Review Paper

Recent Advances in the Treatment of Delusional

Disorder

Theo C Manschreck, MD, MPH1, Nealia L Khan, MPH2

Objective: Often considered difficult to treat in the past, even treatment-resistant,

delusional disorder is now regarded as a treatable condition that responds to medication in
many instances. Munro and Mok previously reviewed the published record of its treatment
to 1994. This review aims to update and extend their observations and to examine the
impact of new second-generation antipsychotic agents on the treatment of this condition.
Method: We attempted to gather all published reports of delusional disorder from 1994 to
2004, using various database strategies. We then assessed the reports for clarity and
completeness, treatment, and outcome descriptions, thereby selecting a patient sample for
analysis.
Results: Of 224 cases identified as delusional disorder, only 134 case descriptions
provided sufficient treatment and outcome data to inform this review. The demographics of
this sample were similar to those of the earlier review. Depression as a comorbid condition
was more frequent than before. Adherence to medication regimens was seldom explicitly
addressed. Most cases showed improvement regardless of which antipsychotic medication
the patients received. Pimozide and other conventional antipsychotics, as well as
second-generation antipsychotics, and even clozapine, were used in many of the case
reports. Family history of delusional disorder was seldom recorded.
Conclusions: A positive response to medication treatment occurred in nearly 50% of the
cases in our review, which is consistent with the earlier review.
(Can J Psychiatry 2006;51:114–119)
Information on funding and support and author affiliations appears at the end of the article.

Clinical Implications
· Pessimism about whether delusional disorder can be treated effectively is not consistent with
the evidence in the recent literature.
· Overcoming potential adherence issues and addressing the dysphoric nature of this illness also
appear essential to achieving treatment success.

Limitations
· Most of the evidence was derived from clinical case reports rather than from double-blind,
randomized clinical trials.
· Clinicians may be reluctant to publish negative-outcome observations.

Key Words: delusional disorder, treatment, antipsychotic drugs, paranoia, outcome

aranoia was a late 19th century diagnosis that originated ally diagnosed as forms of schizophrenia, and the term para-
P with Kahlbaum and was refined by Kraepelin (1,2). Para- noia fell into disuse. In 1987, the revision of the DSM-III (that
noia was considered distinct from schizophrenia. For most of is, the DSM-III-R) reintroduced the concept of paranoia, call-
the 20th century, however, cases of paranoid illness were usu- ing it “delusional disorder,” which was similar to the concept

