ANALISIS JURNAL

EFEKTIVITAS FARMAKOTERAPI UNTUK GANGGUAN

DELUSI DI SWEDIA
Disusun Sebagai Syarat Memenuhi Tugas Praktik Stase
Keperawatan Jiwa Fakultas Ilmu
Kesehatan Program Studi Profesi Ners

Nama Kelompok A4:

Risti Rosanti 2020206023

Zyaskia Monika 2020206035

PROGRAM STUDI PROFESI NERS

FAKULTAS ILMU KESEHATAN
UNIVERSITAS ‘AISYIYAH
YOGYAKARTA
2021
EFEKTIVITAS FARMAKOTERAPI UNTUK GANGGUAN DELUSI
DI SWEDIA

No. Komponen yang di kritisi Hasil penelitian

1. Judul Efektivitas farmakoterapi untuk gangguan delusi di
Swedia
2. Nama Peneliti Markku Lähteenvuo a, Heidi Taipale , Antti
Tanskanen, Ellenor Mittendorfer-Rutz b, Jari
Tiihonen.
3. Tahun Jurnal 2021
4. Abstrak Latar Belakang: Sedikit yang diketahui
tentang pengobatan farmakologis yang efektif
untuk gangguan delusi.

Tujuan: Mempelajari perbandingan efektivitas

farmakoterapi dalam pencegahan rawat inap
akibat psikosis dan ketidakmampuan kerja pada
gangguan waham.

Metode penelitian: studi kohort berbasis

registri observasional termasuk semua orang di
Swedia yang didiagnosis dengan gangguan
delusi (N = 9076; waktu tindak lanjut rata-rata
4,9 tahun). Analisis utama adalah Cox
Proportional Hazards dalam analisis individu.

Hasil: Di antara kohort (4835 laki-laki/4241

perempuan; rata-rata [SD] usia 44,1 [12,5]
tahun), 2074 orang memiliki setidaknya satu
rawat inap karena psikosis. Risiko rawat inap
karena psikosis adalah 46% lebih rendah ketika
antipsikotik digunakan (HR 0,54, 95% CI 0,38-
0,77, p <0,001). Penggunaan clozapine (HR
0,24, 95% CI 0,07-0,77, p = 0,016), injeksi
jangka panjang (LAI; HR 0,28, 95%CI 0,16-
0,49, p <0,0001) dan olanzapine oral (HR 0,36,
95%CI 0,20-0,67, p = 0,001) dikaitkan dengan
risiko terendah. Di antara mereka yang tidak
menjalani pensiun cacat pada awal tindak lanjut
(n = 5025), dibandingkan tanpa penggunaan
antipsikotik, penggunaan clozapine (HR 0,08,
95% CI 0,01-0,52, p = 0,008), LAI apa saja (HR
0,44, 95%CI 0,25–0,79, p = 0,006) dan
aripiprazole oral (HR 0,52, 95%CI 0,31–0,85, p
= 0,009) dikaitkan dengan risiko kecacatan
kerja yang paling rendah.

Kesimpulan: Penggunaan antipsikotik

dikaitkan dengan penurunan risiko rawat inap
karena psikosis dan kecacatan kerja pada
gangguan delusi, dengan penggunaan clozapine
dan suntikan jangka panjang dikaitkan dengan
risiko terendah untuk titik akhir yang sangat
relevan ini baik untuk penderitaan individu
maupun biaya bagi masyarakat. Uji klinis
dengan perawatan ini sangat dibutuhkan untuk
membuat rekomendasi perawatan klinis yang
terinformasi
 Kekuatan:
Dalam abstrak sudah didapatkan mengenai latar
belakang, tujuan penelitian, metode, hasil, dan
kesimpulan.

Kekurangan:
Kekurangan dalam abstrak ini belum ada evaluasi
dari penelitian dan di bagian latar belakang kurang
lengkap.
5. Latar belakang Gangguan waham adalah gangguan mental
kronis yang serius dengan perkiraan prevalensi
seumur hidup sebesar 0,2% (American Psychiatric
Association,2013). Berbagi fitur psikotik serupa
seperti skizofrenia, delusi gangguan sering diobati
dengan pendekatan serupa, meskipun ada banyak
perbedaan antara kedua sindrom ini (Opjordsmoen,
1988; Marneros dkk., 2012; Opjordsmoen, 2014).
Stabilitas diagnostik dari gangguan delusi telah
dilaporkan sekitar 60-80% (Opjordsmoen, 1988;
Marneros et al., 2012; Opjordsmoen, 2014), dan
hanya sejumlah kecil pasien yang kemudian
mengalami transisi ke skizofrenia (Opjordsmoen,
1988; Opjordsmoen, 2014).
Tidak seperti di skizofrenia, pasien dengan
gangguan delusi sering fit untuk bekerja, jika
delusi mereka dapat diobati dengan sukses.
Mereka juga umumnya membutuhkan jauh lebih
sedikit perawatan rumah sakit dan rawat inap paksa
dibandingkan pasien dengan skizofrenia, membuat
rawat inap menjadi ukuran hasil suboptimal untuk
mengevaluasi mengatasi penyakit. Ukuran hasil
seperti cacat kerja jangka panjang telah dipelajari,
meskipun mereka mungkin lebih relevan dalam
menilai koping pasien secara keseluruhan.
Sementara pengobatan farmakologis skizofrenia
telah dipelajari secara ekstensif, tidak banyak data
yang ada pada gangguan delusi. Sebuah tinjauan
Cochrane sistematis baru-baru ini oleh Skelton et
al. hanya menemukan satu uji coba terkontrol acak
(RCT) yang memenuhi syarat untuk dianalisis, dan
bahkan itu adalah untuk terapi perilaku kognitif vs
plasebo, dan tidak ada yang memenuhi syarat
untuk terapi farmakologis ditemukan (Skelton et
al., 2015a; Skelton dkk., 2015b). Meskipun
kurangnya RCT, banyak ulasan tentang
pengobatan farmakologis dari gangguan delusi
telah dilakukan keluar selama bertahun-tahun dari
beberapa laporan kasus dan studi observasional.

