Brit. 3. Psychiat. (1976), 129, 513—31
`
`Review Article
`
`Treatment Adherence
`
`By BARRY BLACKWELL
`
`A large part of medical practice is complicated
`by two problems;
`the degree to which treatments
`are
`specific
`(the
`placebo
`problem)
`and
`the
`extent
`to which
`they
`are
`implemented
`(the
`adherence
`problem). Depending
`on setting and
`circumstance,
`up
`to half
`of
`the
`benefits
`of
`treatment
`are either
`non-specific
`or never ob
`tained. This
`review considers
`the problem of
`adherence
`in the context of use of medication
`in
`psychiatry.
`
`health
`of preventive
`the benefits
`establishing
`such
`as hypertension,
`diseases
`in
`programs
`recurrent mania, where
`and
`hyperlipidaemia
`adherence
`is a particular
`problem because
`the
`short-term side effects or sacrifices of treatment
`often appear
`to exceed the remote consequences
`of the disease. Finally,
`there have been techno..
`logical advances which facilitate drug detection
`in body fluids, and these have enabled more
`accurate
`study of the adherence
`issue.
`
`SCOPE OF THE PROBLEM
`document
`Two major
`sources of information
`to which
`an upsurge
`of interest
`in the extent
`patients
`adhere
`to therapeutic
`regimens.
`In
`preparation
`for the First International Workshop
`on
`Therapeutic
`Compliance,
`Haynes
`and
`Sackett
`(1976) developed
`an annotated
`biblio
`graphy which included
`246 articles written
`up
`to 1973. The National Library
`of Medicine
`has
`since added
`a further
`74 references
`in English
`up to September
`1975 (Pothier,
`1975). As with
`other
`areas of medical
`knowledge,
`information
`on adherence
`is roughly
`doubling
`in amount
`every five years. Between
`1956 and 1960 there
`were 12 publications,
`from 1961 to 1965 there
`were 45, from 1966 tO 1970 there were 79, and
`in the most
`recent
`five-year
`interval
`(up to
`September
`1975)
`there were
`133 articles.
`In
`April 1976 the First
`International
`Congress on
`Patient Counseling
`devoted
`a major
`session to
`Patient
`Compliance
`with Therapeutic
`Regi
`mens. This
`increase
`in interest must be deter
`mined by both social and scientific
`influences.
`Among the former
`are an enhanced
`awareness
`of patient
`rights
`and a decline
`in professional
`paternalism.
`Some
`slackening
`in the pace of
`drug
`discovery may
`have
`encouraged
`closer
`attention
`to the better use of existing remedies.
`There
`has also been an increased
`interest
`in
`
`lÀ
`
`513
`
`OF THE PROBLEM
`DEFINITION
`(MESH)
`subject headings
`The list of medical
`compiled
`by the National Library
`of Medicine
`has
`included
`the
`term ‘¿(cid:3)patientcompliance'
`de
`only since
`1975;
`before
`then
`the major
`is
`scriptive
`term was
`‘¿(cid:3)patientdrop-out'.
`It
`interesting
`that
`the word ‘¿(cid:3)compliance'has no
`counterpart
`in the German
`or Dutch languages
`(where perhaps
`adherence
`is taken for granted).
`In America
`the
`coercive
`connotation
`of
`the
`word ‘¿(cid:3)compliance'has led to increased
`use of
`‘¿(cid:3)adherence'as an alternative.
`The First
`Inter
`de
`national
`Congress
`on Patient Counseling
`fined the problem as: ‘¿(cid:3)whena patient
`does not
`follow the treatment
`schedules
`suggested to him
`by the physician
`for
`the management
`of some
`illness,
`then the patient
`can be described as non
`compliant.'
`and
`restrictive
`This definition is both unduly
`inadequately
`descriptive. Adherence
`is a prob
`lem encountered
`by all health professionals.
`It
`encompasses
`a wide variety of behaviours
`on the
`part of the patient:
`failure to enter a treatment
`program,
`premature
`termination
`of
`therapy,
`and incomplete
`implementation
`of instructions,
`including
`prescriptions.
`In this review the teim
`‘¿(cid:3)adherence'will be preferred,
`but
`is to be con
`sidered
`synonymous with
`‘¿(cid:3)compliance'.
`
`Par Pharm., Inc.
`Exhibit 1057
`Page 001
`
`

