human psychopharmacology

Hum. Psychopharmacol Clin Exp 2016

Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/hup.2542

Haloperidol versus second-generation antipsychotics in the long-term

treatment of schizophrenia
Massimiliano Buoli1,2*, René S. Kahn2, Marta Serati1, A. Carlo Altamura1, Wiepke Cahn2
1
Department of Psychiatry, University of Milan, Milan, Italy
2
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands

Objective The purpose of the study was to compare antipsychotic monotherapies in terms of time to discontinuation in a sample of
schizophrenia patients followed-up for 36 months.
Methods Two hundred and twenty schizophrenia patients, treated with antipsychotic monotherapy and followed-up in psychiatric
outpatient clinics of Universities of Milan and Utrecht were included in the study. A survival analysis (Kaplan–Meier) of the 36-month
follow-up period was performed to compare the single treatment groups. End-point was considered as discontinuation of treatment for
recurrence, side effects or non-compliance.
Results Patients treated with haloperidol discontinued more than the other groups (Breslow: risperidone p < 0.001, olanzapine p < 0.001,
quetiapine p = 0.002, clozapine p < 0.001, aripiprazole p = 0.002). Lack of efficacy (recurrence) was a more frequent reason for discontinu-
ation in the haloperidol group than in the olanzapine group (p < 0.05). Extrapyramidal side effects (EPS) were more frequent in the haloper-
idol group than with olanzapine (p < 0.05). The olanzapine group presented more frequently weight gain than the other groups, without
reaching statistical significance.
Conclusions Patients treated with atypical antipsychotics appear to continue pharmacotherapy longer than patients treated with haloperidol.
In addition, atypical antipsychotics seem to be more protective against recurrences than haloperidol. However, these results should be
cautiously interpreted in the light of potential confounder factors such as duration of illness. Copyright © 2016 John Wiley & Sons, Ltd.

key words—schizophrenia; haloperidol; second-generation antipsychotics; maintenance treatment

INTRODUCTION duration of illness and number of recurrences have

Schizophrenia is a highly disabling condition, affect-
ing about 0.6–0.8% of the general population without
significant differences between countries (McGrath
et al., 2008). Many schizophrenia patients show a sig-
nificant decline in social functioning which can be fur-
ther more serious in case of delayed proper
pharmacological treatment (Penttilä et al., 2014).
Pharmacological treatment of schizophrenia is not
limited to the remission of acute symptoms (e.g. delu-
sions, and hallucinations), but is aimed to the preven-
tion of recurrences (Glick et al., 2011). Of note, long
*Correspondence to: M. Buoli, MD, Department of Psychiatry, University
of Milan, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico,
Via F. Sforza 35, 20122, Milan, Italy. Tel.: +39-02-55035983; Fax: +39-
02-55033190 E-mail: massimiliano.buoli@hotmail.it
Disclosure: Dr. Buoli has served as a consultant for Roche. Prof. Altamura
has served as a consultant or on Advisory Boards for Roche, Merck, Astra
Zeneca, Bristol Myers Squibb, Janssen/Cilag and Lundbeck. Prof. Kahn is a
member of DSMBs for Janssen, Otsuka, Roche and Sunovion. Drs Cahn
and Serati do not have any affiliation with or financial interest in any
organization that might pose a conflict of interest with the present article.
Funding Sources: No funding sources were received for the present article
been associated with severity of brain changes, level
of social functioning and risk of chronicity (Haijma
et al., 2013; Meyer-Lindenberg and Tost, 2014).
Kane, 1996 showed that continuous pharmacologi-
cal treatment is superior to intermittent treatment for
prevention of relapses of schizophrenia patients. A re-
cent meta-analysis compared intermittent versus con-
tinuous drug techniques in schizophrenia, reaching
the same conclusions (Sampson et al., 2013). As about
50% of schizophrenia patients have poor compliance
to pharmacological treatment, depot medications are
really advantageous in terms of continuity of treatment
(Leucht et al., 2012), but they present higher risk of
acute severe side effects with respect to oral medica-
tions (Gentile, 2013). Among oral medications, it is
currently debated if some molecules (e.g. first versus
second-generation antipsychotics) have a clear advan-
tage in terms of effectiveness in long-term treatment
of schizophrenia patients (Lewis and Lieberman,
2008). From a pharmacodynamic point of view,
second-generation antipsychotics should be more

