Treatments for Primary Delusional Infestation: Systematic Review

Background Delusional infestation, also known as Ekbom syndrome, is a rare delusional disorder characterized by the fixed belief that one is infested with parasites, worms, insects, or other organisms. Although delusional infestation is a psychiatric condition, patients often consult dermatologists with skin findings, and it is currently unclear what treatments are recommended for this disorder. Objective We aimed to systematically review and describe the treatment and management of patients presenting with primary delusional infestation. Methods A systematic search was conducted using Ovid on MEDLINE, Embase, PsycINFO, and the Cochrane Register of Clinical Trials. Relevant data, including treatment, dosage, response, adherence, and side effects, were extracted and analyzed. Results A total of 15 case series were included, comprising 280 patients (mean age 53.3 years, 65.4% female) with delusional infestation. Overall, aripiprazole had the highest complete remission rate at 79% (11/14), although this was limited to 14 patients. Among drug classes, selective serotonin reuptake inhibitors were the most effective with a 79% (11/14) complete remission rate and 43% (9/21) partial remission rate in patients with comorbid depression, anxiety, or trichotillomania. First-generation antipsychotics and second-generation antipsychotics had similar complete remission rates (56/103, 54.4% vs 56/117, 47.9%, respectively) and partial remission rates (36/103, 35% vs 41/117, 35%, respectively). Conclusions Due to the rarity of delusional infestation, we only found 15 case series. However, we found that first-generation antipsychotics appear to be similar in effectiveness to second-generation antipsychotics for the treatment of primary delusional infestation. Larger studies and randomized controlled trials are needed to evaluate the efficacy of pharmacological therapy for delusional infestation. Trial Registration PROSPERO CRD42020198161; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=198161


Introduction
Delusional infestation, also known as delusional parasitosis, is a rare delusional disorder characterized by the fixed belief that one's skin is infested by parasites, worms, insects, or other organisms [1]. The prevalence of delusional infestation is estimated to be 27.3 per 100,000, and it is more frequent in individuals over the age of 50 years and in socially isolated women [2,3]. Despite the lack of microbiological evidence, patients are convinced they are infected and often present with cutaneous sensations, such as itching, crawling, and formication. These delusions may lead patients to injure themselves through cuts and chemical burns or destroy their furniture in an attempt to eliminate the perceived infestation [4]. The "specimen sign" is a classic feature of the illness present in about half of all patients, in which patients present fragments of skin, particles, threads, or insects to their healthcare provider as evidence of skin infestation [5].
Delusional infestation can be classified as either a primary or secondary variant. Primary delusional infestation is an isolated psychiatric disorder diagnosed after the exclusion of other causes, such as infection or an underlying medical or psychiatric condition. In secondary delusional infestation, the delusions are attributed to other conditions, including substance use, medications, other psychiatric conditions, and infections. Primary delusional infestation comprises approximately 56% of cases [6].
The etiology of primary delusional infestation is unclear, though disruptions in dopamine pathways are suspected to play a role. Antipsychotics improve delusional infestation symptoms, likely due to inhibition of dopamine transmission. Dopamine plays a role in probabilistic reasoning, and its disruption may cause patients to incorrectly attribute a rash or itch to skin infestation [1,7]. Another hypothesis suggests that dysfunction of striatal dopamine transporters leads to more postsynaptic dopamine, increasing the risk of developing delusional infestation [8].
Conditions associated with reduced dopamine transporter function, such as schizophrenia, depression, and alcoholism, have been associated with delusional infestation. Moreover, medications that inhibit dopamine reuptake, such as cocaine and amphetamines, often induce delusional infestation symptoms, such as formication [8]. There is also evidence that dysfunction in the fronto-striato-thalamic network mediates symptoms of delusional infestation [9].
The clinical management of delusional infestation is challenging, and dermatologists are often consulted due to patients conceptualizing the disease as somatic. Patients frequently refuse psychiatric therapy or referral and often present proof of infestation, which is commonly referred to as a "specimen sign" or "matchbox sign" and can include skin particles or hair. On average, dermatologists will manage 2 to 3 patients with delusional infestation every 5 years [10]. Common treatments reported in the literature include first-generation antipsychotics (FGAs) (eg, pimozide, fluphenazine, and haloperidol) and second-generation antipsychotics (SGAs) (eg, risperidone and olanzapine). A 2007 systematic review of papers on delusional infestation found FGAs and SGAs were effective in the majority of patients with primary delusional infestation, but remission rates did not differ between these 2 groups of antipsychotics [11]. A more recent systematic review reported similar results; there was no strong evidence to suggest any single antipsychotic agent over another [12]. Both of these reviews restricted their search strategy to antipsychotics; however, other pharmacological agents may also prove effective in treating delusional infestation. As such, we conducted a systematic review to identify pharmacological treatments used for primary delusional infestation to better understand their effectiveness and establish recommendations for the management of primary delusional infestation.