6. Tujuan penelitian Mempelajari perbandingan efektivitas

farmakoterapi dalam pencegahan rawat inap
akibat psikosis dan ketidakmampuan kerja pada
gangguan waham.
7. Metode penelitian dan Mengidentifikasi semua pasien yang menerima
pengambilan sampel diagnosis gangguan delusi (ICD-10:F22, setara
dengan DSM-5:297.1, N = 9076) di Swedia
selama tahun 2005-2016 baik rawat inap atau
rawat jalan khusus perawatan menggunakan daftar
Pasien Nasional (NPR) yang dikumpulkan secara
prospektif, termasuk data dari pasien rawat inap
(sejak 1964) dan pasien rawat jalan khusus
perawatan (sejak 2001).
Seorang pasien dimasukkan ke dalam kohort
pada saat diagnosis pertama untuk gangguan
delusi atau 1 Januari 2006 jika diagnosis pertama
sebelum itu. Data dikumpulkan dari NPR
(rawat inap), Data mikro untuk analisis daftar
asuransi sosial (MiDAS) (cacat kerja,
didefinisikan sebagai absen karena sakit dan
pensiun cacat), dan daftar Obat Resep (obat yang
dibagikan). yang sesuai Kode ICD-8 dan -9
digunakan untuk menghitung waktu sejak
diagnosis pertama (ICD-9:297B–297C, 297W,
297X, ICD-8:297). Orang dengan diagnosis
skizofrenia sebelumnya, skizoafektif gangguan
atau gangguan bipolar (F20, F25, F30-31)
dikeluarkan dan tindak lanjut disensor jika subjek
penelitian menerima salah satu dari diagnosis ini
selama tindak lanjut. Individu dengan rawat inap
karena psikosis selama periode tindak lanjut (n =
2074) dianalisis untuk risiko rawat inap. Sub-
kohort pasien yang belum menjalani pensiun cacat
pada awal tindak lanjut (n = 5025) dianalisis
untuk risiko kecacatan kerja PRE2DUP yang telah
divalidasi sebelumnya (Pembelian obat resep ke
mengidentifikasi semua pasien yang menerima
diagnosis gangguan delusi (ICD-10:F22, setara
dengan DSM-5:297.1, N = 9076) di Swedia
selama tahun 2005-2016 baik rawat inap atau
rawat jalan khusus perawatan menggunakan daftar
Pasien Nasional (NPR) yang dikumpulkan secara
prospektif, termasuk data dari pasien rawat inap
(sejak 1964) dan pasien rawat jalan khusus
perawatan (sejak 2001). Seorang pasien
dimasukkan ke dalam kohort pada saat diagnosis
pertama untuk gangguan delusi atau 1 Januari
2006 jika diagnosis pertama sebelum itu. Data
dikumpulkan dari NPR (rawat inap), Data mikro
untuk analisis daftar asuransi sosial (MiDAS)
(cacat kerja, didefinisikan sebagai absen karena
sakit dan pensiun cacat), dan daftar Obat Resep
(obat yang dibagikan). yang sesuai Kode ICD-8
dan -9 digunakan untuk menghitung waktu sejak
diagnosis pertama (ICD-9:297B–297C, 297W,
297X, ICD-8:297).
Orang dengan diagnosis skizofrenia
sebelumnya, skizoafektif gangguan atau
gangguan bipolar (F20, F25, F30-31)
dikeluarkan dan tindak lanjut disensor jika subjek
penelitian menerima salah satu dari diagnosis ini
selama tindak lanjut. Individu dengan rawat inap
karena psikosis selama periode tindak lanjut (n =
2074) dianalisis untuk risiko rawat inap. Sub-
kohort pasien yang belum menjalani pensiun cacat
pada awal tindak lanjut (n = 5025) dianalisis untuk
risiko kecacatan kerja
Data dianalisis untuk seluruh periode tindak
lanjut 2006–2016. Analisis utama adalah model
bahaya proporsional Cox dalam individu, yang
dijelaskan dalam publikasi kami sebelumnya secara
lebih rinci (Tiihonen et al., 2017). Jenis analisis ini
hanya mempertimbangkan pasien dengan hasil yang
tercatat dan variasi dalam paparan. Analisis
disesuaikan untuk efek waktu sejak masuknya
kohort, urutan pengobatan sementara, dan
penggunaan pengobatan farmakologis lainnya saat
ini. Hanya perawatan yang digunakan di luar
periode rumah sakit dapat dicatat dari pendaftar dan
urutan temporal karena itu hanya mengacu pada
perawatan digunakan dalam pelayanan rawat jalan.
Jadi, jika seorang pasien menggunakan tiga
perawatan yang berbeda pada rawat inap awal,
hanya perawatan pasien yang dipulangkan dengan
akan ditugaskan sebagai pengobatan pertama.
Pengaruh urutan kronologis perawatan di rawat
jalan disesuaikan dengan mengkategorikan
perawatan pertama, kedua, ketiga, dan keempat atau
lebih. Hasil adalah dilaporkan sebagai rasio
bahaya yang disesuaikan (HR) dengan interval
kepercayaan 95% (95% CI). Nilai-P di bawah 0,05
setelah penemuan palsu Benjamini-Hochberg
koreksi tingkat untuk beberapa perbandingan
dianggap secara statistik penting. Nilai p nominal
ditampilkan di seluruh naskah. Analisis sekunder
dilakukan dengan menggunakan tradisional
perbandingan antara individu dengan model hazard
proporsional Cox. Analisis tambahan disesuaikan
untuk usia saat masuk kohort, jenis kelamin,
penyalahgunaan zat, percobaan bunuh diri
sebelumnya, penyakit kardiovaskular, diabetes,
asma/PPOK, kanker, jumlah rawat inap sebelumnya
karena psikosis, penggunaan LAI sebelumnya, dan
penggunaan farmakoterapi tambahan (antidepresan,
benzodiazepin dan obat terkait, penstabil mood),
opioid, analgesik non-opioid, dan obat anti-
parkinson, didefinisikan seperti pada penelitian
sebelumnya (Tiihonen et al., 2017). Semua data
yang tersedia di register yang direkam sebelum
dimulainya tindak lanjut digunakan untuk
identifikasi dari kovariat. Risiko rawat inap juga
dianalisis dalam subkohort pasien yang tidak
menjalani pensiun cacat pada awal tindak lanjut,
berfungsi sebagai analisis sensitivitas.