114 W Can J Psychiatry, Vol 51, No 2, February 2006


Kraepelin had used earlier. The condition was renamed delu-
sional disorder because of concerns that the common clinical
term paranoid was vague in meaning and often applied
inappropriately (3). This condition is no longer regarded as
rare, but systematic study of delusional disorder and the
development of effective treatment remain unfinished tasks.
Indeed, in the history of medicine, discovery of successful
treatment often precedes basic understanding of a disorder.
Riding and Munro reported on the use of the antipsychotic
agent pimozide to treat several cases of what was termed
“monosymptomatic hypochondriacal psychosis” (4). They
replicated their work for additional publications (5,6), indicat-
ing that a form of delusional disorder (the somatic subtype)
was treatable with this medication. They further found that, in
unimproved cases, nonadherence to medication regimens was
an important and frequent factor affecting outcome. Despite
such reports, the impression of most practitioners has been
that antipsychotic medications are of marginal value and that
this condition is treatment-resistant (7).
Munro and Mok reviewed clinicians’ published experience
with antipsychotic treatment of delusional disorder from the
1960s to 1994 (5). They critically analyzed approximately
1000 articles on delusional disorder dating from 1961, with
most published between 1980 and 1994. Noting that case
descriptions were often incomplete, they only selected cases
where the patients’ presentation conformed to DSM-IV crite-
ria (1). Of the 257 cases finally accumulated, only 209 cases
were sufficiently detailed to report meaningfully on treat-
ment. The authors concluded that even this refined body of
data was disparate and confusing and that only the “broadest
conclusions” could be drawn. Nevertheless, they asserted that
delusional disorder was an illness with a reasonably good
prognosis when adequately treated. They also observed that
treatment response was positive regardless of the specific
delusional content (the subtype) of the disorder. Interestingly,
they proposed that pimozide appeared to show the strongest
evidence of good results in clinical reports.
This report extends those observations and reviews the cur-
rent status of the treatment of delusional disorder, paying spe-
cial attention to recent experience with second-generation
antipsychotic agents.
Methods
Our initial intent was to capture all reports of delusional dis-
order published since 1994. We searched for cases of the dis-
order through Medline queries of journal articles, including
letters to editors, and also examined the Cochrane database
and book chapters. In addition, we contacted pharmaceutical
companies producing major antipsychotic drugs for case
reports of delusional disorder treatment. This search strategy
yielded 153 articles on delusional disorder, which we then
Can J Psychiatry, Vol 51, No 2, February 2006 W
Recent Advances in the Treatment of Delusional Disorder
assessed for clarity and completeness, treatment, and outcome
descriptions. Articles were published between 1994 and
2004. Of the 153 articles, 68 had adequate diagnostic rigour
(criteria and method of diagnosis were identified). Fewer still
(n = 35) contained sufficient information to characterize treat-
ment. Of 34 articles reporting clear outcome data, only 9
assessed treatment outcome systematically with objective
measures, while the remaining 25 relied on clinician judgment
for outcome estimates.
After excluding cases of organic delusional disorder, our
selection process identified 224 cases of delusional disorder.
However, sufficient treatment information was available for
only 136 cases, with the reports providing outcome data and
follow-up information for 134. As Munro and Mok com-
mented in their previous review (5), the treatment regimens
described were seldom explicit concerning, for example, the
order of medication application when multiple medications
had been tried.
Results
Demographics
Consistent with Munro and Mok’s 1995 review (5), women
outnumbered men in a ratio of nearly 4 to 3 (57% compared
with 43%) in the newer set of cases (Table 1a). However, this
sample of recent cases also showed some differences.
Although patients with delusional disorder were similar in
mean age (48.8 years for men; 44.9 years for women) to their
counterparts of a decade ago (44.3 years for men; 51.2 years
for women), women were no longer significantly older than
men at the time of case identification. Age ranged from 29 to
78 years among women and from 17 to 72 years among men;
these ranges are similar to prior observations. However, most
patients in our sample were in their late 30s.
The average follow-up period (10 months; range, 1 to 36
months) for this newer group was shorter than for the earlier
sample (22 months; range, 0 to 36 months).
Most subjects had delusions with a persecutory theme (n = 85)
(Table 1b). Somatic delusions was the delusion subtype with
the greatest recorded detail about course, treatment, and
follow-up (n = 80). Twelve patients experienced a mixture of
delusions.
Comorbid Conditions
Recent cases of delusional disorder differed from those
reviewed in 1995 in the occurrence of medical and psychiatric
comorbid disorders (Table 2). Among Munro and Mok’s
cases, the most prevalent comorbid conditions were also
known risk factors for delusional disorder (5). For example,
head injury or trauma and history of substance abuse were
common. In our sample, depression or depressive symptoms
115
The Canadian Journal of Psychiatry—Review Paper