Received 26 October 2015

Revised 4 May 2016
Copyright © 2016 John Wiley & Sons, Ltd. Accepted 4 May 2016
 m. buoli et al.
effective in terms of prevention of recurrences than
haloperidol, in light of their broad spectrum of action
and their consequent activity on the different clinical
dimensions of schizophrenia (Altamura and Dragogna,
2013). In contrast, haloperidol has a clear advantage
with respect to placebo in terms of amelioration of
positive symptoms, but it can worsen motor and nega-
tive symptoms (King, 1998). Despite these specula-
tions, a number of studies reported equal (Peuskens
et al., 2009; Crespo-Facorro et al., 2011; McEvoy
et al., 2014; Nielsen et al., 2015;) or even less effec-
tiveness of second-generation antipsychotics than
first-generation antipsychotics in long-term treatment
of schizophrenia (Kennedy et al., 2009). In contrast,
in 2011 preliminary results by the group investigators
from the University of Milan showed a clear advantage
of olanzapine and risperidone compared to haloperidol
(Altamura et al., 2011). Similar results have been re-
ported by meta-analyses (Kishimoto et al., 2013;
Soares-Weiser et al., 2013) as well as by an open-label
study (Crespo-Facorro et al., 2012)
The purpose of the present paper is to replicate
previous data about the time of discontinuation of anti-
psychotics in the long-term treatment of schizophrenia
(Altamura et al., 2011), comparing a greater number of
monotherapies (haloperidol, clozapine, risperidone,
olanzapine, quetiapine, aripiprazole) in a more exten-
sive sample of patients both from the University of
Milan and Utrecht.
METHODS
Patients were selected from those treated and followed-
up at outpatient psychiatry clinics of Universities of
Milan and Utrecht between 1997 and 2013. All pa-
tients with a diagnosis of schizophrenia according to
DSM-IV-TR (Diagnostic and Statistical Manual of
Mental Disorders; SCID-I) (First et al., 1997) were
taken into consideration, including in the study only
those who were oral antipsychotic monotherapy and
had been in clinical remission for at least 1 month ac-
cording to Andreasen’s criteria (Andreasen et al.,
2005). Follow-up period was set at 3 years correspond-
ing to the observational period of Group schizophrenia
cohort of University of Utrecht. As in our previous
study follow-up period corresponded to 4 years
(Altamura et al., 2011), survival data of the University
of Milan were rearranged over a period of 3 years.
Patients did not change antipsychotic doses during
the observational period.
Patients, who were treated with concomitant psycho-
tropic medications (with the exception of occasional
Copyright © 2016 John Wiley & Sons, Ltd.
use of benzodiazepines for insomnia) or with medical
therapies that could interfere with overall psychopa-
thology (e.g. cortisone), were excluded. In the Milan
database, patients with concomitant use of mood stabi-
lizers or antidepressants were excluded from this anal-
ysis to limit confounding factors (the concomitant
therapy with mood stabilizers or antidepressants was
not an exclusion criterion in previously published
data). None of the patients received specific rehabilita-
tion programs during the follow-up period with the