Kelebihan:
.
1. Penelitian yang dilakukan juga dengan
memberikan asuhan keperawatan secara
lengkap mulai ari pengkajian hingga
evaluasi.
Kekurangan:
1. Pengambilan sampel peneliti tidak
menyebutkan cara pengambilannya, apakah
secara acak atau bagaimana.
8. Hasil & Pembahasan Ditemukan bahwa penggunaan antipsikotik
dikaitkan dengan penurunan risiko rawat inap
karena psikosis dan ketidakmampuan kerja
dalam delusi kekacauan. Sebelum penelitian
kami, disabilitas kerja sangat jarang digunakan
sebagai ukuran hasil dalam studi registri. Sebelum
studi kita, pengetahuan pada farmakoterapi yang
paling efektif untuk gangguan delusi telah juga
langka, meskipun umumnya dianggap sebagai
gangguan yang sulit diobati karena ketidakpatuhan
dan anosognosia, sering menyebabkan pengobatan
nihilisme. Di sisi lain, pasien gangguan delusi
memiliki lebih sedikit kebutuhan untuk rawat inap
dan mempertahankan kognisi mereka dan
berfungsi lebih baik daripada pasien dengan
skizofrenia, dan sering dapat terus bekerja
meskipun gangguan mereka jika delusi mereka
dikendalikan (Opjordsmoen, 1988; Marneros et al.,
2012; Opjordsmo 2014). Definisi operasional
Untuk hasil klinis dalam delusi gangguan masih
dalam diskusi dan seringkali kriteria yang sama
digunakan seperti untuk skizofrenia. Ini
bermasalah, karena kedua gangguan itu jelas
berbeda, baik dalam hal perjalanan alami penyakit
tetapi juga dalam hal tingkat fungsi yang dapat
dicapai dengan perawatan yang tepat.
Dengan demikian, kecacatan kerja mungkin
merupakan hasil yang lebih penting untuk
kelompok pasien ini daripada rawat inap, dan
menemukan perawatan yang paling efektif untuk
ini gangguan cenderung memiliki dampak besar
tidak hanya pada kualitas pasien kehidupan tetapi
juga pada beban ekonomi masyarakat.
Hasil menunjukkan bahwa meskipun
kepatuhan mungkin menjadi masalah,
antipsikotik tampaknya efektif jika digunakan,
seperti yang juga telah ditunjukkan oleh banyak
orang. ulasan yang telah dilakukan (Munro dan
Mok, 1995; Manschreck dan Khan, 2006; Lepping
dkk., 2007; Mews dan Quante, 2013; Roudsari
dkk., 2015; Skelton dkk., 2015a; Skelton dkk.,
2015b; Muñoz-Negro dan Cervilla, 2016; Muñoz-
Negro dkk., 2020). Namun, perbedaan dalam
efektivitas antipsikotik yang berbeda juga diamati.
Meskipun gangguan delusi telah dianggap sebagai
gangguan yang mempengaruhi terutama sistem
dopaminergik (Morimoto et al., 2002), gunakan
clozapine dikaitkan dengan penurunan risiko rawat
inap karena untuk psikosis dan kecacatan kerja
dalam kelompok pasien Swedia ini dengan
gangguan delusi. Meskipun setidaknya satu
jaringan besar yang lebih tua meta-analisis
menempatkan clozapine pada dasar yang rata
dengan yang lain antipsikotik generasi kedua
dalam mengobati skizofrenia (Samara et al., 2016),
 meta-analisis yang lebih baru telah menunjukkan
clozapine lebih unggul terhadap antipsikotik lain
baik pada skizofrenia yang resisten terhadap
pengobatan, tetapi juga pada skizofrenia yang
resisten terhadap pengobatan (Masuda et al., 2019).
Di dalam sejalan dengan ini, hasil kami juga
menunjukkan bahwa clozapin tidak dapat dianalisis
menggunakan metode ini, dan mungkin atau
mungkin tidak lebih lazim pada individu yang
menggunakan farmakoterapi dengan rasio bahaya
untuk hasil utama.

Kelebihan :

Kekurangan: Pemaparan yang Panjang sehingga

memerlukan waktu dan konsentrasi yang lebih untuk
menelaahnya
9. Kesimpulan Menurut data yang disajikan di sini, banyak
antipsikotik efektif dalam pengobatan gangguan
delusi, sehingga tidak ada alasan untuk nihilisme
pengobatan, meskipun uji klinis sangat diperlukan
untuk membuat rekomendasi perawatan klinis yang
terinformasi.
Namun, sampai saat itu, karena clozapine dan
injeksi jangka panjang tidak digunakan secara luas,
tetapi masih dikaitkan dengan risiko kecacatan dan
kecacatan kerja yang paling rendah. rawat inap
karena psikosis dalam penelitian kami, mereka
harus lebih luas dipertimbangkan untuk pasien
dengan gangguan delusi yang tidak memenuhi
kontraindikasi

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Schizophrenia
Contents lists available
Research at ScienceDirect
228 (2021)
367–372

Schizophrenia Research

es
Effectiveness of pharmacotherapies for delusional disorder in a
Swedish national cohort of 9076 patients☆
Markku Lähteenvuo a,⁎, Heidi Taipale a,b,c, Antti Tanskanen a,d, Ellenor Mittendorfer-Rutz b,
Jari Tiihonen a,d,e
a
Niuvanniemi Hospital, Niuvankuja 65, 70240 Kuopio, Finland
b
Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Berzelius väg 3, 17177 Stockholm, Sweden
c
School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70210 Kuopio, Finland
d
Department of Clinical Neuroscience, Karolinska Institutet, Tomtebodavägen 18A, 171 77 Stockholm, Sweden
e
Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm Health Care Services, Region Stockholm, Norra Stationsgatan
69, 11364 Stockholm, Sweden