Table 1a Demographic data (n = 224) clinical judgment rather than on objective measures. How-
ever, where actual numbers were presented, recovery was
n %
defined as a clinically significant reduction in scores on the
Men 94 42.3
assessment tool used. Outcomes are summarized in Tables 3a,
Women 128 57.7
3b, and 3c.
Married 2 1
Never married 1 0.5 Adherence
Separated, divorced, or widowed 1 0.5
Only one article discussed adherence issues (9); the authors
Table 1b Delusion types (n = 224) noted that 12 (5.4%) of their patients might not have taken
Somatic 80 35.71 their medications exactly as prescribed. This finding likely
Erotomanic 5 2.2 underestimates actual nonadherence. In several articles, spo-
Jealous 12 5.4 radic comments suggested that nonadherence was a problem
Persecutory 85 37.95 in an infrequent number of cases. Again, these observations
Grandiose 0 0.0 probably underestimate actual nonadherence.
Mixed 12 5.4
Other (not specified) 30 13.4 Use of Medications
The introduction of second-generation (atypical)
antipsychotic medications may have appreciably changed the
treatment of delusional disorder. Munro and Mok focused
Table 2 Conditions comorbid with delusional disorder much attention on the efficacy differences found between
in 224 reported cases (1994–2004) pimozide and other neuroleptic medications (the typical
Prevalence n %
antipsychotics), but trends in medication therapy have
changed. First, polypharmacy regimens have emerged in the
Depression 51 22.76
treatment of delusional disorder. Many of these patients also
Leprosy 5 2.23
report depressive symptoms, and most patients now are
Dementia 5 2.23
treated with both an antipsychotic and an antidepressant med-
Organic brain pathology 5 2.23
ication. Second, patients commonly receive more than one
Diabetes 3 1.34
antipsychotic medication over the course of their illness. This
Trichotillomania 3 1.34
is important to note because, although the symptoms may ulti-
Intellectual disability 2 0.89
mately resolve, the exact source of success is not always clear.
Hepatitis 2 0.89
Third, treatment regimens often mention cognitive-
Hypertension 2 0.89
behavioural therapy or even electroconvulsive therapy with
Prostatic hypertrophy 2 0.89
concomitant antipsychotic medication. Most reports empha-
size medication treatment, primarily with antipsychotic
agents. Treatment actually encompasses various approaches,
were most commonly mentioned as comorbid conditions (n = including medication, although evidence of such mixed
51, 23%). Only 5 patients (2.2%) were identified as having strategies is meagre.
organic brain disorder or head trauma, and 2 patients (1%) had In the current sample, nearly 45% of the patients with delu-
a known history of substance abuse. It seems highly likely that sional disorders received pimozide. Using the Wilcoxon rank
more patients in our current sample would have such sum test, we found a difference in recovery rates that
comorbid disorders, but they may not have been recorded. approached statistical significance (P = 0.055) between those
Strikingly, there was no mention in the newer articles of who were treated with pimozide and those who were not,
family history of mental illness. independent of delusion type, yet the raw data suggested that
the trend from the earlier review was reversed. Among the
Outcome group treated with pimozide, 77.9% were either fully recov-
We classified outcomes in 3 categories—recovered, ered or improved at follow-up (Table 3c). Among patients
improved, and no improvement—which were determined by receiving all other antipsychotic agents (including clozapine),
symptomatology at follow-up. Thus a patient who was 93.9% showed full recovery or improvement. In this newer
symptom-free at the time of follow-up was identified as sample, no particular method of medication treatment pro-
recovered, whereas one whose symptoms had not changed duced a more favourable outcome. Most patients, regardless
was considered as showing no improvement. A caveat here is of which medication they used, had a favourable outcome
that the description of recovery in many cases relied on after treatment.

116 W Can J Psychiatry, Vol 51, No 2, February 2006

 Recent Advances in the Treatment of Delusional Disorder

Table 3a Treatment outcomes

Outcome n %
Recovered 66 49.3
Improved 54 40.3
No improvement 14 10.4
Lost to follow-up 3 —

Table 3b Outcome by delusion typea

Recovered Improved No improvement Total

Somatic 40 24 6 70
Erotomanic 3 1 1 5
Jealous 1 0 0 1
Persecutory 0 8 7 15
Grandiose 0 0 0 0
Mixed 0 0 0 0
Other (not specified) 0 13 0 13

P Wilcoxon Rank Sum – Outcome in somatic, compared all other, delusion types = 0.0004
a
Delusion types were not explicit in all referenced articles; thus, totals do not sum to Table 3a.

Table 3c Outcome by treatment typea

Pimozide 29 17 13 59
Typical (conventional) 19 11 0 30
Second generation (atypicals) 11 21 1 33
Other prescription: 4 4 0 8
Total 63 53 14 130

P Wilcoxon Rank Sum – pimozide compared with other typicals and atypicals = 0.0548
P Wilcoxon Rank Sum – typicals compared with pimozide and atypicals = 0.2112
P Wilcoxon Rank Sum – atypicals compared with pimozide and other typicals = 0.4594
a
Treatment types were not explicit in all referenced articles; thus, totals do not sum to Table 3a.