`

`5,4
`
`TREATMENT
`
`ADHERENCE
`
`OF STUDY
`PRoBLEMs
`is
`adherence
`the wealth of literature,
`Despite
`and
`an inadequately
`studied
`subject. Haynes
`in
`Sackett's
`(1976)
`annotated
`bibliography
`cluded a careful appraisal
`of the scientific merit
`and study design of each publication.
`Of
`the
`185 studies
`that were
`evaluated
`less
`than
`a
`quarter
`obtained
`scores of 12 or over on a 24
`point scale, and only 15 per cent had a random
`ized design. Another major
`problem of inter
`pretation
`has been the lack of definition
`of the
`term ‘¿(cid:3)compliance'.In only half
`the studies was
`this described
`in a manner
`adequate
`to permit
`independent
`replication.
`in
`is partly
`This
`lack of sound information
`the
`placebo
`herent
`in the
`problem.
`Unlike
`response, which increases with attention
`paid to
`people, poor adherence
`tends to disappear
`under
`scrutiny. This may continue
`to be a problem,
`since it can only be avoided
`by subterfuge
`or
`strategies
`unacceptable
`in today's
`climate
`of
`informed consent.
`in data
`inadequacies
`these
`Taken
`together
`to a marked lack of
`collection have contributed
`consensus
`in
`the
`conclusions
`dci ived
`from
`studies on adherence.
`
`AND THE PSYCHIATRIST
`ADHERENCE
`need
`There
`are two reasons why psychiatrists
`of
`concern
`themselves
`with
`the
`problems
`adherence.
`The
`first
`is the implication
`it has
`for personal
`practice;
`another
`is
`to provide
`expert consultation
`to other health professionals
`on the management
`of adherence
`in general
`medical
`practice.
`Two of the most
`significant
`contributions
`of psychiatry to the rest of medicine
`may well be an understanding
`of the extent
`to
`which treatment
`is specific and of the degree to
`which treatment
`can be implemented.
`Out of the 320 articles
`listed in the two major
`sources
`(Haynes
`and Sackett,
`1976; Pothier,
`1975)
`and
`in
`previous
`review
`(Blackwell,
`1973b)
`(17
`per
`cent)
`deal
`directly
`with
`problems
`in psychiatry.
`Table
`I
`lists
`these
`studies
`by author,
`treatment
`population
`and
`type of adherence
`problem. Almost
`every kind
`of patient
`has been studied,
`including
`narcotic
`addicts,
`alcoholics,
`psychotherapy
`clients,
`de
`pressed,
`anxious
`and schizophrenic
`adults,
`and
`disturbed
`or
`retarded
`children.
`Adherence
`
`a
`
`of
`
`in a variety
`have been evaluated
`problems
`units, out-patient
`including
`in-patient
`settings,
`health
`centres,
`community
`mental
`clinics,
`guidance
`clinics.
`houses
`and
`child
`halfway
`treatment
`account
`relating
`to drug
`Problems
`for just under
`half of the studies,
`and the re
`mainder
`pay attention
`to issues such as failure
`of first attendance
`after
`referral
`(‘noshows'),
`premature
`discharge
`from hospital
`(against
`medical
`advice or ‘¿(cid:3)AMA'),early or late drop
`outs from treatment,
`refusal
`to attend follow-up,
`and attendance
`patterns
`in general.
`It
`is difficult
`and
`sometimes
`inappropriate
`derive
`general
`conclusions
`from such
`to
`heterogeneous
`data. The behaviour
`of patients
`may be differently
`determined
`between
`those
`who decline
`referral,
`drop out early,
`terminate
`against advice or stay in treatment
`but frustrate
`effective care. This review is mainly concerned
`with
`the
`specific
`problems
`relating
`to drug
`adherence
`in psychiatric
`patients,
`but
`reference
`will be made to more general aspects when rele
`vant
`in order
`to create a model
`for understanding
`that can be applied both in psychiatric
`practice
`and in consultation
`to medical
`colleagues.
`
`DRUG ADHERENCE IN PSYCHIATRIC POPULATIONS
`I Types
`of
`.Won-Adherence
`to Drug
`Therapy
`Errors in drug adherence may be categorized
`into
`four
`groups
`(Malahy,
`1966):
`errors
`of
`omission,
`errors
`of purpose
`(taking medicine
`for
`the wrong reasons),
`errors of dosage,
`and
`mistakes
`in timing or sequence.
`Schwartz
`et al
`(1962)
`added
`another
`group
`of patients
`who
`took additional medications
`not prescribed
`by
`the
`physician,
`of which
`nearly
`half were
`potentially
`dangerous.
`The
`literature
`on non
`adherence
`in drug therapy
`has confined
`itself
`almost
`entirely
`to the study of errors of omission.
`Unfortunately,
`the method
`of calculation
`dif
`fers
`between
`studies
`and
`has
`been
`variously
`defined—from
`taking
`less
`than
`the
`correct
`amounts
`to taking none at all of the prescribed
`medication.
`Another
`problem has
`been
`the
`tendency
`to rely on isolated spot checks rather
`than
`on repeated
`observations.
`Two
`studies
`have
`addressed
`this
`issue. Pollack
`(1958)
`noted
`that nine psychiatric
`patients
`tested repeatedly
`negative
`for drugs on 27 occasions, and Willcox
`et al (1965) examined
`the urine of
`twelve psy
`
`@
`
`Par Pharm., Inc.
`Exhibit 1057
`Page 002
`
`