a r t i c l e info
abstract
Article history:
Received 13 October 2020 Background: Little is known on the effective pharmacological treatment of delusional
Received in revised form 17 disorder. Aims: Study the comparative effectiveness of pharmacotherapies in the prevention of
December 2020 Accepted 18 hospitalization due to psy- chosis and work disability in delusional disorder.
January 2021 Methods: Observational registry based cohort study including everyone in Sweden diagnosed
Available online 3 February 2021 with delusional dis- order (N = 9076;mean follow-up time 4.9 years). The primary analysis
was Cox Proportional Hazards within- individual analysis. Results are reported as adjusted
Keywords: hazard ratios (HRs).
Psychosis
Results: Among the cohort (4835 males/4241 females;mean [SD] age 44.1 [12.5] years), 2074
Pharmacoepide
persons had at least one hospitalization due to psychosis. Risk for hospitalization due to
miology
psychosis was 46% lower when any antipsy- chotic was used (HR 0.54, 95%CI 0.38–0.77, p <
Hospitalization
Work disability 0.001). Use of clozapine (HR 0.24, 95%CI 0.07–0.77, p = 0.016), any long-acting injectable
(LAI; HR 0.28, 95%CI 0.16–0.49, p < 0.0001) and oral olanzapine (HR 0.36, 95%CI 0.20–
0.67, p = 0.001) were associated with lowest risk. Among those not on disability pension at
start of follow-up (n = 5025), in comparison to no use of antipsychotics, use of clozapine (HR
0.08, 95%CI 0.01–0.52, p = 0.008), any LAI (HR 0.44, 95%CI 0.25–0.79, p = 0.006) and
oral aripiprazole (HR 0.52, 95%CI 0.31–0.85,
p = 0.009) were associated with lowest risk of work disability.
Conclusions: Use of antipsychotics was associated with a reduced risk of hospitalization due to
psychosis and work disability in delusional disorder, with use of clozapine and long-acting
injectables being associated with the lowest risk for these very relevant end-points for both
individual suffering and costs to society. Clinical trials with these treatments are urgently
needed to make informed clinical treatment recommendations.
© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-
NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

1.Introduction
Delusional disorder is a serious chronic mental disorder
with a life- time prevalence estimate of 0.2% (American
Psychiatric Association, 2013). Sharing similar psychotic
features as schizophrenia, delusional disorder is often treated
with similar approaches, although there are many differences
between these two syndromes (Opjordsmoen, 1988;
Marneros et al., 2012; Opjordsmoen, 2014). The diagnostic
stability of delusional disorder has been reported to be
around 60–80% (Opjordsmoen, 1988; Marneros et al., 2012;
Opjordsmoen, 2014), and only a small number of patients
later experience a transition to
☆ Previous presentation: Our initial results have been presented at the
ACNP conference in Dec 2019 in Florida. An abstract has been submitted
to the ECNP meeting for the fall of 2020.
⁎ Corresponding author.
E-mail address: Markku.Lahteenvuo@niuva.fi (M. Lähteenvuo).
schizophrenia (Opjordsmoen, 1988; Opjordsmoen, 2014).
Unlike in schizophrenia, patients with delusional disorder
are often fit to work, if their delusions can be treated
successfully. They also generally require markedly less
hospital care and involuntary hospitalizations than pa-
tients with schizophrenia, making hospitalization a
suboptimal out- come measure to evaluate coping with
illness. Outcome measures such as long-term work
disability have been understudied, although they might be
more relevant in assessing the overall coping of the pa-
tients. While the pharmacological treatment of
schizophrenia has been studied extensively, not much data
exists on delusional disorder. A recent systematic
Cochrane review by Skelton et al. found only one el- igible
randomized controlled trial (RCT) to be analyzed, and
even that was for cognitive behavioral therapy vs. placebo,
and no eligible ones for pharmacological therapies were
found (Skelton et al., 2015a; Skelton et al., 2015b). Despite
the lack of RCTs, multiple reviews of the pharmacological
treatment of delusional disorder have been carried out
during the years from the few case reports and
observational studies

https://doi.org/10.1016/j.schres.2021.01.015
0920-9964/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
M. Lähteenvuo, H. Taipale, A. Tanskanen et Schizophrenia Research 228 (2021) 367–
al. 372

available, totaling to a few hundred patients (Munro and Mok, 1995; separately) based on package information recorded for each filling of
Manschreck and Khan, 2006; Lepping et al., 2007; Freudenmann a prescription. Based on drugs used by this cohort, main exposure
and Lepping, 2008; Huber et al., 2011; Mews and Quante, 2013; measures included five most commonly used oral antipsychotics
Roudsari et al., 2015; González-Rodríguez et al., 2016; Muñoz- (olanzapine, clozapine, quetiapine, risperidone, aripiprazole) and all
Negro and Cervilla, 2016; Muñoz-Negro et al., 2020). The latest other orals were grouped
review stated that antipsychotics are an effective treatment in
general, although no specific compound has clearly been found to
be superior over another and in general more research on the topic
is needed (Muñoz-Negro et al., 2020). Of note, the TAILOR study
reported to start in Denmark, is aiming to study antipsychotic
treatments for delusional disorder in addition to schizophrenia
(Stürup et al., 2017).
Since little is known about the comparative effectiveness of specific
pharmacological treatments of delusional disorder, we aimed to study
the comparative real-world effectiveness of pharmacological agents to
prevent hospitalization due to psychosis and work disability in a Swed-
ish national cohort of patients with delusional disorder (N = 9076). To
our knowledge, this is the first study overall looking at the
effectiveness of pharmacological therapies in preventing work
disability.

2.Materials and methods

2.1. Study design and data acquisition

We identified all patients who received a diagnosis of delusional

dis- order (ICD-10:F22, equates to DSM-5:297.1, N = 9076) in
Sweden dur- ing the years 2005–2016 in either inpatient or
specialized outpatient care using prospectively gathered National
Patient register (NPR), in- cluding data from inpatient (since 1964)
and specialized outpatient care (since 2001). A patient was entered
into the cohort at time of first diagnosis for delusional disorder or
January 1, 2006 if the first diag- nosis was before that. Data was
collected from NPR (hospitalizations), Micro-data for analyses of
social insurance (MiDAS) register (work dis- ability, defined as
sickness absence and disability pension), and Pre- scribed Drug
register (dispensed medications). The corresponding ICD-8 and -9
codes were used to calculate time since first diagnoses (ICD-
9:297B–297C, 297W, 297X, ICD-8:297).
Persons with previous diagnoses of schizophrenia,
schizoaffective disorder or bipolar disorder (F20, F25, F30–31)
were excluded and the follow-up censored if study subject received
any of these diagnoses dur- ing follow-up. Individuals with a
hospitalization due to psychosis during the follow-up period (n =
2074) were analyzed for hospitalization risk. A sub-cohort of
patients not already on disability pension at start of follow-up (n =
5025) were analyzed for risk of work disability.