exception of social supports by caregivers and nurses.
Patients who were treated with antipsychotic depot
medications were excluded for three reasons: 1) depot
treatments identify patients with a more severe illness
(subjects with poor insight and consequently
partial/no compliance) 2) the lack of availability of
depot medications for all atypical antipsychotics (e.g.
clozapine) 3) the impossibility to compare depot
versus oral medications in terms of treatment adherence.
Patients who suffered from any medical comorbidity
that might be associated with psychiatric symptoms
(such as dementias or hyperthyroidism) were not taken
into consideration. Apart from these exclusion criteria,
2 patients from Milan (1 with zuclopenthixol and 1 with
trifluoperazine) and 3 from Utrecht (2 with perfenazine
and 1 with flupentixol) were excluded from survival
analysis for the small sample size of the potential sub-
groups (number for a statistical analysis)
Collected data included:
• demographic variables: age and gender
• clinical variables: antipsychotic oral monotherapy,
antipsychotic mean dose and its haloperidol
equivalents, side effects, reason of discontinuation,
substance and alcohol misuse, number of previous
acute episodes, duration of illness, duration of
untreated psychosis (DUP), baseline PANSS total
scores, baseline PANSS “hostility item” scores.
Patients were divided into groups according to their
oral antipsychotic monotherapy (haloperidol,
clozapine, risperidone, olanzapine, quetiapine and
aripiprazole).
The demographic and clinical variables were
compared between the treatment groups using χ 2 tests
for dichotomous variables or multivariate analyses of
variance (MANOVAs) for continuous variables. In
case of statistically significant differences between
groups or potential confounders (e.g. lifetime sub-
stance misuse), Cox regression analyses have been
provided to detect factors which might influence time
to recurrence. A survival analysis (Kaplan-Meier) of
the follow-up period (36 months) was performed to
Hum. Psychopharmacol Clin Exp 2016.
DOI: 10.1002/hup
 long-term treatment of schizophrenia
compare the single-treatment groups. End-point was Table 1. Demographic and clinical variables of the total sample
considered discontinuation of treatment for recurrence, Gender Male 62.3%
side effects or non-compliance. Reasons of discontinua- Female 37.7%
tion (recurrences, side effects, non-compliance) and
types of side effects were also compared between Age 31.61 (+10.713) years
Duration of illness 6.98 (+8.104) years
the treatment groups, using χ2 tests with Bonferroni’s Duration of untreated 1.294 (+3.413) years
post hoc analyses. A recurrence was defined as a score psychosis (DUP)
of 58 or higher on the Positive and Negative Syn- Number of previous 1.90 (+2.271)
acute episodes
drome Scale (PANSS) for schizophrenia (Leucht PANSS baseline score 39.868 (+5.146)
et al., 2005). PANSS “hostility item” 1.154 (+0.462)
baseline score
Substance misuse lifetime None 73.2%
Cannabis 26.4%
Cocaine 0.4%
RESULTS Cannabis misuse lifetime No 73.6%
Yes 26.4%
459 patients from Utrecht and 212 patients from Milan Alcohol misuse lifetime No 79.1%
(N = 671) were initially screened as they had a diagno- Yes 20.9%
