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` European Neuropsychopharmacology 8 (1998) 55—66
`
`
`
`EUROPEAN NEURO-
`PSYCHDPHARMACOLOGY
`
`
`
`“AV_‘\"
`r“Vv
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`\-
`
`Guidelines for depot antipsychotic treatment in schizophrenia
`
`John M. Kane“, Eugenio Agugliah, A. Carlo Altamurac, José Luis Ayuso Gutierrez“,
`Nicoletta Brunelloem’”: W. Wolfgang Fleischhacker1,Wolfang Gaebelg, Jes Gerlachh, Julien—
`D. Guelfii, Werner Kisslingj, Yvon D. Lapierrek, Eva Lindstroml, Julien Mendlewiczm,
`Giorgio Racagni", Luis Salvador Carulla", Nina R. Schoolerp
`
`ilDepartment of Psychiatry, Hillside Hospital, Division of Long Island Jewish Medical Center, Glen Oaks, NY 11004, USA
`hInstitute of Psychiatric Clinic, University of Trieste, Via S. Cilino 16, 34126 Trieste, Italy
`DInstitute of Psychiatric Clinic, Via Liguria,
`l3, Cagliari, Italy
`dPsiquiatria, Alcalé 152, 28028 Madrid, Spain
`cDept. Pharmaceutical Sciences, University of Marlena, Via Campi' 183, 41100 Modena, Italy
`lDept. of Biological Psychiatry, Innsbruck Univ. Clinics, Aniclistrasse 35, A-6020 Innsbruck, Austria
`theinische Lanclesklinik, Psychiatrische Klinik a'er Heinrich—Heine-Univ. Dusseldorf, Bergische Landestrasse 2, 4000 Dusseldorf Germany
`hSCT Hans Hospital, Dept. 2, 4000 Roskilde, Denmark
`iHopital Paul Brousse, 12 Av. P.V. Couturier, 94804 Villejuif, France
`’Dept of Psychiatry, Technisclie Universitiit Munchen, Ismaningerstrasse 22, 81675 Munchen, Germany
`kDept of Psychiatry, Institute of Mental Health Research, University of Ottawa, [145 Carling, Ottawa, Ontario, Canada KIZ 7K4
`1Department of Psychiatry, University Hospital, S- 751 85 Uppsala, Sweden
`"‘Dept. of Psychiatry, University of Brussels, Erasure Hospital, 808 Rue de Lennik, 1070 Brussels, Belgium
`"Center of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy
`"Urb. El Basque E/Cycas 7°C, 11405 Jerez de la Frontera, Cadiz, Spain
`"Western Psychiatric Inst. and Clinic, 3811 O’Hara St., Pittsburgh, PA 15213, USA
`
`Received 1 December 1996; received in revised form 30 April 1997; accepted 16 May 1997
`
`
`
`Abstract
`
`These guidelines for depot antipsychotic treatment in schizophrenia were developed during a two—day consensus conference held on
`July 29 and 30, 1995 in Siena, Italy.
`Depot antipsychotic medications were developed in the 1960s as an attempt to improve the long-term treatment of schizophrenia (and
`potentially other disorders benefiting from long—term antipsychotic medication). Depot drugs as distinguishable from shorter acting
`intramuscularly administered agents can provide a therapeutic concentration of at least a seven day duration in one parenteral dose.
`The prevention of relapse in schizophrenia remains an enormous public health challenge worldwide and improvements in this area can
`have tremendous impact on morbidity, mortality and quality of life, as well as direct and indirect health care costs. Though there has been
`debate as to what extent depot (long-acting injectable) antipsychotics are associated with significantly fewer relapses and rehospitaliza-
`tions, in our view when all of the data from individual trials and metaanalyses are taken together, the findings are extremely compelling in
`favor of depot drugs. However in many countries throughout the world fewer than 20% of individuals with schizophrenia receive these
`medications.
`
`The major advantage of depot antipsychotics over oral medication is facilitation of compliance in medication taking. Non-compliance is
`very common among patients with schizophrenia and is a frequent cause of relapse. In terms of adverse effects, there are not convincing
`data that depot drugs are associated with a significantly higher incidence of adverse effects than oral drugs. Therefore in our opinion any
`patient for whom long-term antipsychotic treatment is indicated should be considered for depot drugs.
`In choosing which drug the clinician should consider previous experience, personal patient preference, patients history of response
`(both therapeutic and adverse effects) and pharmacokinetic properties.