2.2. Exposure

The previously validated PRE2DUP (Prescription drug purchases to

Drug Use Periods) method was used to define exposure and non-
exposure periods for medications (Taipale et al., 2016; Tanskanen
et al., 2015, 2017). The method calculates the current dose on a
daily basis with a sliding mean, uses package information (eg,
number of tab- lets and administration intervals for injections), and
takes into account stockpiling and hospitalizations when
constructing time periods of con- tinuous use. The method allows
variation in dose and thus no artificial grace periods are used.
Antipsychotics were defined as Anatomical Therapeutic Chemical
code N05A except for lithium carbonate (N05AN01);
antidepressants as N06A, mood stabilizers as N03AF01
(carbamazepine), N03AG01 (valproic acid), N03AX09
(lamotrigine), and N05AN01 (lithium); benzodiazepines and related
drugs as N05BA, N05CD and N05CF. Antipsychotics were modeled
according to drug form (ie, oral and long-acting injectables, LAIs,
36
M. Lähteenvuo, H. Taipale, A. Tanskanen et Schizophrenia Research 228 (2021) 367–
together
al. (other orals), as were all
LAIs (any LAI) and concurrent use into sub-cohorts according to their372 work-disability status at the

of multiple antipsychotics (polytherapy). beginning of follow-up is shown in

2.3. Outcomes

The main outcome measures were hospitalization due ICD-10 codes

F20-F29 “Schizophrenia, schizotypal, delusional and other non-mood
psychotic disorders” (subsequently referenced to as “psychosis”) and
work disability, defined as start of sickness absence or disability
pension (regardless of level of compensation or diagnoses).
Additional analysis
was conducted for sickness absence with psychiatric diagnoses
(ICD- 10:F-diagnoses) as an outcome.

2.4. Statistical analyses

The data were analyzed for the whole follow-up period of 2006–
2016. The primary analysis was a within-individual Cox propor-
tional hazards model, described in our earlier publications in more
de- tail (Tiihonen et al., 2017). This analysis type only considers
patients with a recorded outcome and variation in exposure. Analyses
were ad- justed for the effects of time since cohort entry, temporal
order of treat- ments, and current use of other pharmacological
treatments. Only treatments used outside hospital periods could be
recorded from the registries and the temporal order therefore refers
only to treatments used in outpatient care. Thus, if a patient used
three different treatments at initial hospitalization, only the treatment
the patient got discharged with would be assigned as the first
treatment. The effect of chronologi- cal order of treatments in
outpatient care was adjusted for by categoriz- ing treatments as first,
second, third, and fourth or more. Results are reported as adjusted
hazard ratios (HRs) with 95% confidence intervals (95%CI). P-values
below 0.05 after Benjamini-Hochberg false discovery rate correction
for multiple comparisons were considered statistically significant.
Nominal p-values are displayed throughout the manuscript. Secondary
analyses were performed using traditional
between-individual comparisons with Cox proportional hazard models.
The analyses were additionally adjusted for age at cohort entry,
gender, substance abuse, previous suicide attempts, cardiovascular
disease, dia- betes, asthma/COPD, cancer, the number of previous
hospitalizations due to psychosis, prior use of LAI, and use of
adjunctive pharmacother- apies (antidepressants, benzodiazepines and
related drugs, mood stabi- lizers), opioids, non-opioid analgesics and
anti-parkinson drugs, defined as in a previous study (Tiihonen et al.,
2017). All available data in the registers recorded before start of
follow-up were used for identification of covariates. The risk of
hospitalization was also analyzed in a sub- cohort of patients not on
disability pension at the start of follow up, to
serve as a sensitivity analysis.

2.5. Ethical statement

The Regional Ethics Board of Stockholm approved this research

pro- ject (decision 2007/762–31).

3.Results

3.1. Cohort

The cohort included 9076 individuals of whom 4835 (53.3%)

were male. The mean age (SD) of the cohort was 44.1 (12.5) years.
The mean follow-up was 4.9 years, totaling to a total observation
time of 41,793 person-years. During the follow up, 2074 (22.9%)
individuals had a hospitalization due to psychosis. At the start of
the follow-up, 4051 (44.6%) individuals were already on disability
pension and thus, were excluded from work disability analyses,
leaving 5025 to be in- cluded. Of these 5025, 2153 (42.8%) had a
work disability event during follow up. The division of the patients
36
Supplemental Fig. 1. The sociodemographic, clinical and treatment Person Expected
Treatment -years events Events HR (95% CI) p-value
char- acteristics of the total cohort, also divided into sub-cohorts of
patients using or not using clozapine, are shown in detail in Table 1. No use 22208 1257 1257 1 reference
Any
Clozapine users were on average younger, but had a more severe antipsychotic 19585 1165 629 0.54 (0.38 to 0.77) 0.0007*
disease history, with more previous hospitalizations, suicide Clozapine 522 59 14 0.24 (0.07 to 0.77) 0.0161*
attempts, substance abuse, comorbid personality disorders, prior Any LAI 2350 218 62 0.28 (0.16 to 0.49) <0.0001*
use of LAIs, and polypharmacy with other psychiatric medications. Aripiprazole 1459 68 24 0.35 (0.13 to 0.94) 0.0372
The same informa- tion for the sub-cohort of patients not initially Olanzapine 4175 191 69 0.36 (0.20 to 0.67) 0.0011*
on work disability are shown in Supplemental Table 1 in the Polytherapy 3504 409 217 0.53 (0.34 to 0.83) 0.0052*
Supplement. Risperidone 3048 137 78 0.57 (0.32 to 0.99) 0.0474
Other oral 3426 104 118 1.13 (0.66 to 1.94) 0.6517
3.2. Risk of hospitalization due to psychosis Quetiapine 1100 21 47 2.24 (0.94 to 5.34) 0.0683
Adjunct
In comparison to no use of any antipsychotic, among the treatments
individuals who had hospitalizations due to psychosis during the No use 24735 1431 1431 1 reference
follow-up period (n = 2074), the risk for psychotic hospitalization Mood stabilizer 787 29 23 0.80 (0.36 to 1.80) 0.5936
was 46% lower when BZDR 4355 203 166 0.82 (0.52 to 1.28) 0.3797
any antipsychotic was used (HR 0.54, 95%CI 0.38–0.77, p < 0.001). Antidepressant 5918 100 83 0.83 (0.49 to 1.40) 0.4779
Any
Among specific pharmacological agents reaching statistical significance, combination 5887 159 176 1.11 (0.70 to 1.76) 0.6575
use of clozapine (HR 0.24, 95%CI 0.07–0.77, p = 0.016), any LAI (HR Lithium 110 5 7 1.33 (0.26 to 6.70) 0.7298
0.28, 95%CI 0.16–0.49, p < 0.0001), olanzapine (HR 0.36, 95%CI
0.20–0.67, p = 0.001) or polytherapy with any two or more Fig. 1. Risk of hospitalization due to psychosis by pharmacological treatment in the
antipsychotics (HR 0.53, 95%CI 0.34–0.83, p = 0.005) was associated total cohort of patients with a hospitalization outcome. HR = hazard ratio, CI =
with a reduced risk of hospitalization due to psychosis. Use of adjunct confidence interval, LAI = long-acting injectable, BZDR = benzodiazepine or related
drug. * and green markers denote results significant after Benjamini-Hochberg false
pharmacological treat- ments were not associated with a significantly
discovery rate correction for multiple comparisons at a 0.05 threshold. Expected
lower risk. These results are shown in Fig. 1. In the traditional events are calculated as events/HR.
between-individual analyses, the re- sults were similarly beneficial for
clozapine, LAIs, olanzapine and polytherapy, although use of
aripiprazole was associated with the lowest risk of hospitalization due
to psychosis (Supplemental Table 2). 3.3. Risk of work disability on those not already disabled
In the sub-cohort of patients not on disability pension at the start
of follow-up, use of clozapine (HR 0.06, 95%CI 0.01–0.52, p = Almost half (n = 4051, 45%) of the patients were already on disabil-
ity pension at the time of cohort entry. Among those who were not, in
0.010), any LAI (HR 0.11, 95%CI 0.04–0.29, p < 0.001), olanzapine
(HR 0.17, 95% CI comparison between use and no use of any antipsychotic, use of any
0.05–0.50, p = 0.002), polytherapy with two or more
antipsychotics (HR 0.32, 95%CI 0.15–0.66, p = 0.002) and
risperidone (HR 0.38, 95%
CI 0.18–0.81, p = 0.011) was associated with a decreased risk of
hospi- talization due to psychosis (Table 2).

