Effect of aripiprazole versus haloperidol on PANSS Prosocial items

Schizophrenia Research 120 (2010) 199–203
Contents lists available at ScienceDirect
Schizophrenia Research
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Effect of aripiprazole versus haloperidol on PANSS Prosocial items in
early-episode patients with schizophrenia
J.P. Docherty a,⁎, R.A. Baker b, J. Eudicone b, S. Mathew c, R.N. Marcus d,
R.D. McQuade e, R. Mankoski b
Weill-Cornell Medical College, White Plains, NY, USA
Bristol-Myers Squibb, Plainsboro, NJ, USA
Otsuka America Pharmaceutical Inc., Rockville, MD, USA
Bristol-Myers Squibb, Wallingford, CT, USA
Otsuka Pharmaceutical Development and Commercialization Inc., Princeton, NJ, USA
a r t i c l e
i n f o
Article history:
Received 23 November 2009
Accepted 31 March 2010
Available online 23 May 2010
a b s t r a c t
Background and aim: Improving social functioning is critically important in early-episode
schizophrenia, if patients are to achieve functional recovery. This post-hoc, pooled analysis of
two studies compared the effect of aripiprazole versus haloperidol on social functioning in
early-episode schizophrenia.
Methods: Data were pooled from two 52 week, randomized (2:1), double-blind, multicenter
studies involving 1294 patients with chronic schizophrenia who were in an acute psychotic
episode and had a history of positive antipsychotic response during previous episodes. The
early-episode group was defined as patients who are ≤ 40 years of age with ≤ 5 years' duration
of illness. Social functioning was assessed by mean change from baseline on the PANSS
Prosocial subscale (ANCOVA and LOCF), comprising six PANSS items, and the Modified
Prosocial subscale, comprising four PANSS items. Measurements were taken at approximately
monthly intervals for up to 1 year.
Results: Aripiprazole (n = 237) demonstrated significant improvement versus haloperidol
(n = 123) as early as Week 18 on both the Prosocial subscale (−4.75 versus − 3.78, p b 0.05)
and on the Modified Prosocial subscale (− 3.16 versus − 2.28, p b 0.05). Patients receiving
aripiprazole continued to show similar significant improvement versus haloperidol at all
remaining timepoints through Week 52 using the Modified Prosocial subscale, but less
consistent improvement with the Prosocial subscale. Significant advantage for the aripiprazoletreated patients was observed at Weeks 46 and 52 (endpoint) with both subscales.
Conclusion: In patients with early-episode schizophrenia, aripiprazole demonstrates greater
improvement than haloperidol on PANSS items related to social functioning. The cognitive and
functional implications of these findings remain to be clarified in future studies.
© 2010 Published by Elsevier B.V.
1. Introduction
⁎ Corresponding author. Weill-Cornell Medical College, 21 Bloomingdale
Road, White Plains, NY 10605, USA. Tel.: +1 914 843 2541; fax: +1 914 234
E-mail address: [email protected] (J.P. Docherty).
0920-9964/$ – see front matter © 2010 Published by Elsevier B.V.
Many patients with schizophrenia – up to two-thirds – are
unable to perform fundamental social functions, even in the
absence of florid psychosis (Bellack et al., 2007). This social
dysfunction in schizophrenia can have devastating consequences, with few patients being successfully married or in
regular productive employment (Bellack et al., 2007). Deficits
J.P. Docherty et al. / Schizophrenia Research 120 (2010) 199–203
in social function impact negatively on the patient's community and economic status, increasing the risk of isolation,
exclusion and poverty (Barrowclough and Tarrier, 1990;
Yager and Ehmann, 2006).
Importantly, social functioning impairments are already
present at the first psychotic episode (Grant et al., 2001) and
these impairments, if left untreated, pose a progressively
increasing barrier to overall functional recovery and become
increasingly difficult to remedy. Thus, monitoring and
management of social functioning is imperative from an
early stage of the illness. A Prosocial subscale of the Positive
and Negative Syndrome Scale (PANSS) that reflects impairment of interpersonal engagement has been derived by factor
analysis (Purnine et al., 2000). It consists of six items
(Table 1), four of which reflect a lack of social interaction or
emotional withdrawal or suspiciousness. In addition, a
Modified Prosocial subscale (Baran and Docherty, 2008)
was derived that consists of four PANSS items, including
difficulty with abstract thinking, an item that is not contained
in the Prosocial subscale but one that is empirically
demonstrated as a prominent residual symptom following
resolution of an acute psychotic episode (Table 1). A high
score on the Prosocial or Modified Prosocial subscales reflects
emotional withdrawal and a lack of social interaction.