sis of schizophrenia, they had been followed-up for at Reasons of discontinuation Non-discontinuation 51.8%
Inefficacy (recurrences) 36.4%
least three years, were in clinical remission for at least Side effects 5.0%
one month and they had no changes in doses of oral Non-compliance 6.8%
antipsychotics. Side effects None 75.9%
Extrapyramidal symptoms 9.1%
After the application of exclusion criteria (depot Weight gain 13.2%
medications, polytherapies and medical comorbidities Sedation 1.4%
associated with psychiatric symptoms), the total sam- Diabetes 0.4%
ple included 220 patients, 137 men (62.3%) and 83 PANSS: Positive and Negative Syndrome Scale.
women (37.7%); mean age was 31.61 years (s.d. Standard deviations for continuous variables are reported into brackets.
= 10.713). Data about clinical and demographic
variables of the whole sample are reported in Table 1. Table 2. Antipsychotic distribution, mean dosages and haloperidol
The distribution of antipsychotic monotherapies in equivalent doses
the sample, their dosages and the related mean equiva-
Mean
lent haloperidol doses (Andreasen et al., 2010) are haloperidol
reported in Table 2. Mean duration of antipsychotic Frequency % Mean dose equivalent
treatment was 24.764 ± 13.82 months. Patients who Antipsychotic (N) Patients (mg/day) dose (mg/day
did not discontinue therapy during the follow-up Risperidone 48 21.8 3.26 3.26
period were 51.8%; reasons for discontinuation were Olanzapine 82 37.2 14.82 5.93
recurrences (36.4%), side effects (5.0%) and non- Quetiapine 15 6.8 463.33 4.63
Clozapine 36 16.4 325 4.33
compliance (6.8%). Haloperidol 27 12.3 4.3 4.33
75.9% of subjects did not experience side effects. Aripiprazole 12 5.5 18.33 3.67
The more represented adverse reactions were weight
gain (13.2%), extrapyramidal symptoms (EPS)
(9.1%), sedation (1.4%) and diabetes (0.4%). In contrast, statistically significant differences were
No statistically significant differences were found found for age (F = 6.509, p < 0.001), duration of illness
among treatment groups in relation to number of previ- (F = 2.824, p = 0.017), mean haloperidol equivalent
ous acute episodes (F = 0.42, p = 0.834), DUP doses (F = 11.074, p < 0.001), gender distribution
(F = 1.851, p = 0.104), baseline PANSS total scores (χ 2 = 19.931, df = 5, p = 0.01), reason of discontinuation
(F = 1.26, P = 0.29), baseline PANSS “hostility item” (χ2 = 26.754, df = 15, p = 0.033) and type of side effects
scores (F = 1.13, p = 0.35), lifetime cannabis misuse (χ2 = 40.65, df = 20, p = 0.008) (Table 3). In addition,
(χ 2 = 8.653, df = 5, p = 0.121), lifetime substance mis- haloperidol and risperidone were more frequently
use (χ 2 = 10.339, df = 10, p = 0.369), lifetime alcohol prescribed in Milan, while clozapine and quetiapine in
misuse (χ 2 = 2.095, df = 5, p = 0.847). In addition, life- Utrecht (χ2 = 66.701, df = 5, p < 0.001), while no differ-
time cannabis (OR = 0.41, p = 0.38), cocaine ences in frequency of prescription between the two sites
(OR = 0.27, p = 0.2) and alcohol misuses (OR = 1.27, were found for aripiprazole and olanzapine (p > 0.05).
p = 0.37) were not found to be predictive of treatment With regard to age, patients in treatment with halo-
discontinuation. peridol were older (mean age: 39.59 + 11.119) than