`In conclusion the use of depot antipsychotics has important advantages in facilitating relapse prevention. Certainly pharmacotherapy
`
`*Corresponding author. Tel: +39 2 20488331; Fax: +39 2 29403673;
`e-mail: brunello@imiucca.csi.unimi.it
`
`0924-977X/98/$19.00 © 1998 Elsevier Science B.V./ECNP. All rights reserved.
`
`P” 30924'977X(97)°°°45'x
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`56
`
`J.M. Kane et al.
`
`/ European NeurnpsychOplmrmaealogy 8 (I998) 55—66
`
`must be combined with other treatment modalities as needed, but the consistent administration of the former is often what enables the
`latter. © 1998 Elsevicr Science BM/ECNP.
`
`Keywords: Depot antipsychotics; Schizophrenia; Treatment; Relapse
`
`
`1. Introduction
`
`These guidelines were developed during a two-day
`consensus conference held on July 29 and 30, 1995 in
`Siena, Italy. The need for this effort was based on the
`recognition that the prevention of relapse in schizophrenia
`remains an enormous public health challenge world wide
`and that improvements in this area can have tremendous
`impact on morbidity, mortality and quality of life, as well
`as direct and indirect health care costs. Despite over-
`
`whelming evidence that non-compliance in medication-
`taking is a major contributing factor to unnecessarily high
`relapse rates, there is still inadequate attention being paid
`to strategies which can enhance medication acceptance and
`adherence, ranging from better psychoeducation directed at
`patients and families to the more extensive use of depot
`antipsychotic administration. Estimates
`suggest
`that
`in
`many countries throughout the world fewer than 20% of
`individuals with schizophrenia receive long-acting inject-
`able medication. It is hoped that the promulgation of clear
`and concise guidelines for the use of depot drugs will help
`to remedy one important aspect of this problem.
`
`1.1. Schizophrenia and the need for long-term treatment
`
`Schizophrenia is a chronic illness usually beginning in
`late adolescence or early adulthood. The condition is
`characterized by remissions and exacerbations,
`though a
`proportion of patients remain persistently ill. There is
`evidence that after 10 to 20 years some patients may
`improve in terms of their overall level of psychopathology
`and community adjustment. The disease affects 1% of
`lnost populations of the Western World, but consumes a
`disproportionate share of health care costs. A large number
`of persons with schizophrenia are permanently disabled,
`and in many countries, homeless.
`in 10,
`l
`The risk of suicide may be as high as
`particularly in the early years after illness onset and among
`males (Miles, 1977; Drake et al., 1984). Mortality is also
`higher due to accidental deaths and other causes (Bland et
`al., 1976). Patients suffering from this illness often receive
`sub-optimal general medical care and frequently have
`undiagnosed comorbid medical conditions.
`The treatment of schizophrenia requires an integration of
`biologic, psychologie and psychosocial perspectives. There
`is increasing evidence that early diagnosis and appropriate
`treatment can improve long-term outcome (May et al.,
`1981). Antipsychotic drugs are a critical modality in
`managing this disease in all phases — acute, stabilization
`
`and relapse prevention. These drugs cannot only alleviate
`or improve psychopathology, but may also enhance psy-
`chosocial and vocational adjustment and improve subjec-
`tive well being. Although medications can be highly
`effective, response varies and some patients derive con-
`siderably less benefit than others. Despite heterogeneity in
`drug responsiveness, antipsychotic drugs are indicated for
`all patients with schizophrenia.
`in
`Long-term treatment with medication is critical
`optimizing outcome and is the focus of these guidelines.
`
`1.2. Definition and measurement of relapse
`
`The participants defined relapse as “the appearance,
`reappearance or exacerbation of symptoms (typically psy-
`chotic) of schizophrenia which may require a change in
`clinical care.”
`
`When a relapse is observed, clinicians should make a
`differential diagnosis and assess possible contributing
`factors, e.g. natural course of the illness, non-compliance,
`underdosage (or drug discontinuation), stress, comorbid
`conditions, drug abuse, medical
`illness, adverse effects,
`etc.
`
`Alternative clinical
`
`interventions should be considered
`
`such as increased surveillance or intervention of a psycho—
`therapeutic/ psychosocial or pharmacotherapeutic nature
`(e.g. reinstitute drug treatment, increase dosage, prescribe
`adjunctive pharmacotherapy, change antipsychotic).