Aripiprazole is an atypical antipsychotic with a novel
mechanism of action, exerting partial agonist activity at
dopamine D2 and D3 (Burris et al., 2002; Shapiro et al., 2003;
Tadori et al., 2005, 2008) and serotonin 5-HT1A receptors, and
antagonist activity at 5-HT2A receptors (Jordan et al., 2002,
2004). In addition to efficacy for the treatment of primary
positive and negative symptoms of schizophrenia (Kane et al.,
2002; Kasper et al., 2003; Pigott et al., 2003; Potkin et al.,
2003), aripiprazole has shown benefits on quality of life
outcomes in patients with schizophrenia (Kane et al., 2007;
Kerwin et al., 2007; Wolf et al., 2007). In addition, patients
switched from either olanzapine or risperidone to aripiprazole manifested improvements in subjective well-being
(Mizrahi et al., 2009).
Although improvement in social functioning is an important treatment goal, limited data exist on the effect of
antipsychotics on social functioning outcomes. This paper
presents the results of a post-hoc pooled analysis of two
52 week studies of aripiprazole versus haloperidol in patients
with early-episode schizophrenia. The aim of these analyses
was to assess the comparative effect of aripiprazole compared
with haloperidol on the PANSS Prosocial items in patients
with early-episode schizophrenia, given the importance of
minimizing the impact of these symptoms early in the course
of illness.
Table 1
PANSS items associated with social functioning.
Prosocial items
Purnine et al. (2000)
Modified Prosocial items
Baran and Docherty (2008)
G16: Active social avoidance
N2: Emotional withdrawal
N4: Passive social withdrawal
N7: Stereotyped thinking
P3: Hallucinatory behavior
P6: Suspiciousness/persecution
G16: Active social avoidance
N2: Emotional withdrawal
N4: Passive/apathetic social withdrawal
N5: Difficulty in abstract thinking
PANSS, Positive and Negative Syndrome Scale.
2. Methods
2.1. Study design
Data from two 52 week, double-blind, randomized, controlled trials comparing aripiprazole with haloperidol in the
treatment of schizophrenia were pooled for post-hoc analysis
(31-98-217 and 31-98-304). The primary study results and
associated methodology have previously been described
(Kasper et al., 2003).
2.2. Patients
The parent studies included males and females, aged 18–
65 years with a DSM-IV diagnosis of schizophrenia, who were
experiencing an acute relapse—defined as PANSS score ≥60,
and a score of ≥4 on at least two of four PANSS psychotic
items. For inclusion in this analysis, patients also had to meet
criteria for early episode: ≤40 years of age and ≤5 years
duration of illness.
2.3. Dosing
Patients were randomly assigned in a 2:1 ratio to
aripiprazole (30 mg) or haloperidol (5 mg, Days 1–3; 10 mg,
Day 4 onwards). The study medication was administered orally
once-daily after breakfast. After completion of the first week of
the double-blind acute treatment phase, a one-time dose
reduction was permitted as determined by clinical judgement
(20 mg for aripiprazole or 7 mg for haloperidol). Thus, patients
in the two studies received either 20–30 mg/day of aripiprazole or 5–10 mg/day of haloperidol.