Copyright © 2016 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2016.
DOI: 10.1002/hup
 m. buoli et al.
Table 3. Demographic and clinical variables in the treatment sub-groups

Variables Risperidone Olanzapine Quetiapine Clozapine Haloperidol Aripiprazole

Gender Male 64.6% 68.3% 66.6% 75% 25.9% 50.0%

Female 35.4% 31.7% 33.4% 25% 74.1%* 50.0%
Age 31.98 (10.73) 32.37 (11.83) 28.13 (7.05) 26.72 (5.3) 39.59 (11.12)^ 26 (5.19)
Duration of illness (years) 6.65 (7.6) 7.02 (9.4) 3.74 (3.84) 6.16 (4.57) 11.64 (10.02)Δ 4.05 (2.64)
Duration of untreated 1.24 (2.69) 1.43 (3.99) 0.91 (2.29) 0.24 (0.69) 2.88 (5.25) 0.77 (1.29)
psychosis (DUP) (years)
Number of previous 1.85 (1.89) 1.93 (2.6) 1.4 (0.63) 2.19 (1.62) 2.07 (3.4) 1.33 (0.78)
acute episodes
PANSS baseline score 39.06 (4.83) 39.84 (5.25) 41.66 (5.6) 40.72 (5.06) 38.66 (4.18) 41.16 (6.85)
PANSS “hostility item” 1.13 (0.44) 1.13 (0.44) 1.00 (0.0) 1.22 (0.59) 1.3 (0.54) 1.08 (0.29)
baseline score
Substance None 75% 73.1% 66.7% 61.1% 92.6% 66.7%
misuse lifetime Cannabis 25% 25.6% 33.3% 38.9% 7.4% 33.3%
Cocaine 0% 1.3% 0% 0% 0% 0%
Cannabis misuse lifetime No 75% 74.4% 66.7% 61.1% 92.6% 66.7%
Yes 25% 25.6% 33.3% 38.9% 7.4% 33.3%
Alcohol misuse lifetime No 81.2% 78.7% 73.3% 80.6% 74.1% 91.7%
Yes 18.8% 21.3% 26.7% 19.4% 25.9% 8.3%
Reasons of Non-discontinuation 47.9% 60.1% 60% 61.1% 11.1% 58.3%
discontinuation Inefficacy 39.6% 29.3% 33.3% 30.6% 66.7%⌂ 25%
(recurrences)
Side effects 6.25% 5.3% 0% 2.8% 11.1% 0%
Non-compliance 6.25% 5.3% 6.7% 5.5% 11.1% 16.7%
Side effects None 83.3% 73.2% 86.7% 72.2% 63% 91.7%
Extrapyramidal 8.35% 2.4% 13.3% 8.3% 33.3%∞ 0%
symptoms
Weight gain 8.35% 22% 0% 16.7% 0% 8.3%
Sedation 0% 1.2% 0% 2.8% 3.7% 0%
Diabetes 0% 1.2% 0% 0% 0% 0%

*p < 0.05 compared to risperidone, olanzapine and clozapine.

⌂
p < 0.05 compared to olanzapine.
^
p < 0.05 compared to the other groups.
∞
p < 0.05 compared to olanzapine.
Δ
p < 0.05 compared to quetiapine.
Standard deviations for continuous variables are reported into brackets.

other groups (risperidone: 31.98 + 10.73, p = 0.042;
olanzapine: 32.37 + 11.83, p = 0.015; quetiapine:
28.13+ 7.049, p = 0.009; clozapine: 26.72 + 5.295,
p < 0.001; aripiprazole: 26.00 + 5.187, p = 0.001). A
Cox regression analysis was then performed to see if
age could influence the continuation in treatment how-
ever age was not found to be predictive of treatment
discontinuation (OR = 1.008, p = 0.383).
With regard to duration of illness, Bonferroni’s post
hoc analyses showed only statistical significance be-
tween haloperidol and quetiapine groups (haloperidol:
11.636 + 10.026 years, quetiapine: 3.74 + 3.844 years;
p = 0.041). Cox regression analysis did not indicate
an influence of duration of illness on continuation in
treatment (OR = 0.99, p = 0.7)
With regard to haloperidol mean equivalent doses,
the olanzapine group was treated with higher haloper-
idol equivalent doses than other groups with the excep-
tion of quetiapine (olanzapine versus risperidone:
p < 0.001; olanzapine versus quetiapine: p = 0.414;
olanzapine versus clozapine: p = 0.004; olanzapine
versus haloperidol: p = 0.010; olanzapine versus
aripiprazole: p = 0.008). The other treatment groups
were comparable in terms of haloperidol equivalent
doses. A Cox regression analysis was then performed
to see if haloperidol equivalent doses could influence
the continuation in treatment, however the doses were
not found to be predictive of continuation in treatment
(OR = 0.952, p = 0.282).
With regard to gender distribution, females were
more frequently treated with haloperidol than with
risperidone (p < 0.05), olanzapine (p < 0.05) and
clozapine (p < 0.05). Cox regression analysis did not
indicate an influence of gender distribution on contin-
uation in treatment (OR = 0.95, p = 0.79)
With regard to reason of discontinuation, inefficacy
(recurrence) was more frequently reason of discontinua-
tion in haloperidol group than in olanzapine group
(p < 0.05). Levels of compliance did not result to be sig-
nificantly different between treatment groups (p > 0.05)
With regard to side effects, EPS were more frequent
in haloperidol group (33.3%) than in olanzapine one