`Given the fluctuating course of this illness, an important
`aspect of treatment focuses on the maintenance of thera-
`
`peutic gains and the prevention of clinical exacerbation,
`relapse and rehospitalizations. This is a concern not only
`because of
`the immediate personal and psychosocial
`disruption, but also because frequent relapses can increase
`the likelihood of poorer long-term outcome.
`The definition of relapse has been an important Variable
`in studies of long-term treatment
`in schizophrenia. The
`basis on which we strongly recommend continued antipsy-
`chotic drugs is the significant reduction in relapse rate
`(despite variability in definition) across numerous studies
`with treatment as compared to untreated cases or placebo—
`treated controls. The manner in which relapse is defined,
`however, takes on critical importance in understanding the
`clinical implications of those findings as well as making
`comparisons across studies. The efficacy of specific treat—
`ment strategies may vary depending upon what definitions
`of relapse are applied.
`recently reviewed 66 studies
`Gilbert et al.
`(1995)
`involving neuroleptic withdrawal. They found that 22
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`./.M. Kane ('I (II. / European Neuropsyclwpliurmacology 8 (1998) 55—66
`
`57
`
`studies did not provide any definition of relapse. In 11
`studies relapse was defined as “a return to active medica-
`tion”. The remaining 33 studies defined relapse as either
`the emergence of “behavioral worsening” (with agitation,
`aggression, insomnia, anxiety, hallucinations, delusions, or
`assaultive or suicidal behavior). Some of these inves-
`tigations utilized a specified change seen on particular
`items on a clinical rating scale such as the Brief Psychiat—
`ric Rating Scale (BPRS).
`In one large
`scale study
`(Schooler et al., 1995), psychotic relapse was defined by a
`rating of “moderate" or greater representing an increase of
`at least two scale points on any of five psychotic items of
`the BPRS (conceptual disorganization, grandiosity, suspi-
`ciousness, hallucinatory behavior and unusual
`thought
`content). This increase in psychotic symptoms had to
`persist for two successive scheduled ratings separated by
`four weeks or a scheduled rating and an unscheduled rating
`associated with the initiation of open (non—blind) active
`medication.
`
`Similar criteria were employed by Kane et a1. (1983) in
`a previous study. Marder et a1. (Marder et al., 1984, 1987)
`defined three levels of unfavorable outcome that would
`lead to an antipsychotic dosage increase. When patients
`had an increase of 3 or more points on the BPRS cluster
`scores for
`thought disturbance or paranoia they were
`considered to have had a “psychotic exacerbation”. These
`exacerbations were relatively mild and seldom led to
`rehospitalization. Clinicians were allowed to essentially
`increase the dosage by up to 100%. If symptoms could not
`be adequately controlled within this range,
`they were
`considered to have had a “relapse”. The third level of
`outcome was rehospitalization. Those criteria for relapse,
`therefore, not only involved an objective measure of
`worsening psychopathology, but also failure to respond to
`a specified clinical intervention.
`As can be seen from these examples in defining relapse,
`a number of key factors need to be considered:
`
`1. Absolute degree of increase in psychopathology
`2. Nature of psychopathology increasing (i.e. psychotic or
`non—psychotic)
`3. Degree of increase in psychopathology relative to the
`“baseline” state of the patient
`4. Duration of the exacerbation
`LII
`
`. Response of the exacerbation to treatment intervention
`(which may be pharmacologic and/or non pharmaco-
`logic)
`
`The critical question in attempting to define relapse is the
`desired balance between specificity and sensitivity. This
`judgment will
`in turn be influenced by the relative risk
`associated with acting on the basis of a false positive and
`not acting on the basis of a false negative. The potential
`consequences of a relapse for that given individual based
`on history, current life situation, etc., must be factored into
`
`the ultimate clinical judgment. Though at present we are
`not aware of significant risks associated with treatment of a
`false positive “relapse”,
`there is
`some reason to be
`concerned about unnecessary increases in antipsychotic
`drug dosage in relation to the development of tardive
`dyskinesia (Kane, 1995).
`Definitions of relapse which can be used by clinicians in
`routine practice will never be a substitute for experienced
`clinical
`judgment, but can provide a useful
`frame of
`reference for organizing and systematizing the decision
`making process.