2.4. Assessments
Efficacy for the treatment of positive and negative
symptoms was evaluated by the mean change in PANSS
Total score from baseline to Week 52 and those results have
been reported elsewhere (Girgis et al., submitted for
publication; Kim et al., 2007). Social functioning was assessed
by the mean change in the PANSS Prosocial subscale (Purnine
et al., 2000) and the Modified Prosocial subscale (Baran and
Docherty, 2008). The items included in the Prosocial and
Modified Prosocial scale are shown in Table 1. The “stereotyped thinking” item is assigned an opposite sign in the scale,
as it had an opposite signed factor-loading. Safety and
tolerability were evaluated by reports of adverse events
(AEs), serious adverse events (SAEs), discontinuations from
study due to AEs, change in weight and clinical laboratory
2.5. Statistical analysis
Analysis of covariance (ANCOVA) was used to analyze the
least squares mean change from baseline for the earlyepisode population in both treatment groups, with treatment
and protocol as the main effects and baseline score as
covariate with last observation carried forward (LOCF) for
the PANSS Total score and the two subscales — Prosocial and
Modified Prosocial. An observed case (OC) analysis was also
J.P. Docherty et al. / Schizophrenia Research 120 (2010) 199–203
3. Results
3.1. Patients
The mean age of this population of early-episode patients
was 27.5 years in the haloperidol group and 27.0 years in the
aripiprazole group. The majority of patients in both groups
were Caucasian males. Baseline PANSS Total scores were
similar in both groups: haloperidol, 92.5; aripiprazole, 95.2.
The full demographics of this population have been published
previously (Girgis et al., submitted for publication; Kim et al.,
2007). A greater proportion of patients with early-episode
schizophrenia treated with aripiprazole versus haloperidol
completed double-blind treatment (48% versus 28%, p b 0.01)
(Table 2). Significantly fewer patients discontinued due to
AEs unrelated to worsening schizophrenia from the aripiprazole versus haloperidol groups (11% versus 29%, p b 0.01)
(Table 2).
3.2. Dosing
The mean daily dose of aripiprazole was 28.1 (SD = 3.1)
mg/day and that of haloperidol was 8.9 (SD = 1.3) mg/day for
those subjects with early-episode schizophrenia.
3.3. Efficacy results
Mean change in PANSS Total score at Week 52 was
significantly greater in patients receiving aripiprazole versus
haloperidol (−21.8 versus −15.3; p = 0.02).
3.4. Social functioning results
Aripiprazole demonstrated significant improvements versus haloperidol as early as Week 18 on both the Prosocial
subscale (−4.75 versus − 3.78, LOCF, p b 0.05) (Fig. 1A) and
on the Modified Prosocial subscale (−3.16 versus −2.28,
LOCF, p b 0.05) (Fig. 1B). Using the LCOF analysis, patients
showed similar significant improvements over time at all
remaining testing intervals through Week 52 using the
Modified Prosocial subscale, but less consistent improvement
over time with the Prosocial subscale. Similar significant
improvements at Weeks 46 and 52 (endpoint) were observed
with both subscales (LOCF). Using an OC analysis, the
direction of change in both scales was consistent. However,
Table 2
Disposition of patients with early-episode schizophrenia.
Reason for discontinuation
Efficacy sample
Discontinued double-blind treatment
Lost to follow-up
Withdrawal of consent
Insufficient clinical response
Adverse event (worsening schizophrenia)
Other adverse event
Protocol violation
Patient met withdrawal criteria
Completed double-blind treatment
*pb 0.01 versus haloperidol, Chi-square test.
89 (72)
4 (3)
20 (16)
8 (7)
15 (12)
36 (29)
4 (3)
1 (1)
1 (1)
34 (28)
123 (52)
6 (3)
42 (18)
20 (8)
23 (10)
25 (11)*
6 (3)
1 (0)
114 (48)*
the magnitude of the treatment differences at Week 34 and
beyond was approximately two-thirds that of the LOCF
analyses, and not large enough for a statistically significant
difference to be observed except at Week 34, with a trend
toward significance (p b 0.10) at Week 52.
3.5. Safety results
The tolerability profile of aripiprazole in this subgroup of
patients with early-episode schizophrenia was generally
similar to the overall population. The most common AEs in
the aripiprazole group were insomnia, anxiety and akathisia.
The three most common AEs in the haloperidol group were
extrapyramidal syndrome (EPS), akathisia and insomnia.
4. Discussion
These data suggest that aripiprazole is superior to haloperidol for the reduction of social functioning impairment in earlyepisode schizophrenia patients, as measured by the PANSS
Prosocial and Modified Prosocial subscales. Such an effect may
provide an important advantage for patients in the early phase
of their illness in the achievement of a greater degree of overall
functional recovery. The efficacy of aripiprazole in improving
social functioning is in addition to the known efficacy in
treating a broad range of other symptoms (Janicak et al., 2009).