Comparison of Conventional With Second-Generation

Antipsychotic Treatment
When we examined the available outcome data for our patient
sample, we found no significant differences in outcome by
type of medication used. Using the Wilcoxon rank sum test for
differences between groups, we noted no significant differ-
ence in outcome between the treatment types (that is,
pimozide, other typical [conventional] antipsychotics, and
second-generation [atypical] antipsychotics) (Table 3c).
Our follow-up analysis using the Yates-corrected chi-square
test confirmed that the differences in outcome were not statis-
tically significant. Although the data initially suggested the
advantages of the newer medications, further analysis
revealed a lack of statistical significance (P value only
approached significance at the 0.05 level).
Clozapine Use
Four articles reported the use of clozapine (10–13) in the treat-
ment of delusional disorder, with mixed results (Table 4). The
sample was small (n = 5). Clozapine is reserved for use in
cases of intractable side effects and treatment-resistant delu-
sions. Its use here resulted from the failure of previous
antipsychotic drug trials. Clozapine appeared to have little
effect on the central delusional theme. That is, although each
author noted a reduction in the associated symptoms of delu-
sional disorder, the delusion often persisted. Interestingly, the
articles suggested that the patients’ quality of life improved
when their treatment was switched to clozapine, despite the
persistence of the delusions.
Outcome in Somatic Delusions Compared With Other
Subtypes
Thirty-six percent of the reported cases (n = 80) experienced
somatic delusions, in contrast with the 38% who experienced
delusions of persecution (Table 3b). Unfortunately, little
treatment information was recorded for most of the patients
with persecutory delusions.
In this updated review, we noted that 47/64 patients (73.4%)
with somatic delusions were treated with pimozide. Using the

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The Canadian Journal of Psychiatry—Review Paper
Table 4 Clozapine
Author Delusion type
Songer and others (10) Somatic
Buckley and others (11) Persecutory
Persecutory
Joos and others (12) Persecutory
Silva and others (13) Erotomanic
Wilcoxon rank sum test, we found a significant difference in
outcomes between delusion subtype groups (that is, somatic
compared with other), based on the treatment received (P =
0.0004). That is, among patients treated with pimozide, there
was a significant difference in outcome between those with
somatic delusions and those with other types of delusions. As
well, those treated with other types of medication showed a
similar difference in outcome, despite the delusional theme.
A follow-up, Yates-corrected chi-square test confirmed a sig-
nificant difference in outcome between patients with
somatic-themed delusions and those with other delusion
types.
Discussion
Despite certain limitations, the last decade’s literature on
delusional disorder treatment suggests optimism about the
potential for treatment effectiveness. Of 131 reported cases, a
positive response was noted in nearly 50%. This observation
contrasts with widely held pessimism about treatment of delu-
sional disorder. However, some caveats exist. First, the pub-
lished literature seldom provides a forum for negative results,
and clinicians may be reluctant to prepare reports on negative
outcomes. Since case reports are the usual source of data,
rather than controlled trials, they constitute our major source
of evidence on this disorder. Thus the actual rate of successful
treatment may be lower. Second, the lack of double-blind,
randomized controlled studies raises concerns about the
strength of the evidence for a positive response. Third, the fre-
quent use of combination treatments suggests that
monotherapy with antipsychotic medication may be insuffi-
cient in many cases. Fourth, the introduction of second-
generation antipsychotics may have contributed to a reduced
reliance on pimozide (68% and 44%, respectively), or it may
reflect concern about pimozide’s potential for QTc prolonga-
tion. Perhaps the more reliable outcome from these atypical
118
Previous medication use Delusional symptom outcome
Haloperidol, perphenazine, Symptoms persisted with
molindone decreased intensity
Chlorpromazine, fluphenazine, Symptoms persisted with
haloperidol, loxapine, decreased intensity
perphenazine trifluoperazine
Chlorpromazine, trifluoperazine Symptoms persisted with
decreased intensity
Haloperidol, zuclopenthixol Symptoms persisted
Risperidone, amitriptyline Symptoms persisted with
decreased intensity
antipsychotics, coupled with their reduced side effects, has
resulted in reduced reliance on pimozide for treatment.
Conversely, claims about treatment effectiveness may be
sound because factors such as nonadherence have not been
adequately considered. In the earlier review, Munro com-
mented that adherence to medication regimens was a central
factor in treatment success (5). The fact that, in case descrip-
tions, so few studies in our review indicated the level of such
adherence raises the possibility that this factor, when not spe-
cifically addressed, is critical to treatment success. Whether it
might also be responsible for the difference in treatment
response between patients with somatic delusions and those
with other delusion types is a question for further investiga-
tion. One reasonable explanation for the differential success
(patients with somatic delusions being more responsive) is
adherence to medication regimens. Unfortunately, we do not
have data to support this assertion. However, recognizing
nonadherence to treatment among patients with delusional
disorder is clearly relevant to understanding this
phenomenon.
Indeed, the occurrence of any treatment success is notewor-
thy. The recovery rates we reported would be welcome in any
clinic for any of the major psychotic disorders. Further, the
general concordance of our review’s observations with those
of Munro and Mok’s earlier review (5) strengthen the idea that
d e lu s io n a l d is o r d e r s h o u ld n o t b e c o n s id e r e d a
treatment-resistant condition; medication can be effective if
the patient adheres to the treatment regimen. In the cases we
reviewed, clinicians possible overlooked or did not detect
adherence problems and, in so doing, reinforced the percep-
tion that delusional disorder is difficult to treat, perhaps even
treatment-resistant.
The newer, possibly more acceptable, second-generation
antipsychotic agents had sporadic yet positive reports of treat-
ment effectiveness associated with their use; the experience is
thus far limited, but it parallels that of the older agents. All this
W Can J Psychiatry, Vol 51, No 2, February 2006
 Recent Advances in the Treatment of Delusional Disorder