`

`Author(s)
`
`Adams, Capel & Bloom, ci al
`Adler, Goin, Yamamoto
`Atkinson
`
`Brown & Brewster
`Bumpass, Via &
`Forgotson,
`ci al
`Carr & Whittenbaugh
`Cusky, chambers & Weiland
`Deykin, Weissman & Tanner,
`ci al
`Ewalt, Cohen & Harmatz
`Fiester, Mahrer & Giambra,
`ci al
`
`Forest, Geiter & Snow, ci at
`
`Glick
`Gould, Paulson & Daniels
`Epps
`Hare & Wilcox
`
`Harris
`
`Heine & Trosxnan
`Hoenig & Ragg
`Hogarty & Goldberg
`
`Howard, Rickels & Mock ci a!
`Irwin, Weitzell & Morgan
`
`Johnson & Freeman
`
`Kidd & Euphrat
`
`Kline & King
`
`Krakowski & Smart
`Krebs
`
`Lipman, Rickels &
`Uhienhuth,
`ci at
`
`Mason, Forrest & Forrest,
`eta!
`McCabe, Kurland &
`Sullivan
`McCldlan & Cowan
`
`Mester
`
`Michaux
`
`BARRY
`
`BLACKWELL
`
`T@rn@aI
`Adherence studies in p@ychiatricpopulations
`
`515
`
`Treatment
`
`populations
`
`Type of adherence
`
`Year
`
`1971
`1963
`1971
`
`1973
`
`1974
`1968
`1971
`1975
`
`1972
`
`addicts
`Narcotic
`General out-patients
`Neuropsychiatric
`in-patients
`
`Narcotic
`
`addicts
`
`psychotherapy
`Analytic
`General out-patients
`Narcotic
`addicts
`Depressed
`out-patients
`
`Child
`
`guidance
`
`clinic
`
`Treatment dropouts
`Failed first attendance
`Discharge
`‘¿(cid:3)againstmedical
`advice'
`Treatment
`
`dropouts
`
`Therapeutic
`Cooperation
`Treatment
`Treatment
`Attendance
`Attendance
`
`alliance
`in follow-up
`dropouts
`dropouts
`patterns
`patterns
`
`dropouts
`Treatment
`Drug compliance
`phenothiazines
`Dropouts
`in drug study
`
`Failed first attendance
`Drug compliance
`chiorpromazine,
`amitriptyline
`Drug compliance—minor
`tranquilizer
`Treatment dropouts
`Failed first attendance
`Relapse rates—drug &
`social
`therapy
`Dropouts
`in drug study
`Drug compliance—.
`phenothiazines
`Attendance & relapse
`long actingphenothiazines
`Failed first attendance
`
`Treatment dropouts
`
`Treatment dropouts
`Attendance patterns
`
`Drug compliance—minor
`tranquillizers
`Relapse—phenothiazines
`
`Treatment dropouts
`Drug compliance
`antidepressants & major
`tranquilizers
`Drug compliance—all
`drugs
`Drug compliance
`major tranquillizer
`
`‘¿(cid:3)974-
`
`1964
`
`1965
`
`Community Mental health
`centre
`Schizophrenic
`
`in-patients
`
`Depressed
`
`out-patients
`
`1970
`@67
`
`General
`General
`
`out-patients
`in-patients
`
`‘¿(cid:3)974
`
`ig6o
`1966
`1973
`
`1970
`‘¿(cid:3)97'
`
`1972
`
`1971
`
`‘¿(cid:3)973
`
`1974
`‘¿(cid:3)97'
`
`1965
`
`1963
`
`1974
`1970
`
`1972
`
`ig6z
`
`Anxious out-patients
`
`General out-patients
`General out-patients
`Schizophrenic
`out-patients
`
`Neurotic out-patients
`General
`in-patients &
`out-patients
`Schizophrenic out-patients
`
`Community mental health
`centre
`Community mental health
`centre
`addicts
`Narcotic
`Community mental health
`centre
`
`Neurotic out-patients
`
`Schizophrenic
`
`out-patients
`
`Narcotic
`General
`
`addicts
`out-patients
`
`General
`
`out-patients
`
`General outpatients
`
`Par Pharm., Inc.
`Exhibit 1057
`Page 003
`
`