Further analysis of the dataset presented herein confirmed that
aripiprazole provides significantly greater improvement than
haloperidol on the PANSS Total score, even when the Prosocial
(−17.3 versus −12.2, p = 0.03) or Modified Prosocial items
(−18.7 versus −13.5, p = 0.03) are excluded, confirming that
efficacy is not restricted to those items. However, an evaluation
of all timepoints and effect sizes suggests that the items from
the Modified Prosocial subscale have slightly more effect than
other PANSS items in determining differences in efficacy
between aripiprazole and haloperidol (data not shown).
Social functioning deficits in schizophrenia are already
present early in the course of illness (Grant et al., 2001), and
improvement in such domains is of essential clinical value.
Social withdrawal and social exclusion are more likely among
patients with social functioning impairments, as these
patients often have problems holding an appropriate conversation, conveying their needs and feelings, or developing
close personal relationships (Bellack et al., 2007).
One strength of this analysis is the duration of the studies
from which the data is derived, an important consideration
since improvements in social functioning can only be meaningful if they endure. This study demonstrated that the
beneficial effect of aripiprazole, once achieved, was maintained
for up to one year. Another strength is the use of PANSS-derived
measures of social function. The broad use of the PANSS in
clinical studies makes a large number of studies accessible to
post-hoc analyses regarding social functioning.
A primary limitation of this paper is the post-hoc nature of
the analysis. In addition, the dose of haloperidol (5–10 mg/day)
used in this study, although within a range commonly seen
both in clinical practice and in other published studies, may be
considered to exceed optimal levels and may account for the
observed differences. It is important to note, however, that
lower doses of haloperidol may be accompanied by an
increased risk of relapse (Csernansky et al., 2002; Marder et
J.P. Docherty et al. / Schizophrenia Research 120 (2010) 199–203
Fig. 1. A. Mean change from baseline in PANSS Prosocial subscale (LOCF, efficacy sample) (*p b 0.05 versus haloperidol). B. Mean change from baseline in PANSS
Modified Prosocial subscale (LOCF, efficacy sample) (*p b 0.05 versus haloperidol).
al., 2003; Potkin et al., 2009). Post-hoc subgroup analyses raise
the potential for a Type I error. There are also limitations to the
speculation that functional recovery may be positively influenced by improvement in the Prosocial items. Overall functional recovery is influenced by many variables, and the effect
of an improvement in a PANSS-derived measure of social
functioning on overall functional recovery still needs to be
empirically assessed. Finally, consideration must be given to the
fact that the treatment differences observed in the OC analyses
were less robust than those seen in the LOCF analyses, although
the sample sizes in the former were considerably smaller.
In conclusion, however, these data do suggest that for
patients with early-episode schizophrenia, aripiprazole treatment may have an important enduring benefit over haloperidol in providing improvement in social function.
Role of funding source
This study was supported by Bristol-Myers Squibb(Princeton, NJ) and
Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). Bristol-Myers Squibb had a
role in the study design, analysis interpretation of the data, writing of report
and decision to submit the paper for publication. Editorial support for the
preparation of this manuscript was provided by Ogilvy Healthworld Medical
Education; funding was provided by Bristol-Myers Squibb.
J.P. Docherty developed one of the subscales used in these post-hoc
evaluations; independently proposed the idea for the analyses; and was
involved in directing the analysis and interpretation of the findings and
drafting, reviewing and approving the manuscript. R.A. Baker, S. Mathew, R.N.
Marcus, R.D. McQuade, and R. Mankoski played a critical role in designing the
post-hoc analyses, analysis and interpretation of data, literature searches and
analyses, or drafting, reviewing and approving the manuscript. J. Eudicone
undertook the statistical analysis and was involved in reviewing and
approving the manuscript.
Conflict of interest
Dr John Docherty has been on the Advisory Boards, Speakers Bureau or
has received grants from: Bristol-Myers Squibb, AstraZeneca, Janssen, and
Forest, Pfizer, and Merck.
Ross A Baker, James Eudicone, Ronald N. Marcus, and Raymond
Mankoski are employees of Bristol-Myers Squibb.
Suja Mathew is an employee of Otsuka America Pharmaceutical Inc.,
Rockville, MD, USA.
Robert D. McQuade is an employee of Otsuka Pharmaceutical Development & Commercialization, Inc.