Copyright © 2016 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2016.
DOI: 10.1002/hup
 long-term treatment of schizophrenia
(2.4%) (p < 0.05). Olanzapine group presented more
frequently weight gain than the other groups without,
however, reaching statistical significance (p > 0.05; ris-
peridone 8.3%, olanzapine 21.9%, quetiapine 0.0%,
clozapine 18.7%, haloperidol 0.0%, aripiprazole 8.3%).
The antipsychotic showing the highest rate of
survival was clozapine (61.1% of patients, mean sur-
vival 27.5 months), followed by olanzapine (61.0% of
patients, mean survival 27.098 months), quetiapine
(60.0% of patients, mean survival 28.6 months),
aripiprazole (58.3% of patients, mean survival
27.583 months), risperidone (47.9% of patients, mean
survival 24.417 months) and haloperidol (11.1% of
patients, mean survival 11.259 months).
Patients treated with risperidone survived in the
study significantly more than patients treated with hal-
operidol (Log-Rank χ 2 = 18.293, p < 0.001; Breslow
χ 2 = 19.575, p < 0.001). Patients treated with
olanzapine survived significantly more than patients
treated with haloperidol (Log-Rank χ2 = 30.571,
p < 0.001; Breslow χ2 = 27.190, p < 0.001). Patients
treated with quetiapine survived significantly more
than patients treated with haloperidol (Log-Rank
χ2 = 11.282, p = 0.001; Breslow χ2 = 9.287, p = 0.002).
Patients treated with clozapine survived significantly
more than patients treated with haloperidol (Log-Rank
χ2 = 23.343, p < 0.001; Breslow χ2 = 22.36,
p < 0.001). Patients treated with aripiprazole survived
significantly more than patients treated with haloperi-
dol (Log-Rank χ2 = 9.925, p = 0.002; Breslow
χ2 = 9.81, p = 0.002). Finally, patients treated with hal-
operidol survived less than the other groups (Breslow:
risperidone p < 0.001, olanzapine p < 0.001,
quetiapine p = 0.002, clozapine p < 0.001, aripiprazole
p = 0.002) (Figure 1.) No further significant differences
were found between groups in terms of survival
(p > 0.05).
DISCUSSION
The first result to be highlighted is that only half of pa-
tients maintained the initial prescribed therapy in the
follow-up period, similarly to previous observational
studies (Kahn et al., 2008). This means that mainte-
nance treatment of schizophrenia is really challenging
as a result of several reasons which include the partial
effectiveness of pharmacological treatments, poor
compliance of the patients and the development of se-
rious side effects.
Patients in treatment with atypical antipsychotics ap-
pear to maintain pharmacotherapy longer than patients
treated with haloperidol. In addition, inefficacy was
more frequently reason of discontinuation in
Copyright © 2016 John Wiley & Sons, Ltd.
haloperidol group than in olanzapine one. No signifi-
cant differences were found among atypical antipsy-
chotics. These results are consistent with those
published in previous observational naturalistic studies
(Dossenbach et al., 2008; Altamura et al., 2011;
Crespo-Facorro et al., 2012). In our previous pub-
lished data (Altamura et al., 2011), patients in treat-
ment with olanzapine survived significantly more
than those treated with risperidone. In the current anal-
ysis, risperidone is the compound which presents the
worst “survival” among atypical compounds, although
this difference did not reach statistical significance.
Probably a broader spectrum of action allows for better
protection on the recurrences in patients with schizo-
phrenia in light of the different neurotransmitter alter-
ations involved in the etiology of schizophrenic
illness (Janicak et al., 2009). This study supports a ma-
jor effectiveness of atypical antipsychotics compared
to haloperidol in the long-term treatment of schizo-
phrenia. This result has important implications with
respect to public management of schizophrenia
patients. Of note, the recent economic crisis and the
cuts in mental health spending may lead local officials
to promote and enhance the use of first-generation