`

`516
`
`TREATMENT
`
`ADHERENCE
`
`T@aI2 i—Continued
`
`Author(s)
`
`Year
`
`Treatment populations
`
`Type of adherence
`
`Orford
`Pam, Rachlin & Bryskin, ci a!
`
`‘¿(cid:3)974
`‘¿(cid:3)973
`
`Alcoholics Halfway house
`Psychiatric
`in-patients
`
`Park & Lipman
`
`Parkes, Brown & Monck
`
`Pollack
`
`Porter
`
`Raynes & Warren
`
`Raynes & Patch
`Renton, ci al
`
`Reynolds,
`
`Joyce & Swift, ci a!
`
`Richards
`
`Rickels & Briscoe
`
`1964
`
`1962
`
`1958
`
`1969
`
`‘¿(cid:3)97'
`
`1973
`1963
`
`1965
`
`1964
`
`1970
`
`Rickels, Boren & Stuart
`Rickels, Raab & Gordon,
`
`ci at
`
`1964
`1968
`
`Rosenberg & Raynes
`Rosenberg, Davidson & Patch
`Seeman
`Shapiro
`Tapp, Slaikeu & Tulkin
`Uhienhuth, Park & Lipman
`ci al
`Van Putten
`
`Wilder & Stoycheff
`
`Wilcox, Gillan & Hare
`
`‘¿(cid:3)973
`1972
`‘¿(cid:3)974
`‘¿(cid:3)974
`‘¿(cid:3)974
`1965
`
`‘¿(cid:3)975
`
`‘¿(cid:3)974
`
`1965
`
`Depressed out-patients
`
`Schizophrenic
`
`out-patients
`
`Schizophrenic
`
`in-patients
`
`in
`
`Depressed patients
`general practice
`Community mental health
`centre
`Narcotic addicts
`Schizophrenic out-patients
`
`Miscellaneous
`
`out-patients
`
`Schizophrenic in-patients
`
`Neurotic out-patients
`
`Neurotic out-patients
`Neurotic out-patients
`
`Alcoholic out-patients
`Narcotic addicts
`Psychotherapy out-patients
`Child & Family out-patients
`General out-patients
`Neurotic out-patients
`
`out
`
`Manic-depressive
`patients
`Subnormal child
`out-patients
`General out-patients
`
`Wilson & Enoch
`
`1967
`
`Schizophrenic
`
`in-patients
`
`Treatment dropouts
`Discharge
`‘¿(cid:3)againstmedical
`advice'
`Drug compliance—drug
`study
`Drug compliance—major
`tranquilizers
`Drug compliance
`phenothiazines
`Drug compliance
`antidepressants
`Dropouts
`after
`
`first visit
`
`in drug
`
`Early dropouts
`Drug compliance
`phenothiazines
`Drug compliance
`barbiturates
`Drug compliance—major
`tranquillizers
`Drug compliance
`study
`Dropoutsindrug study
`Drug compliance
`in drug
`study
`Treatment dropouts
`Treatment dropouts
`Treatment
`dropouts
`Treatment dropouts
`Failed first attendance
`Drug compliance in drug
`study
`Drug compliance-lithium
`
`Treatment compliance
`
`Drug compliance
`imipraminc & chiorpro
`mazine
`Drug compliance
`
`to five times and
`from three
`out-patients
`chiatric
`found that all except one were consistently
`non
`adherent. Most of the conclusions
`derived from
`the literature
`are therefore based on findings
`in
`which
`a
`single
`observation
`suggests
`that
`a
`significant
`portion
`or all of the medication
`has
`been omitted.
`
`2 Methods
`of Detection
`or studying
`None of the methods of detecting
`non-adherence
`are without
`shortcomings
`or
`
`this
`
`in studying
`
`used
`The methods
`difficulties.
`problem include
`the following:
`about
`patient
`(a) Interrogation Asking
`the
`tablet
`taking is not always
`reliable. Thirty-one
`per cent of psychiatric
`out-patients who claimed
`to be taking their drugs had a negative
`urine
`test
`(Wilicox
`ci al, 1965). Park
`and Lipman
`(1964)
`showed
`that
`while
`verbal
`reports
`suggested that only 15 per cent of out-patients
`were
`non-adherent,
`a pill
`count
`revealed
`an
`actual
`figure of5I per cent. These authors made
`the
`interesting
`observation
`that
`patients
`are
`
`Par Pharm., Inc.
`Exhibit 1057
`Page 004
`
`