J.P. Docherty et al. / Schizophrenia Research 120 (2010) 199–203
The authors would like to acknowledge the contributions of Edward Kim,
Kimberly Portland, formerly of Bristol-Myers Squibb and Andrei Pikalov,
formerly of Otsuka on the design and interpretation of these analyses.
Baran, X., Docherty, J., 2008. The A-effect of aripiprazole. Presented at the
American Psychiatric Association meeting. Washington, May 3–8 2008.
Barrowclough, C., Tarrier, N., 1990. Social functioning in schizophrenic
patients. I. The effects of expressed emotion and family intervention. Soc.
Psychiatry Psychiatr. Epidemiol. 25 (3), 125–129.
Bellack, A.S., Green, M.F., Cook, J.A., Fenton, W., Harvey, P.D., Heaton, R.K.,
Laughren, T., Leon, A.C., Mayo, D.J., Patrick, D.L., Patterson, T.L., Rose, A.,
Stover, E., Wykes, T., 2007. Assessment of community functioning in people
with schizophrenia and other severe mental illnesses: a white paper based
on an NIMH-sponsored workshop. Schizophr. Bull. 33 (3), 805–822.
Burris, K.D., Molski, T.F., Xu, C., Ryan, E., Tottori, K., Kikuchi, T., Yocca, F.D.,
Molinoff, P.B., 2002. Aripiprazole, a novel antipsychotic, is a high-affinity
partial agonist at human dopamine D2 receptors. J. Pharmacol. Exp. Ther.
302 (1), 381–389.
Csernansky, J.G., Mahmoud, R., Brenner, R., 2002. A comparison of
risperidone and haloperidol for the prevention of relapse in patients
with schizophrenia. N. Engl. J. Med. 346 (1), 16–22.
Girgis, R., Merrill, D., Vorel, S., Kim, E., Portland, K., You, M., Pikalov, A.,
Whitehead, R. and Lieberman, J., submitted for publication. Aripiprazole
versus haloperidol treatment in early-stage schizophrenia. J. Psychiatr. Res.
Grant, C., Addington, J., Addington, D., Konnert, C., 2001. Social functioning in
first- and multiepisode schizophrenia. Can. J. Psychiatry 46 (8), 746–749.
Janicak, P.G., Glick, I.D., Marder, S.R., Crandall, D.T., McQuade, R.D., Marcus, R.N.,
Eudicone, J.M., Assuncao-Talbott, S., 2009. The acute efficacy of aripiprazole
across the symptom spectrum of schizophrenia: a pooled post hoc analysis
from 5 short-term studies. J. Clin. Psychiatry 70 (1), 25–35.
Jordan, S., Koprivica, V., Chen, R., Tottori, K., Kikuchi, T., Altar, C.A., 2002. The
antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT
(1A) receptor. Eur. J. Pharmacol. 441 (3), 137–140.
Jordan, S., Koprivica, V., Dunn, R., Tottori, K., Kikuchi, T., Altar, C.A., 2004. In
vivo effects of aripiprazole on cortical and striatal dopaminergic and
serotonergic function. Eur. J. Pharmacol. 483 (1), 45–53.
Kane, J.M., Carson, W.H., Saha, A.R., McQuade, R.D., Ingenito, G.G., Zimbroff,
D.L., Ali, M.W., 2002. Efficacy and safety of aripiprazole and haloperidol
versus placebo in patients with schizophrenia and schizoaffective
disorder. J. Clin. Psychiatry 63 (9), 763–771.
Kane, J.M., Meltzer, H.Y., Carson Jr., W.H., McQuade, R.D., Marcus, R.N.,
Sanchez, R., 2007. Aripiprazole for treatment-resistant schizophrenia:
results of a multicenter, randomized, double-blind, comparison study
versus perphenazine. J. Clin. Psychiatry 68 (2), 213–223.
Kasper, S., Lerman, M.N., McQuade, R.D., Saha, A., Carson, W.H., Ali, M.,
Archibald, D., Ingenito, G., Marcus, R., Pigott, T., 2003. Efficacy and safety
of aripiprazole vs. haloperidol for long-term maintenance treatment
following acute relapse of schizophrenia. Int. J. Neuropsychopharmacol 6
(4), 325–337.
