K. Heinssen, Ph.D., is Director, Partial
Hospitalization and Psychiatric Rehabilitation for
Schizophrenia, Chestnut Lodge Hospital, Rockville, MD.