`

`5,7
`ct al, 1957; Neve,
`(Sprogis
`reliable
`or
`sensitive
`1958). A more
`sensitive
`test was developed
`by
`Willcox ci al (1965), but
`it is more complex and
`has notbecome a standardprocedure.
`
`BARRY BLACKWELL
`problem
`if a major
`to be accurate
`likely
`more
`exists. This was later
`confirmed
`in a large
`survey
`involving
`over 300 psychiatric
`clinic and general
`practicepatients(Rickelsand Briscoe,1970).
`Over
`two-thirds
`with major
`problems
`in ad
`herence
`recognized
`their
`own difficulties,
`com
`pared
`to
`a
`quarter
`of
`those whose
`records
`indicated
`minor
`oversights.
`Success
`of
`interro
`gationmay clearlydepend on thetypeofpatient
`concerned.Schizophrenicin-patientsare es
`peciallynotedforthelengthstowhich theymay
`
`go to ‘¿(cid:3)cheek'medication(Neve, 1958).
`
`(b) TabletEstimatesCountingtabletsmay be
`as misleading
`as interrogation,
`since
`there
`is no
`assurance
`that what
`has left
`the bottle
`has been
`throughthe patient.Porter(1969)found that
`3 out of ig patientstakingImipramine had
`negativeurinetestsbutcompletepillcounts.
`
`(c)Drug MarkersAttemptshave been made
`tofindsubstancesneitherharmfulnor alarming
`to thepatientthatcan be reliablyidentifiedin
`body fluidsasindexesofadherence.A frequently
`used urinemarker has been riboflavin,which
`has
`been
`successfully
`employed
`in psychiatric
`populations(Scarpattici a!,1964).A single
`attempthas been made to utilizethe stoolsof
`psychiatricpatientsby givingan opaque barium
`sulphatetracerwhich was detectedby x-raysin
`the faeces(Essercia!,1969).Falsenegatives
`occurredin thosewho chewed theircapsulesor
`remainedconstipatedforlongerthan thelifeof
`themarker.
`
`urine
`the patient's
`(d) Drug Detection Testing
`isthe simplestand most convenientmeans of
`drug
`identification,
`especially
`since
`it
`is
`the
`major
`route
`of excretion
`for most
`drugs.
`The
`first urine
`test
`for phenothiazines
`was developed
`in 1957 by Drs Fred
`and
`Irene
`Forrest,
`husband
`and wife team of psychiatrist
`and bio
`chemist, who
`devised
`a series of ferric
`chloride
`colour
`reactions
`for both
`phenothiazines
`and
`tricyclicantidepressants(Forrestci al,ig6i).
`These
`tests have
`become
`known
`by their
`name,
`and
`their
`validity
`has
`been
`independently
`corroborated
`(Pollack,
`1958). Additional
`tests for
`phenothiazineshave been developedforuse in
`mentally
`retarded
`children
`and other psychiatric
`populations,
`but
`have
`not
`proved
`sufficiently
`
`a
`
`EXTENT AN]) SIGNIFICANCE OF NON-ADHERENCE
`TO DRUGS
`re
`I973a)
`review
`(Blackwell,
`A previous
`of medication
`significant
`omission
`vealed
`that
`cent
`of out
`occurs
`in between
`25 and
`50 per
`in-patients.
`patients
`but
`is less common
`among
`The
`significance
`of such findings
`had been most
`intensively
`debated
`in the
`treatment
`of schizo
`phrenia, where
`the paradox
`of declining
`hospital
`populationsand risingreadmissionrateshas
`given
`rise
`to the
`‘¿(cid:3)revolvingdoor'
`concept.
`A
`previous
`review of
`the
`literature
`(Hughes
`and
`Little,
`1967) was
`sceptical
`of
`the
`need
`for
`continuous
`medication
`among
`schizophrenic
`in-patients.
`The
`authors
`claimed
`to prove
`their
`point by controlled withdrawal
`of phenothiazines
`from 21 patients,
`17 of whom remained
`well
`eighteen
`months
`later,
`even
`though
`the ward
`became
`‘¿(cid:3)arather
`noisier
`place'.
`Patients
`in this
`study
`received
`intensive
`milieu
`therapy
`and
`support.The resultsconflictwith thoseof a
`large
`collaborative
`Veterans
`Administration
`study
`(Caffey
`et al, 1964). Twenty-five
`per cent
`of 348 in-patients
`relapsed within
`sixteen weeks
`of having
`a placebo
`substituted
`for maintenance
`phenothiazines.
`In
`another
`study,
`controlled
`prospective
`evaluation
`of schizophrenic
`patients
`discharged
`from hospital
`found
`that
`after
`six to
`eighteen
`months
`82 per
`cent
`of drug-treated
`patients were
`still at home,
`but only 37 per cent
`of
`those
`on placebo
`remained
`outside
`hospital
`(Scarpatti
`ci
`al,
`1964).
`Forrest
`ci al
`(1964)
`of
`documented
`the
`injudicious
`effects
`non
`adherence
`on readmission
`rates
`in 3000 chronic
`psychiatric
`patients
`studied
`over
`a
`ten-year
`period.
`Some
`studies
`do
`not
`confirm
`such
`clear-cut
`association
`between
`non-adherence
`and morbidity
`in schizophrenia
`(Renton
`ci a!,
`1963),butone
`dramaticfindingwas
`that
`izoniazid
`reduced
`the incidence
`of tuberculosis
`by 8o per
`cent
`in general
`patient
`populations,
`but by only
`eighteen
`per cent
`in schizophrenics
`who adhered
`less readily
`to treatment
`(Ferebee,
`1964).
`A more
`charitable
`view of the consequences
`non-adherence
`was proposed
`by Uhlenhuth
`
`a
`
`of
`ci a!
`
`Par Pharm., Inc.
`Exhibit 1057
`Page 005
`
`