Kerwin, R., Millet, B., Herman, E., Banki, C.M., Lublin, H., Pans, M., Hanssens, L.,
L'Italien, G., McQuade, R.D., Beuzen, J.N., 2007. A multicentre, randomized, naturalistic, open-label study between aripiprazole and standard of
care in the management of community-treated schizophrenic patients.
Schizophrenia Trial of Aripiprazole (STAR) Study. Eur. Psychiatry 22 (7),
Kim, E., Eudicone, J., Portland, K. and Pikalov, A., 2007. Efficacy of aripiprazole
versus haloperidol in early episode schizophrenia. Presented at the
American Psychiatric Association 160th Annual Meeting, San Diego, CA,
May 19–24, 2007. NR283.
Marder, S.R., Glynn, S.M., Wirshing, W.C., Wirshing, D.A., Ross, D., Widmark,
C., Mintz, J., Liberman, R.P., Blair, K.E., 2003. Maintenance treatment of
schizophrenia with risperidone or haloperidol: 2-year outcomes. Am. J.
Psychiatry 160 (8), 1405–1412.
Mizrahi, R., Mamo, D., Rusjan, P., Graff, A., Houle, S., Kapur, S., 2009. The
relationship between subjective well-being and dopamine D2 receptors
in patients treated with a dopamine partial agonist and full antagonist
antipsychotics. Int. J. Neuropsychopharmacol 12 (5), 715–721.
Pigott, T.A., Carson, W.H., Saha, A.R., Torbeyns, A.F., Stock, E.G., Ingenito, G.G.,
2003. Aripiprazole for the prevention of relapse in stabilized patients
with chronic schizophrenia: a placebo-controlled 26-week study. J. Clin.
Psychiatry 64 (9), 1048–1056.
Potkin, S.G., Saha, A.R., Kujawa, M.J., Carson, W.H., Ali, M., Stock, E.,
Stringfellow, J., Ingenito, G., Marder, S.R., 2003. Aripiprazole, an
antipsychotic with a novel mechanism of action, and risperidone vs
placebo in patients with schizophrenia and schizoaffective disorder.
Arch. Gen. Psychiatry 60 (7), 681–690.
Potkin, S.G., Weiden, P.J., Loebel, A.D., Warrington, L.E., Watsky, E.J., Siu, C.O.,
2009. Remission in schizophrenia: 196-week, double-blind treatment
with ziprasidone vs. haloperidol. Int. J. Neuropsychopharmacol 12 (9),
Purnine, D.M., Carey, K.B., Maisto, S.A., Carey, M.P., 2000. Assessing positive
and negative symptoms in outpatients with schizophrenia and mood
disorders. J. Nerv. Ment. Dis. 188 (10), 653–661.
Shapiro, D.A., Renock, S., Arrington, E., Chiodo, L.A., Liu, L.X., Sibley, D.R., Roth,
B.L., Mailman, R., 2003. Aripiprazole, a novel atypical antipsychotic drug
with a unique and robust pharmacology. Neuropsychopharmacol 28 (8),
Tadori, Y., Miwa, T., Tottori, K., Burris, K.D., Stark, A., Mori, T., Kikuchi, T., 2005.
Aripiprazole's low intrinsic activities at human dopamine D2L and D2S
receptors render it a unique antipsychotic. Eur. J. Pharmacol. 515 (1–3),
Tadori, Y., Forbes, R.A., McQuade, R.D., Kikuchi, T., 2008. Characterization of
aripiprazole partial agonist activity at human dopamine D(3) receptors.
Eur. J. Pharmacol. 597 (1–3), 27–33.
Wolf, J., Janssen, F., Lublin, H., Salokangas, R.K., Allain, H., Smeraldi, E.,
Bernardo, M., Millar, H., Pans, M., Adelbrecht, C., Laughton, J., Werner, C.,
Maier, W., 2007. A prospective, multicentre, open-label study of
aripiprazole in the management of patients with schizophrenia in
psychiatric practice in Europe: Broad Effectiveness Trial with Aripiprazole in Europe (EU-BETA). Curr. Med. Res. Opin. 23 (10), 2313–2323.
Yager, J.A., Ehmann, T.S., 2006. Untangling social function and social cognition:
a review of concepts and measurement. Psychiatry 69 (1), 47–68.