Table 1
Sociodemographics, clinical and treatment variables for the total cohort and sub-cohorts of clozapine users and non-clozapine users at the start of follow up. *p-Value: t-test for
age, chi- squared test for categorical variables between clozapine users and non-users. SD = standard deviation, LAI = long-acting injectable, CED = cohort entry date,
a
percentage of those on disability pension.

Baseline covariates Total cohort Sub-cohort of clozapine non-users Sub-cohort of clozapine users p-Value* (clozzapine non-user
(N = 9076) (n = 8639) (n = 437) vs. user)

Age, mean (SD) 44.1 (12.5) 45.4 (12.4) 38.6 (12.7) <0.0001
Male gender, % (n) 53.3 (4835) 53.0 (4578) 58.8 (257) 0.0174
Time in years since first delusional disorder 0.2733
diagnosis, % (n)
≤1 88.1 (7994) 88.2 (7619) 85.8 (375)
1–5 3.5 (316) 3.4 (296) 4.6 (20)
>5 8.4 (766) 8.4 (724) 9.6 (42)
The number of previous any psychiatric <0.0001
hospitalizations, % (n)
0–1 65.1 (5907) 66.2 (5722) 42.3 (185)
2–3 17.4 (1579) 17.3 (1493) 19.7 (86)
≥4 17.5 (1590) 16.5 (1424) 38.0 (166)
Previous suicide attempt, % (n) 8.1 (734) 7.9 (679) 12.6 (55) 0.0004
Substance abuse, % (n) 19.3 (1754) 18.9 (1635) 27.7 (119) <0.0001
Personality disorder, % (n) 6.8 (618) 6.5 (562) 12.8 (56) <0.0001
Disability pension, % (n) 44.6 (4051) 44.0 (3802) 57.0 (249) <0.0001
Mental and behavioral disorders a 72.0 (2915) 71.2 (2708) 83.1 (207)
Musculoskeletal conditions a 7.3 (295) 7.5 (286) 3.6 (9)
Unemployment during previous year, % (n) 0.2133
1–179 days 9.2 (836) 9.2 (792) 10.1 (44)
≥180 days 3.2 (291) 3.3 (283) 1.8 (8)
Prior use of LAI, % (n) 5.0 (453) 4.8 (414) 8.9 (39) 0.0001

Medication use during one year before CED

Antidepressant use, % (n) 32.6 (2958) 32.2 (2780) 40.7 (178) 0.0002
Benzodiazepine use, % (n) 18.5 (1683) 18.0 (1552) 30.0 (131) <0.0001
Z-drug use, % (n) 22.1 (2003) 21.7 (1872) 30.0 (131) <0.0001
Mood stabilizer use, % (n) 3.4 (311) 3.2 (279) 7.3 (32) <0.0001
Antipsychotic use, % (n) 45.0 (4080) 44.2 (3817) 60.2 (263) <0.0001
Table 2
Risk of hospitalization due to psychosis by pharmacological treatment in the sub-cohort of patients not on disability pension at the start of follow-up and with a hospitalization
outcome. HR = hazard ratio, CI = confidence interval, LAI = long-acting injectable. *Denote results significant after Benjamini-Hochberg false discovery rate correction for multiple
comparisons at a
0.05 threshold. Expected events are calculated as events/HR.

Treatment Person-years Expected events Events HR (95% CI) p-Value

No use 12,394 653 1 Reference
Clozapine 158 33 2 0.06 (0.01 to 0.52) 0.0104*
Any LAI 790 140 15 0.11 (0.04 to 0.29) <0.0001*
Olanzapine 1999 176 29 0.17 (0.05 to 0.50) 0.0015*
Aripiprazole 839 60 17 0.29 (0.07 to 1.11) 0.0694
Polytherapy 1267 277 88 0.32 (0.15 to 0.66) 0.0022*
Risperidone 1306 128 48 0.38 (0.18 to 0.80) 0.0113*
Other oral 1364 83 50 0.60 (0.26 to 1.40) 0.2401
Quetiapine 549 9 17 1.94 (0.49 to 7.60) 0.3433