`
`1.3. Benefits and risks of neuroleptic I'naintemmce
`treatment
`
`Several extensive reviews have appeared in recent years
`summarizing the data on the impact of continued antipsy—
`chotic medication on rates of relapse in schizophrenia
`(Davis et al., 1989; Gilbert et al., 1995). There is over—
`whelming evidence that the use of medication can have a
`
`in improving
`significant (clinical and statistical) benefit
`outcome. The consequences of relapse are diverse and
`often unpredictable ranging from loss of confidence and
`self-esteem, disruption in psychosocial and vocational
`adjustment and family burden to risk of suicide or aggres-
`sive behavior. There is no question that relapse is associ-
`ated with substantial increase in the costs associated with
`
`the illness (both direct and indirect). In addition, there is
`some suggestion that with each subsequent episode time to
`recovery and degree of recovery are not as good previous-
`ly. It is possible that this reflects the natural course of the
`
`disease as well, but prevention of relapse is a goal which
`may have long-term impact on the ultimate course of the
`disease.
`,
`
`The risks associated with long-term neuroleptic treat-
`ment are largely those related to a variety of adverse
`reactions, particularly neurologic effects such as tardive
`dyskinesia or tardive dystonia. Other side effects such as
`
`drug-induced parkinsonism, akathisia, weight gain and
`sedation can also pose problems to some patients.
`Those adverse reactions which are of most concern in
`
`terms of potential-seriousness and persistence are the
`abnormal involuntary movement disorders associated with
`long-term neuroleptic treatment. Although prevalence esti-
`mates vary widely, on average
`15—20% of patients
`chronically—treated with neuroleptic medication manifest
`some degree of tardive dyskinesia (Kane et al., 1992).
`Incidence studies (Kane, 1995; Glazer and Kane, 1992)
`suggest that approximately 5% of young to middle—aged
`adult patients develop some evidence of abnormal involun—
`
`tary movements with each year of neuroleptic treatment.
`The majority of these cases are mild and nonprogressive
`and a substantial proportion can in fact improve or remit
`entirely if neuroleptic dosage is reduced (Kane et al.,
`1992) or they are switched to a drug such as clozapine
`(Lieberman et al., 1991).
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`58
`
`J.M. Kane et al. / European Neuropsychopharmacalogy 8 (1998) 55—66
`
`In the case of elderly patients, the incidence rate (at least
`in the first year or two of neuroleptic treatment) appears to
`be six-fold higher than among younger adults (Saltz et al.,
`1991; Jeste and Caligiuri, 1993).
`As the epidemiology of tardive dyskinesia became better
`understood, an extensive reevaluation of the benefit-to-risk
`ratio took place and a new generation of maintenance
`treatment studies were initiated to determine if alternatives
`
`to continuous neuroleptic treatment had any substantive
`role to play in the long-term treatment of schizophrenia.
`
`1.4. Are there alternatives to neuroleptic maintenance
`treatment?
`
`As a potential alternative to continuous maintenance
`treatment, a strategy of “intermittent” or early interven-
`tion,
`time-limited “targeted” pharmacotherapy has been
`investigated by several groups in the US and Europe. This
`strategy is an outgrowth of observations that relapses do
`not occur immediately, even following complete neurolep-
`tic drug discontinuation, and that many patients can
`maintain remission for many months without medication
`(Carpenter et al., 1982; Carpenter and Heinrichs, 1983). In
`addition, Herz and Melville (1980) observed that psychotic
`relapses are often preceded by a variety of prodromal
`symptoms the identification of which may be used to
`facilitate early intervention.
`This strategy has been investigated in a number of
`large-scale studies in the US, England and Germany (Herz
`et al., 1982, 1991; Carpenter et al., 1987, 1990; Jolley et
`al., 1989, 1990; Pietzcker et al., 1986, I993; Schooler et
`al., 1993).
`Five of these studies involved a comparison of targeted
`treatment with continuous
`treatment over a two-year
`period. In all of these investigations, the targeted treatment
`was associated with significantly less cumulative drug
`exposure over the course of the trial, however, only some
`of the trials found advantages in terms of adverse effects.
`On the other hand,
`the rate of relapse was significantly
`higher in the targeted treatment groups than in the continu-
`ously treated groups during the second year of treatment in
`all of the studies and in the first year of treatment in four
`out of the five. There were no counterbalancing advantages
`associated with the intermittent treatment such as reduced
`
`improvements in
`
`rates of tardive dyskinesia or overall
`psychosocial adjustment.
`study investigated
`(1993)
`Only the Pietzcker et al.
`whether apparent prodromal symptoms are actually valid
`predictors of subsequent relapse. In terms of relapse and
`rehospitalization rates, this study was similar to the others
`in demonstrating clear superiority for continuous treat—
`ment, but also found no significant relationship between
`prodromal symptoms and relapse (Gaebel et al., 1993).