`

`518
`
`TREATMENT
`
`ADHERENCE
`
`or
`
`that
`own
`the
`to
`to occur
`
`the interestingspeculation
`(1965), who made
`non-adherence
`might
`reflect
`the patient's
`efforts
`to
`self-regulate
`dosage,
`due
`very wide individual
`differences
`known
`in drug metabolism.
`of the adherence
`More
`remote
`consequences
`problem are the economic wastage involved and
`the potential
`hazard
`to health
`created
`by cup
`boards
`stocked with
`unused
`unidentifiable
`the
`tablets
`accumulated
`over
`years. A survey
`of an English
`town
`revealed
`that
`500 out
`of
`30,ooo
`households
`had
`unused
`drugs
`available.
`Sedatives,
`tranquilizers
`and
`hypnotics
`formed
`the
`largest
`single
`category
`(Nicholson,
`1967).
`The
`potential
`significance
`of
`this
`finding was
`by
`illustrated
`Robin
`Freeman-Browne
`and
`in
`(1968), who examined
`unused medications
`the homes of psychiatric
`patients
`and found that
`those with
`suicidal
`risk
`often
`had
`supplies
`of
`potentiallylethalmedicationsavailable.
`pas t
`A final
`important
`consequence
`is
`the
`non-adherence
`may
`play
`in distorting
`the out
`come
`of
`therapeutic
`trials.
`This
`has
`been
`as repeatedly
`emphasized
`as it has been ignored
`(Maddock,
`1967; Porter,
`1969; Uhienhuth
`ci al,
`1965), but
`the majority
`of drug studies
`continue
`to fail
`to make
`any attempt
`at measuring
`non
`adherence
`and
`its
`contribution
`to treatment
`outcome.
`
`RISK FACTORS CONTRIBUTING TO
`NON-ADHERENCE
`with
`associated
`to identify
`features
`Attempts
`results
`conificting
`have yielded
`non-adherence
`with low consensus. A contributory
`factor has
`been the poor quality
`of the research, with a
`tendency
`to study
`relatively
`superficial,
`easily
`observable
`or
`readily measurable
`end
`points.
`For instance, Haynes and Sackett
`(1976)
`identi
`fied more
`than
`two hundred
`variables
`that
`had
`been measured,
`but
`results
`from separate
`studies were
`often
`contradictory.
`Table
`II
`comprises
`the few features
`for which there
`are
`at least four studies yielding the same conclusion
`concerning
`the effect of that
`feature
`on increas
`ing or decreasing
`adherence.
`reflect
`literature
`These
`findings
`in the general
`on psychiatric
`a similar
`uncertainty
`in studies
`the problem as
`populations. By conceptualizing
`a complex interactionbetweenvariables,poten
`
`T@.rn..aI!
`Ru/c factors ejecting adherenceto medicaiion*
`
`IncreaseDecreasePatient
`
`considers disease
`seriousComplexityFamily
`
`stabilityDegree
`requiredCompliance
`
`timePatient
`with other
`aspectsClinic
`
`satisfactionClose
`
`supervision by
`physician
`
`of behaviour
`change
`
`waiting
`
`*Derived from Haynes & Sackctt,
`
`1976
`
`risk factors
`tial
`can be identified
`physician,
`the
`medication
`itself.
`
`to non-adherence
`contributing
`in the patient,
`the illness,
`the
`treatment
`setting
`and
`the
`
`patient
`i The
`behaviour
`human
`complex
`to distil
`Attempts
`rewarded.
`This
`seldom
`into
`stereotypes
`are
`proved true in the search for a ‘¿(cid:3)placeboreactor',
`and has also been the fate of attempts
`to define a
`‘¿(cid:3)drugdefaulter'
`(Blackwell,
`1972). Almost
`fifty
`years ago Hartshorne
`and May (1928)
`showed
`that
`individuals
`who
`are
`unreliable
`in one
`situation may
`not
`be in another.
`Following
`extensive
`research
`in general
`practice
`on both
`medical and psychiatric
`problems, Porter
`(1969)
`concluded
`‘¿(cid:3)ithas not proved possible to identify
`an
`uncooperative
`type.
`Every
`patient
`is a
`potential
`defaulter;
`compliance
`can never
`be
`assumed.'
`
`and Illness Behaviour
`(a) Attitudes
`to be cared
`People's willingness
`to seek help,
`are basic
`for and
`to accept
`or
`i eject
`advice
`characteristics
`which are reflected in how they
`take medication.
`Variations
`of
`the
`attitudes
`that underlie
`this behaviour
`have ranged
`from
`descriptive
`to speculative.
`The
`latter
`includes
`an
`observation
`(Scott,
`1960)
`that
`pills and cap
`sules resemble nothing
`so much the breast
`and
`the penis
`(elixirs presumably
`fall
`into the cate
`gory
`of mother's milk). Better
`substantiated
`observations
`on the
`influence
`of attitudes
`on
`
`Par Pharm., Inc.
`Exhibit 1057
`Page 006
`
`