4. Kraepelin E. Dementia praecox and paraphrenia. Edinburgh (UK) Livingston;

holds promise. That pimozide continues to produce greater
rates of improvement in patients with somatic delusions raises
a question about the uniqueness of this intervention and also
about a potential boundary between somatic and other forms
of delusional disorder.
Nonetheless, the observations from our review underscore the
need for more focused research. Sample sizes were small, and
controlled studies were almost nonexistent. There is a need to
move beyond case reports to collaborative efforts in this area
so that researchers can examine delusional disorder systemat-
ically in sufficient numbers to generate meaningful clinical
conclusions.
Note
A more extensive bibliography of articles consulted for this
analysis, as well as of articles consulted but not used, is available
from the corresponding author.
Funding and Support
No funding or support was received for this article.
References
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1. 7th ed. Baltimore (MD): Williams and Wilkins; 2000. p 1243– 64.
9. Zanol K, Slaughter H. An approach to the treatment of psychogenic parasitosis.
Int J Dermatol 1998;37:56 –63.
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antipsychotic agents [letter]. Am J Psychiatry 1996:153:578–9.
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clozapine. Am J Psychiatry 1994;151:1394–5.
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Manuscript received February 2005, revised, and accepted June 2005.
1
Professor of psychiatry, Department of Psychiatry, Harvard Medical
School, Boston, Massachusetts; Professor of psychiatry, VA Hospital,
Brockton, Massachusetts; Director of research, Laboratory for Clinical and
Experimental Psychopathology, John C Corrigan Mental Health Center,
Fall River, Massachusetts.
2
Research associate, Department of Psychiatry, Harvard Medical School,
Boston, Massachusetts; Research associate, Laboratory for Clinical and
Experimental Psychopathology, John C Corrigan Mental Health Center,
Fall River, Massachusetts.
Address for correspondence: Dr T Manschreck, John C Corrigan Mental
Health Center, 49 Hillside St, Fall River, MA 02720,
theo.manschreck@dmh.state.ma.us

Résumé : Progrès récents dans le traitement du trouble délirant

Objectif : Souvent considéré difficile à traiter dans le passé, même réfractaire au traitement, le
trouble délirant est maintenant vu comme une affection traitable qui répond à la médication dans
bien des cas. Munro et Mok ont précédemment examiné le dossier publié de ce traitement jusqu’en
1994. Le but de cette étude est de mettre à jour et d’élaborer leurs observations, et d’examiner
l’effet des antipsychotiques de la deuxième génération sur le traitement de ce trouble.
Méthode : Nous avons tenté de colliger tous les articles publiés sur le trouble délirant, de 1994 à
2004, à l’aide de diverses stratégies de bases de données. Nous avons ensuite évalué ces articles en
ce qui concerne la clarté, l’exhaustivité, le traitement, et les descriptions des résultats, sélectionnant
ainsi un échantillon de patients aux fins d’analyse.
Résultats : Sur les 221 cas identifiés de trouble délirant, seulement 131 descriptions de cas ont
fourni suffisamment de données sur le traitement et le résultat pour éclairer cette étude. Les données
démographiques de cet échantillon étaient semblables à celles de l’étude précédente. La dépression
comme affection comorbide était plus fréquente qu’auparavant. L’observance de la posologie du
médicament était rarement abordée explicitement. La plupart des cas indiquaient une amélioration,
peu importe le type d’antipsychotique que recevaient les patients. Le pimozide et autres
antipsychotiques classiques, de même que les antipsychotiques de la deuxième génération et même
la clozapine ont été utilisés dans nombre des études de cas.
Conclusions : Une réponse positive au traitement pharmacologique a eu lieu dans presque 50 % des
cas de notre étude, ce qui correspond à l’étude antérieure.

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