antipsychotic was associated with a 29% decreased risk of work disabil-
ity (HR 0.71, 95%CI 0.57–0.90, p = 0.004) as compared to no use.
Among specific pharmacological agents reaching statistical
significance, use of clozapine (HR 0.08, 95%CI 0.01–0.52, p =
0.008), any LAI (HR 0.44,
95%CI 0.25–0.79, p = 0.006), aripiprazole (HR 0.52, 95%CI 0.31–0.85,
p = 0.009), or polytherapy with any two or more antipsychotics (HR
0.52, 95%CI 0.33–0.82, p = 0.005) was associated with a decreased
risk of work disability (Fig. 2). Use of adjunct pharmacological treat-
ments were not associated with a significantly lower risk. In the tradi-
tional between-individual analyses, clozapine was again associated
with the lowest risk, with only clozapine and olanzapine having benefi-
cial HRs, but none of the beneficial results reaching statistical signifi-
cance (Supplemental Table 3). The within-individual analysis for risk
of sickness absence (but not work disability) was also conducted for
psychiatric diagnoses only (ICD-10:F-diagnoses), which indicated that
the majority of work-disability events were from psychiatric sickness
absences (F-diagnoses sickness absence event numbers compared to
any diagnosis work disability event numbers). The rank order and haz-
ard ratios were roughly similar for these two analyses (work disability
due to any diagnosis or sickness absence due to F-diagnoses, data not
shown). When analyzing risk of disability pension per use of
pharmaco- logical treatments in between-individual analysis, all
treatments were associated with an increased hazard ratio (data not
shown).
4.Discussion
We found that use of antipsychotics was associated with a
reduced risk of hospitalization due to psychosis and work disability
in delusional disorder. Prior to our study, work disability has very
seldom been used as an outcome measure in registry studies. Before
our study, knowledge on the most effective pharmacotherapies for
delusional disorder has also been scarce, although generally it has
been considered as a hard- to-treat disorder due to non-compliance
and anosognosia, often causing treatment nihilism. On the other
hand, delusional disorder patients have less need for
hospitalizations and maintain their cognition and functioning
better than patients with schizophrenia, and are often able to
continue working despite their disorder if their delusions are
controlled (Opjordsmoen, 1988; Marneros et al., 2012;
Opjordsmoen, 2014). The operational definitions for clinical
outcomes in delusional disorder are still under discussion and often
the same criteria are used

Person Expected
Treatment -years Events HR (95% CI) p-value
events
No use 4324 1673 1 reference
Any antipsychotic 4217 1470 1045 0.71 (0.57 to 0.90) 0.0037*
Clozapine 38 131 11 0.08 (0.01 to 0.52) 0.0077*
Any LAI 200 160 71 0.44 (0.25 to 0.79) 0.0062*
Aripiprazole 260 219 113 0.52 (0.31 to 0.85) 0.0086*
Polytherapy 289 331 171 0.52 (0.33 to 0.82) 0.0046*
Quetiapine 166 126 91 0.72 (0.42 to 1.25) 0.2434
Olanzapine 568 314 231 0.74 (0.50 to 1.09) 0.1212
Risperidone 383 226 175 0.77 (0.52 to 1.16) 0.2137
Other oral 428 151 182 1.21 (0.79 to 1.84) 0.3843
Adjunct
TREATMENTS

No use 4528 1743 1 Reference

Lithium 32 9 7 0.80 (0.06 to 11.82) 0.8728
Mood stabilizer 90 15 33 2.27 (0.70 to 7.32) 0.1709
Antidepressant 1002 331 420 1.27 (0.87 to 1.85) 0.2139
BZDR 417 219 237 1.08 (0.70 to 1.67) 0.7162
Any combination
497 230 278 1.21 (0.77 to 1.90) 0.4051
of these

0 1 2
Fig. 2. Risk of work disability by pharmacological treatment in the sub-cohort of patients not on disability pension at the start of follow-up. HR = hazard ratio, CI = confidence
interval, LAI = long-acting injectable, BZDR = benzodiazepine or related drug. * and green markers denote results significant after Benjamini-Hochberg false discovery rate
correction for multiple comparisons at a 0.05 threshold. Expected events are calculated as events/HR.
as for schizophrenia. This is problematic, as the two disorders are did not see this in our study in regard to hospitalizations or work dis-
clearly distinct, both in terms of natural course of disease but also in ability. In addition to clozapine, also the use of oral aripiprazole and
terms of level of functioning attainable with proper treatment. Thus, olanzapine were associated with better outcomes. As the age of onset is
work dis- ability may be an even more important outcome for this higher for delusional disorder than schizophrenia, care needs to be
patient group than hospitalization, and finding the most effective
treatments for this disorder is likely to have a huge impact not only on
the patients' quality of life but also on the economic burden to society.
Our results show that although compliance may be an issue,
antipsy- chotics seem to be effective if used, as has also been shown
by the many reviews that have been conducted (Munro and Mok,
1995; Manschreck and Khan, 2006; Lepping et al., 2007; Mews and
Quante, 2013; Roudsari et al., 2015; Skelton et al., 2015a; Skelton et
al., 2015b; Muñoz-Negro and Cervilla, 2016; Muñoz-Negro et al.,
2020). However, differences in the effectiveness of different
antipsychotics were also observed.
Although delusional disorder has been thought to be a disorder
af- fecting mainly the dopaminergic system (Morimoto et al.,
2002), use of clozapine was associated with a reduced risk of
hospitalization due to psychosis and work disability in this cohort
of Swedish patients with delusional disorder. Even though at least
one older large network meta-analysis places clozapine on roughly
even grounds with other second-generation antipsychotics in
treating schizophrenia (Samara et al., 2016), a newer meta-analysis
has shown clozapine to be superior to other antipsychotics both in
treatment-resistant, but also the non- treatment resistant forms of
schizophrenia (Masuda et al., 2019). In line with this, our results
also show that clozapine was effective both on the harsher
outcomes of disability pension and hospitalization, but also on
milder outcomes such as sickness absence, suggesting it's use was
not restricted only to the chronic “no-option” treatment resistant
patients, but also patients not on initial disability pension.
As the exact mechanism by which clozapine exerts a more robust
ef-
fect than other antipsychotics is still under debate, one possible
expla- nation is the finding that also cortical glutamate dysfunction
is related to psychosis (Jauhar et al., 2018), which could also hold
true to the psy- chotic symptoms seen in delusional disorder. In
line with this, some case reports with encouraging results on the
use of clozapine to treat delusional disorder have been previously
published (Buckley et al., 1994; Silva et al., 1995; Songer and
Roman, 1996; Joos et al., 1997), al- though the number of patients
has so far been very low, and many of them have been otherwise
treatment resistant. Also, interestingly, in a review summarizing
these four clozapine cases, the authors noted that although
clozapine treatment was associated with an improvement in overall
quality of life, the delusions themselves often persisted
(Manschreck and Khan, 2006). This improvement in quality of life
sup- ports our finding that use of clozapine is associated with a
markedly lower risk of work disability.
Clozapine treated patients are often seen or screened with blood
work more regularly than patients with other per oral medications,
due to the possible side-effects of clozapine, which might translate
into better adherence and compliance or closer follow-up by the physi-
cian. In addition to clozapine, also LAIs were associated with a reduced
risk of hospitalization due to psychosis, which might again be due to
better adherence and more regular follow ups required. A fairly recent
retrospective study by González-Rodríguez et al. found that delusional
disorder patients with LAI-treatments had higher treatment mainte-
nance rates and less antidepressant and benzodiazepine use at 1-year
follow-up as compared to oral second-generation antipsychotic users
(González-Rodríguez et al., 2014a). Another study by González-
Rodríguez et al. (2014b) also observed significantly lower scores in
PANSS negative symptom scales on LAI users. Although some studies
have suggested that adjunct therapies with psychopharmaca other
than antipsychotics could be useful in delusional disorder (Roudsari
et al., 2015, https://www.ncbi.nlm.nih.gov/books/NBK539855/), we
taken when selecting treatment approaches, as side-effects and disability. Although these are important on both individual and
medica- tion interactions may be more prevalent in the older patient societal level, they do not describe the full set of symptoms or
base. Aripiprazole and olanzapine might thus prove to be valid choices disabilities caused by the disorder. Thus, lesser symptoms not
if clo- zapine and LAIs are not viable or accepted by the patient. leading to these outcomes
Some previous studies have found that delusional disorder may
be more prevalent in women than in men (de Portugal et al., 2010;
González-Rodríguez et al., 2014c). We observed a fairly equal
gender distribution between males and females, as has also been
observed in some other previous studies (Wustmann et al., 2011;
Kulkarni et al., 2017).