`

`BARRY BLACKWELL
`
`by a number
`are provided
`behaviour
`adherence
`literature. A
`in the general medical
`of studies
`farm workers with
`cardiac
`disease
`study
`of
`1967)
`showed
`that
`those with
`a low
`(Davis,
`adherence more often endorsed statements
`on a
`health
`attitude
`questionnaire
`such as ‘¿(cid:3)ifyou
`wait
`long enough you can get over any illness';
`‘¿(cid:3)illnessand trouble
`is one way God shows his
`displeasure';
`‘¿(cid:3)someof the old fashioned remedies
`are still better
`than the things you get at
`the
`drugstore'.
`Another
`study
`(Stimson,
`1974)
`illustrated
`the beliefs
`about medication
`which
`reduce
`adherence,
`including
`‘¿(cid:3)youonly
`take
`medicines when you are ill, not when you are
`better'
`or ‘¿(cid:3)youneed to give your body some
`
`“¿(cid:3)restâ€(cid:157)from the medicine once in a while, other
`wise your
`body becomes
`dependent
`on it o@
`immune
`to it'. Every
`individual's
`behavior
`in relation to health and illness is determined
`by
`such
`personal
`and
`culturally
`endorsed
`belief
`systems;
`in a longitudinal
`study
`over
`fifty years
`in Vienna, Linz (1964) found that people of that
`region who once
`attributed
`their
`aches
`and
`pains to the wrath of God were now preoccupied
`with their health. Behaviour
`in response to such
`attributions
`has presumably
`changed
`over half
`a century from visiting the priest
`(who invoked
`prayer)
`to calling on a physician
`(who writes a
`prescription).
`how people
`studied
`Sociologists who have
`behave
`in relation
`to health
`and disease have
`devised models
`to describe patterns
`of response;
`Becker
`(i@@'@)refers to the ‘¿(cid:3)healthbelief' model
`and Mechanic
`to an ‘¿(cid:3)illnessbehaviour'
`model.
`He says: ‘¿(cid:3)whetherby reason of earlier experi
`ences with illness, differential
`training in respect
`to symptoms
`or whatever,
`some persons will
`make
`light of symptoms,
`shrug them off and
`avoid seeking medical
`care; others will respond
`to the slightest
`twinges of pain or discomfort
`by
`quickly seeking such medical care as is available'
`(Mechanic
`and Volkart,
`1961).
`An individual's
`belief systems and tendency
`toward illness behaviour may influence both his
`utilization
`of mental
`health
`resources
`in general
`and his acceptance
`of medication
`in particular.
`Fiester
`ci al
`(i@7@) studied
`the patients
`at a
`community
`mental
`health
`centre
`and
`distin
`guished
`those who dropped
`out of
`treatment
`almost
`immediately
`from those who continued
`
`5,9
`a set of
`shared
`drop-outs
`The
`in the program.
`them as
`identified
`which
`unique
`characteristics
`treatment
`philosophies
`people who ‘¿(cid:3)shunthe
`and methods
`of mental
`health
`practitioners,
`clinics and hospitals'. The beliefs and behaviours
`of those people who choose to attend
`but not
`to comply with treatment
`are still more complex.
`A collaborative Veterans Administration
`study
`of
`out-patients
`yielded
`some
`information
`in
`this
`respect
`(Michaux,
`ig6i;
`Raskin,
`1961).
`Patients
`were
`prescribed
`medication
`by
`one
`doctor,
`but
`attended
`for psychotherapy
`with
`another.
`Resistance
`to medication
`expressed
`verbally
`to the
`therapist was
`found
`later
`to
`correlate
`significantly with low adherence.
`A
`group
`of 37 individuals who were persistently
`non-adherent
`were
`found
`on testing
`to show a
`greater
`degree
`of overt
`hostility
`and
`aggression
`to the
`prescribing
`physician
`(but
`they
`also
`expressed angry feelings toward psychotherapy).
`The paradox
`of these patients
`can be partly re
`solved
`by
`noting
`that
`anger
`towards
`the
`therapist
`and poor adherence with therapeutic
`regimens
`are ways of sustaining
`attention
`and
`concern
`in those who value care taking highly
`(Wooley and Blackwell,
`1975). Further
`support
`for
`this
`suggestion
`can be derived
`from the
`study by Richards
`(1964), who used Osgood's
`Semantic Differential
`Scale
`to determine
`the
`attitudes
`of 30 schizophrenic
`in-patients with
`high
`or
`low adherence
`to medication.
`The
`author's
`description
`of the chronic schizophrenic
`medication
`was of ‘¿(cid:3)aclosed ward
`patient
`who
`resents
`coercion,
`yet
`doesn't
`value
`freedom
`highly
`and
`doesn't
`dislike
`the
`hospital
`but
`dislikes his parents. He has been in the hospital
`for five or six years, yet hasn't
`been convinced
`that
`taking medication will make him better.
`Forcing this patient
`to swallow medicine
`is very
`different
`from insisting
`that
`an
`acutely
`ill,
`agitated,
`recently
`admitted
`patient
`accept
`medication.'
`recommenda
`of treatment
`The acceptability
`tions may not only differ between
`individuals
`but may vary over
`time. This
`issue has been
`best
`studied
`in patients
`who
`abandon
`psycho
`therapy.
`Interactions
`between the therapist
`and
`client, which may
`result
`in the
`rejection
`of
`treatment
`have
`been
`categorized
`by Seeman
`(i@7@). She
`carefully
`documents
`the
`differing
`
`Par Pharm., Inc.
`Exhibit 1057
`Page 007
`
`