antipsychotics (certainly cheaper) than second genera-
tion ones.
Haloperidol was more frequently prescribed in fe-
male senior patients. This may be because haloperidol
is frequently used in older patients for its little effect on
the cholinergic system and consequently on memory
processes. Moreover, the greater distribution in fe-
males might be explained as a consequence of more
frequent concern of women patients about the meta-
bolic effects and weight gain of atypical antipsychotics
(Karthik et al., 2013).
Finally, similarly to what was found in previous re-
searches, haloperidol treatment resulted to be fre-
quently associated with EPS and olanzapine with
weight gain, although motor symptoms might be
more frequent with chronic treatment with haloperi-
dol than weight gain with olanzapine. However,
treatment groups were not different in terms of
discontinuation because of side effects. This means
that, at equivalent effectiveness (in this case of atypi-
cal antipsychotics), clinicians should select molecules
that are expected to be more tolerated by patients in
order to improve their quality of lives (Briggs et al.,
2008).
These results should be interpreted cautiously be-
cause of the potential confounding factors that may
characterize a naturalistic study like this. Even though
Cox regression analyses failed to find an association
between age/duration of illness and time to
Hum. Psychopharmacol Clin Exp 2016.
DOI: 10.1002/hup
 m. buoli et al.
Figure 1. Survival in the different treatment groups
discontinuation, published data indicate that older
chronic schizophrenia patients may have poor re-
sponse to antipsychotic therapy (Altamura et al.,
2015). Similar considerations may be done for lifetime
substance abuse (DeLisi and Fleischhacker, 2015).
Fortunately, in our sample there were no significant
differences between groups with respect to substance
abuse and haloperidol group presented less lifetime
substance abuse (92.6%) than other groups, identifying
in this case maybe a subgroup with better prognosis.
Female gender was more frequently distributed in hal-
operidol group, although again Cox regression analy-
sis failed to find an association between gender
distribution and time to discontinuation. Different gen-
der distribution between groups may certainly have in-
fluenced the results of the present sample, however
available data indicate that female schizophrenia
patients have usually a better outcome than male ones
(Ceskova et al., 2015; Ochoa et al., 2012). Furthermore,
Copyright © 2016 John Wiley & Sons, Ltd.
different levels of treatment compliance, although not
significantly different between groups, may have af-
fected the time of discontinuation.
Finally some potential limitations of the study are
worth mentioning:
(1) the lack of randomization;
(2) the lack of a complete overview of first-generation
antipsychotics (lack of comparisons with neurolep-
tics different from haloperidol);
(3) different drug mean doses (haloperidol was not the
group with the lowest equivalent doses);
(4) the groups were not homogenous in number as
usual in naturalistic retrospective studies;
(5) schizophrenia patients treated with oral monother-
apies might be a group with a better prognosis than
chronic patients with polytherapies: this could also
explain the discordance with the results published
in other papers (Peuskens et al., 2009);
Hum. Psychopharmacol Clin Exp 2016.
DOI: 10.1002/hup
 long-term treatment of schizophrenia
(6) some clinical variables were collected in Utrecht,
but not in Milan and vice versa and this has limited
the comparison of treatment groups in terms of
clinical variables at baseline;
(7) as patients come from different centres, type of
mental health organization might have influenced
the survival of patients. However, inefficacy was
the main reason of discontinuation, while compli-
ance is probably more influenced by the type of
care given to patients with schizophrenia.
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DOI: 10.1002/hup