4.1. Limitations

As the study presented here is an observational study, some

sources of bias are unavoidable and the results need to be
interpreted with cau- tion. In register-based studies, confounding
by indication can never be fully controlled for, as medication
choices are a product of clinical deci- sion making. This also leads
to an imbalance in the use of certain phar- macotherapies, such as
clozapine, which was less used than many other medications.
However, we have taken efforts to reduce confounding by using
different analytical approaches. The within-individual analysis
used here eliminates selection bias related to characteristics such
as sex, age and initial severity of the illness, as the individuals are
used as their own controls. However, not even this analysis can
exclude the pro- topathic bias related to the fact that treatments
are usually initiated when symptoms appear or get worse. This
may artificially dilute the ob- served therapeutic effect. On the
other hand, it is unlikely that there would be any systematic
differences between specific drugs in this regard. We did not have
information on the forms of non- pharmacological treatment the
patients may have undergone. Thus, pa- tients with good
compliance to medication may also have been more frequent users
of other forms of support or treatment, such as psycho- therapy. It
is therefore possible that the positive effects ascribed to med-
ication treatments are in part due to increased usage of other
forms of treatment.
We had to estimate drug usage based on prescription and drug-
dispensing data, as data on actual daily usage was not available. To
ac- complish this, we used PRE2DUP (Tanskanen et al., 2015), which
takes into account medication stockpiling and the times of
hospitalizations, when the patient receives mediation from the
treating facility, rather than using his/her own stocks. The method
allows for variation in dose and does not use artificial pre-determined
grace periods in deter- mining use and non-use periods. Although not
as accurate for seldomly used/as needed medications, it provides
reliable estimates for daily medication use (Taipale et al., 2016) and is
appropriate for the analyses conducted in this study (Tanskanen et al.,
2017).
The within-individual analysis method can only be employed for
in- dividuals with recorded outcomes in the measure analyzed, and
thus is limited to a sub-population of the total cohort. For broader
generaliz- ability and as a sensitivity analysis, also traditional
between-individual methods were used to include the whole
cohort, and they showed sim- ilar results as the within-individual
analysis. The only exception was between-individual analysis on
disability pension which is likely related to underlying severity of
illness, i.e. residual confounding related to more severe symptoms
and higher intrinsic risk of disability pension among those
individuals who had used antipsychotics during the follow-up. It
also needs be noted that the study population consisted only of
people residing in Sweden, and treatment decisions were made
according to Swedish standards. From this, it also follows that the
work disability results may only be generalized to socio-economic
systems resembling that of Sweden.
The results of the study must also be framed in the context of
the pri- mary outcomes, hospitalization due to psychosis and work
cannot be analyzed using these methods, and may or may not be
more prevalent in individuals using the pharmacotherapies with
the lowest hazard ratios for the main outcomes.
4.2. Conclusion
According to the data presented here, many antipsychotics are
effec- tive in the treatment of delusional disorder, so there is no
reason for treatment nihilism, although clinical trials are urgently
needed to make informed clinical treatment recommendations.
Until then how- ever, as clozapine and long-acting injectables were
not very widely uti- lized, but still associated with the lowest risk of
work disability and hospitalization due to psychosis in our study,
they should more widely be considered for patients with delusional
disorder not meeting any contraindications.
Funding
This work was supported by the Finnish Ministry of Social Affairs and Health
through the developmental fund for Niuvanniemi Hospital; the Academy of Finland
(grants 315969, 320107 to HT); the Finnish Medical Foundation to ML; and Emil
Aaltonen Foun- dation to ML. The financial supporters of the study had no role in
study design, data collec- tion, data analysis, data interpretation, or writing of the
report.
Declaration of competing interest
Jari Tiihonen, Ellenor Mittendorfer-Rutz, Heidi Taipale and Antti Tanskanen have
par- ticipated in research projects funded by grants from Janssen-Cilag and Eli Lilly to
their employing institution. Heidi Taipale reports personal fees from Janssen-Cilag. Jari
Tiihonen reports personal fees from the Finnish Medicines Agency (Fimea), European
Medicines Agency (EMA), Eli Lilly, Janssen-Cilag, Lundbeck, and Otsuka; is a
member of advisory board for Lundbeck, and has received grants from the Stanley
Foundation and Sigrid Jusélius Foundation. Markku Lähteenvuo is a board member
of Genomi Solutions ltd. and DNE ltd., has received honoraria from Sunovion ltd.,
Orion Pharma ltd. and Janssen- Cilag, and research funding from The Finnish
Medical Foundation and Emil Aaltonen Foundation.
Acknowledgement
We would like to thank ms Aija Räsänen for secretarial assistance.
CRediT authorship contribution statement
Concept and design: JT, ML, HT, AT.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: ML, HT.
Critical revision of the manuscript for important intellectual content:
All authors.
Statistical analysis: HT, AT,
Obtained funding: ML, HT, JT.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.schres.2021.01.015.
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