`Perhaps if more valid predictors of relapse (either clinical
`and/or biologic) could be developed (Gaebel and Awad,
`1994), the results of intermittent/ targeted treatment could
`
`be improved. At present, however, continuous medication
`prophylaxis is the treatment of choice and targeted treat’
`ment has little to recommend it, except perhaps in the rare
`situation where continuous treatment is contraindicated or
`
`the patient adamantly refuses maintenance antipsychotio
`drug treatment. Even when tardive dyskinesia develops, it
`is not at all clear that intermittent treatment is preferable to
`continuous (preferably low dose) treatment.
`
`1.5. Compliance: Assessment and cletern-zinants
`
`Although non-compliance is very common among pa
`tients with schizophrenia, detection is often difficult.
`In
`addition,
`though non-compliance is a frequent cause of
`relapse, not all
`relapses are the consequence of non;
`compliance. Even full medication compliance, as insured
`by the regular administration of depot neuroleptics is not a
`guarantee of a relapse free state. As reviewed by Schooler
`(1985), a series of studies that compared depot and oral
`neuroleptic administration found relapse rates on depot
`drugs that ranged between 8 and 40% during 10 to 24
`months. These figures suggest that relapse cannot be taken
`as a reliable marker for non-compliance because relapse
`occurs in patients for whom compliance can be docu—
`mented by depot medication administration. Depot neuro-
`leptics do not completely prevent non—compliance. What
`depot administration insures is that patients have received
`medication and that non-compliance, defined as failure to
`return for a scheduled injection, is immediately detected.
`With oral medication, failure to take medication may not
`be detected until some time after it has first occurred and
`
`often not until the resulting relapse.
`Another problem with the use of relapse to define
`non-compliance is that even if schizophrenia patients are
`non-compliant, relapse may not occur for some time after
`medication has been discontinued. Hogarty et al. (1974)
`reported a cumulative relapse rate of 80% on placebo over
`24 months that is linear—about 3% a month. McEvoy et a1.
`(1984) documented the differences between relapsers who
`are compliant with medication and those who are not.
`Non-compliant
`relapsers have more classic psychotic
`symptoms of schizophrenia and show a gradual onset of
`symptoms — as would be expected from data regarding
`placebo relapse. Compliant patients show a more rapid
`onset of symptoms and prominent affective symptoms.
`Steingard et al. (1994) found that compliant patients who
`relapsed improved during hospitalization regardless of
`whether they received additional medication or not.
`All of these factors — relapse among compliant patients,
`the variable time course of relapse among non-compliant
`patients, the potential differences in the nature of relapse
`for compliant and non-compliant patients and the fact that
`response in compliant relapsers may not be a function of
`medication changes — makes the use of relapse as the sole
`marker for non-compliance unwise although it
`is clearly
`the outcome variable of greatest interest. The compliance
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`n.
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`.I.M. Kane et al. / European NeIIropi‘ychoplmrnmcolagy 8 (1998) 55—66
`
`59
`
`literature in schizophrenia is complicated by the confusion
`of independent variables that may predict compliance such
`as attitudes towards medication, demographic characteris—
`tics, experience of side effects and psychopathological
`symptoms and the dependent variables that define medica-
`tion taking behavior such as pill counts, plasma and urine
`levels, self report, etc. Finally there is actual
`treatment
`outcome which is determined by multiple factors,
`those
`mediated by compliance and others as well.
`
`1.5.]. Definitimls of compliance
`It is generally agreed that compliance is not an all or
`nothing phenomenon. Schizophrenia patients,
`like those
`with other medical illnesses may vary in their compliance
`from taking all medication as prescribed to complete non-
`compliance. Many studies of compliance do not include
`precise
`operational
`definitions. A recent
`study
`by
`Radomsky (1995) represents a notable exception. She used
`plasma determinations of haloperidol and defined com-
`pliance with oral haloperidol by a combination of the
`absolute plasma concentration and variability over multiple
`assays
`
`1.5.2. Measures of compliance
`These can be classified as Direct and Indirect (Sleator,
`
`1985). Direct methods include measures such as plasma or
`urinary measures of the parent drug or its metabolites
`(Perel, 1988), the use of markers such as riboflavin and for
`phenothiazines the very old Forrest Test (Forrest et al.,
`1961). A problem with direct measures is that they assume
`that a level of medication taking behavior is required to
`define compliance. Particularly in schizophrenia it
`is
`unclear how high a level of compliance with prescribed
`medication is needed. Since there is a fairly wide range
`over which most antipsychotic medications are effective,
`skipped doses or taking less than prescribed may represent
`non-compliance but may not have any effect on long—term
`outcome.