`

`520
`
`TREATMENT
`
`ADHERENCE
`
`re
`ex
`and
`
`a
`
`provoke
`that may
`interactions
`therapeutic
`the
`early
`based
`on
`treatment
`jection
`of
`of dependent,
`schizophrenic,
`periences
`patients.
`obsessional
`interaction
`subtle
`is
`In
`addition
`there
`and
`environmental
`between
`the
`individual
`situation
`in which the failure to take medication
`occurs. Bakker
`and Dightman
`(1964)
`studied
`the personalities
`of women who failed to take
`oral
`contraceptives
`regularly.
`They were more
`immature,
`irresponsible
`and
`impulsive,
`but
`in
`addition
`their personality
`profiles deviated more
`from their husbands
`than did those of women
`who took the pill regularly. Though
`there is no
`direct
`confirmation
`within
`the
`psychiatric
`literature,
`it
`is possible
`to speculate
`that
`poor
`adherence
`with medication
`leads
`to results
`which
`elicit
`caretaking
`responses
`from the
`environment,
`and these enable
`the subject
`to
`avoid the anxieties of independent
`existence and
`lead to adoption
`of the ‘¿(cid:3)sickrole'.
`In this way
`it
`is
`possible
`exchange
`a
`back
`ward
`the
`hospital
`a
`back
`room in
`the
`munity.
`
`to
`for
`
`in
`com
`
`(b) Socio-economicfactors
`that difficulty
`allege
`American
`heroin
`addicts
`in finding the money to pay for their methadone
`is
`the major
`factor
`in
`their
`drop-out
`from
`treatment
`(Adams
`ci a!, ‘¿(cid:3)971).Another
`study
`reporting
`a relationship
`with
`socio-economic
`variables
`was
`among
`neurotic
`out-patients
`treated
`with
`meprobamate,
`where
`good
`adherence
`was
`associated
`with
`being middle
`class, well educated
`and white
`(Lipman
`ci a!,
`1965). This
`constellation
`of attributes
`led the
`authors
`to consider
`such patients
`as those likely
`to ‘¿(cid:3)abideby the rules of the game'.
`Intelligent
`middle-class
`patients
`are known
`to be aggressive
`in seeking help of all kinds and may be equally
`resolute
`in
`obtaining
`value
`for money
`by
`pay
`taking what
`they
`for. However,
`this
`supported
`supposition
`is not
`by a study
`using
`attendance
`as a means
`of evaluating
`a com
`munity
`mental
`health
`program
`(Krebs,
`1971).
`This
`study found that patients
`on welfare
`and
`covered
`by private
`insurance
`kept
`as many
`appointments
`as a group
`of patients
`paying
`for their own care.
`
`(c) Social supervision
`A consistent
`finding has been the supervisory
`role of a partner
`or
`spouse
`in ensuring
`that
`medication
`is taken
`as ordered.
`Porter
`(1969)
`found that among general
`practice
`patients
`on
`chronic medication
`social isolation (living alone)
`was
`the major
`contribution
`to non-adherence.
`the
`This feature
`is most
`likely to occur among
`it
`elderly
`or
`unwanted
`in
`society,
`so
`that
`to
`be
`may
`expected
`contribute
`poor
`to
`adherence
`in
`geriatric
`and
`schizophrenic
`populations.
`In psychiatric
`out-patients, Willcox
`ci a! (1965)
`noted
`that 52 per cent of men living
`alone failed to take drugs, compared
`to 35 per
`cent of those living with their wives. When Parkes
`eta!
`(1962)
`investigated
`the fate of schizophrenic
`patients
`discharged
`into the community,
`they
`found that
`it made
`no difference whether
`the
`patient
`obtained
`his drugs
`from a psychiatrist
`or
`a general
`practitioner,
`but
`82
`per
`cent
`of
`those whose drug-taking
`was
`supervised
`by a
`relative
`or
`friend
`took their drugs
`as ordered,
`compared
`to 46 per cent of those who were not
`supervised;
`an
`important
`corollary
`to
`this
`that
`observation was the fact
`there were three
`in
`times
`as many
`patients
`the
`unsupervised
`group. Renton
`ci a!
`(1963)
`also found
`that
`schizophrenics
`living with
`their
`families were
`more likely to adhere.
`
`2 The illness
`that
`suggests
`literature
`The general medical
`of
`adherence
`is affected not only by the nature
`the illness but by its duration
`and the conse
`quences of stopping medication. Non-adherence
`in
`chronic
`diseases
`such
`as
`tuberculosis
`and
`schizophrenia
`tends to increase with the duration
`is
`of remission
`(Blackwell,
`1973a). Adherence
`of
`usually
`encouraged
`when
`the
`consequences
`and
`decreasing
`medication
`are
`immediate
`disruptive
`(as with diabetes).
`In schizophrenia
`and
`severe manic-depressive
`disorders
`the
`disruptive
`consequences
`of non-adherence
`are
`mitigated
`by the way symptoms
`develop
`in
`sidiously
`after
`treatment
`ceases,
`thus blurring
`the cause
`and effect
`relationship
`for patients,
`relatives
`and professionals.
`to cooperate
`capacity
`In psychiatric
`patients,
`may be impaired
`by the illness as well as by
`attitudes
`toward
`health
`and treatment. Renton
`
`Par Pharm., Inc.
`Exhibit 1057
`Page 008
`
`

`

`BARRY BLACKWELL
`
`52!
`
`was
`non-adherence
`that
`found
`(i 963),
`ci al
`who were
`the most
`in schizophrenics
`highest
`but
`found
`it difficult
`ill at
`the time of discharge,
`to disentangle
`the question whether
`this was the
`cause
`or
`result
`of further
`deterioriation.
`Those
`who were less ill attended
`out-patient
`clinics and
`adhered
`to medication more faithfully. Among
`the more
`common
`symptoms which alter
`ad
`herence
`in psychiatric
`practice
`are the paranoid
`delusions which
`cause
`the
`schizophrenic
`to
`equate
`drugs with poison. Wilson and Enoch
`(1967)
`found that out of 8 schizophrenics with
`persistently
`negative
`urines,
`7 had
`paranoid
`delusions
`(compared with only two in a control
`group).
`In a recent
`report
`on maintenance
`therapy
`with
`lithium
`in manic-depressive
`illness, Van
`Putten
`(1975)
`reports
`that
`refusal
`to take lithium was a significant
`problem in 9
`out of i6 patients. This was contributed
`to by
`the
`use of denial
`and
`lack of awareness
`of
`personal
`feelings and their
`relationship
`to treat
`ment.
`in psychotic
`not only occurs
`Poor adherence
`states where
`insight may be lost, but has been
`shown
`to occur
`in neurotic
`illnesses.
`Lipman
`ci a! (1965)
`found
`that
`low adherence
`was most
`common
`among
`the most anxious out-patients
`who had been given a poorer prognosis and had
`been treated
`eleswhere
`before. They speculate
`that
`the treatment
`was rejected
`by this group
`of
`patients
`as being insufficiently
`potent.
`
`3 The physician
`of the physician
`and attitudes
`The behaviour
`to influence patient
`adherence
`can be expected
`The
`physician's
`own reluc
`with medication.
`this fact constitutes
`a major
`tance to recognize
`obstacle
`to effective management.
`In one study
`two-third