`
`Indirect measures include relapse, self report and clini-
`cian judgment. Young et al. (1986) reviewed 23 studies of
`compliance in schizophrenia. Six of these studies used
`direct methods, 17 used interviews or staff reports and only
`two included both direct and indirect methods.
`
`1978); and the Rating of Medication Influences (Weiden et
`al., 1994). Radomsky (1995) developed a questionnaire
`that assesses both attitudes toward medication and medica-
`
`tion taking behaviors. Radomsky’s study highlights an
`important problem. She found that when a direct measure
`of compliance (plasma concentrations of haloperidol) was
`used there was very little relationship between attitude and
`actual compliance. Further, patients substantially overesti—
`mated their compliance as defined by actual medication
`taking behavior.
`As
`indicated above, because measures of attitudes
`
`toward medication-taking and medication-taking behaviors
`are often included in the same assessment instrument, it is
`sometimes difficult to distinguish the predictors of com-
`pliance (attitudes, beliefs and personal predictions of
`medication taking) from the outcome-self report of actual
`medication ingested. The patient’s self-reported attitudes
`are also likely to influence the clinician’s judgments of
`medication taking. Patients who complain about medica-
`tion may be seen as non-compliant even when they are.
`A model of compliance and treatment outcome in
`schizophrenia should include the following variables:
`
`1. Subjective predictors: personal attitudes and beliefs,
`family/ significant other attitudes and beliefs; perceived
`side effects.
`
`2. Objective predictors: symptoms of schizophrenia (par—
`ticularly delusions regarding medication and insight
`into presence of
`illness, cognitive problems);
`side
`effects; environmental supports or deficits (someone to
`monitor medication taking, forgetting).
`3. Medication taking behavior: for patients receiving depot
`preparations this variable is highly reliable; for patients
`taking oral medications its measurement depends on
`self report, reports of others (nurses, care-givers, family
`members) and pill counts.
`4. Direct measures of medication concentration in blood
`or urine or use of biological markers.
`
`5. Measures of treatment outcome, including relapse but
`also measures of psychopathologY, subjective distress
`and side effects.
`
`
`
`1.6. Quality of life
`
`6
`Predictors of non-compliance are classified as “stan-
`dar ” and
`‘subjective” risk factors by Weiden et al.
`(1994). Standard risk factors include such variables as
`Quality of life issues are receiving increasing attention
`complexity of the medication regime, structure provided to
`in health care. Patients
`suffering from schizophrenic
`insure/enhance Inedication taking and symptoms of psy-
`chopathology.
`disorders struggle with numerous quality of life issues
`ranging from subjective comfort with pharmacotherapy
`Subjective risk factors include perceptions and attitudes
`(mainly influenced by medication side effects and general
`such as lack of insight, denial of illness, family beliefs and
`beliefs regarding the value of medication. There has been a
`attitudes toward taking drugs) (Awad and Hogan, 1994;
`substantial and growing interest in this area. Weiden et al.
`Lauer and Stegmuller-Koenemund, 1994)
`to problems
`(1994) describe three instruments that look at subjective
`around housing and psychosocial adaptation (Meise et al.,
`factors: the Drug Attitude Inventory (Hogan et al., 1983);
`1994). It is becoming increasingly accepted that improve-
`ment of psychopathology is not the only relevant outcome
`the Neuroleptic Dysphoria Scale (vanPutten and May.
`Mylan v. Janssen (IPR2020-00440) Ex. 1009, p. 007
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`
`J.M. Kane et (11. / European Neuropsychapliarmacology 8 ([998) 55—66
`
`criterion and other variables related to changes in quality
`of life (Collins et al., 1991) must be assessed. Although
`pharmacologic studies are just beginning to adequately
`address these problems,
`there is reason to believe that a
`significant reduction in rates of relapse and rehospitaliza-
`tion (Pikney et al., 1991) has considerable impact on
`quality of life. The potential advantages of one treatment
`strategy over another (e.g. depot vs. oral antipsychotic)
`need to be demonstrated in controlled clinical studies in
`
`which these issues are given relevant attention. However,
`while we eagerly await such studies, it is important that we
`consider a wide range of quality of life issues in