Methods
The protocol was registered on PROSPERO (CRD42020198161). The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were utilized in this systematic review ( Figure 1).

Search Strategy and Data Extraction
A systematic search was conducted using Ovid on MEDLINE, Embase, PsycINFO, and the Cochrane Register of Clinical Trials from June 2020. The full search strategy is detailed in Textbox 1. Eligibility for inclusion of articles was established a priori. Articles were included if they (1) were written in English and (2) were original articles that evaluated pharmacological treatments for delusional infestation. Articles were excluded if they (1) were nonoriginal articles (eg, conference abstracts or reviews), (2) evaluated fewer than 5 patients (eg, case reports), or (3) did not evaluate pharmacological treatments. All keywords were searched and mapped onto subject headings where appropriate. References of included studies were screened for inclusion.
Screening of titles and abstracts was independently conducted by 2 reviewers (JDL and RDG) and was followed by a full text review. Discrepancies were resolved through consensus or by consulting the corresponding author (CL).
Variables related to general study data, including article title, journal, authors, year of publication, study design, and the number of cases were collected by 2 independent reviewers (JDL and RDG). Variables related to clinical information were also collected, including mean age, proportion of female patients, reported pathogens, psychiatric family history, co-occurring dermatological conditions, treatments (including placebo), dosage, treatment duration, treatment outcomes (including full remission, partial remission, no response, and nonadherence), and side effect profiles.

Risk of Bias
The quality of the included studies was appraised independently by 2 reviewers (JDL and RDG) with a formal risk of bias assessment. The National Institutes of Health (NIH) quality assessment tool for case series was used to evaluate the risk of bias in the included studies. Disagreements were resolved by consensus and discussion with a third reviewer (SV) as necessary. Eligible studies were excluded if they contained a high risk of bias.

Data Analysis
Data were reported as means, frequency, or proportions as needed. Study characteristics and outcome data were recorded, including the number of treatments and treatment efficacy (based on the categories of complete remission, partial remission, no response, and nonadherence). We assigned individual outcomes to 3 main categories: no response, partial remission (ie, some response), and full remission. Efficacy of treatment was synthesized by dividing the total number of patients with a certain response by the total number receiving treatment [11].

Included Studies
A total of 1620 studies were identified by searching the databases and additional references (Textbox 1); 691 articles were duplicates, leaving 929 studies for title and abstract screening. After screening, 84 articles underwent full-text review. Next, 69 articles were excluded due to not involving delusional infestation (n=16), not reporting treatments or outcomes (n=40), not being primary literature (n=6), and having fewer than 5 cases (n=7). A total of 15 articles met the inclusion criteria and were included in the systematic review (Table 1) [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. Most of the available studies had low methodological quality due to small sample sizes or having an uncontrolled or retrospective design, so a meta-analysis was not conducted.

Risk of Bias
The risk of bias assessment is presented in Table 2. Overall, the studies had a low risk of bias based on the NIH quality assessment tool. Out of the 15 included studies, 13 were rated "good" overall and 2 were rated "fair" based on the 9 criteria.

Efficacy of SSRIs
Overall, 2 kinds of SSRI were used. Fluoxetine was used by 11 patients and citalopram was used by 10 patients. These SSRIs were used to treat comorbid depression, anxiety, and trichotillomania. Trichotillomania might also have been a secondary delusional infestation, although this was not specified in these studies. Treatments were effective, with an overall 57% (12/21) complete remission rate and 43% (9/21) partial remission rate (Table 3). Fluoxetine appeared to be more efficacious, with 82% (9/21) complete remission and 18% (2/21) partial remission, compared to citalopram with 30% (3/10) complete remission and 70% (7/10) partial remission.

Principal Findings
We conducted a systematic review of studies on pharmacological treatments for primary delusional infestation. Psychiatric history was unreported by almost half the studies, but of the remaining studies, the most commonly reported psychiatric disorders were anxiety (11/40, 28%) and depression (32/162, 20% Although antipsychotics are the mainstay in the treatment of primary delusional infestation, no antipsychotics are approved for this use and there is no strong evidence suggesting that the use of any specific antipsychotic is more effective than any other [10,28,29]. We compared FGAs and SGAs and found that patients using SGAs had higher rates of complete remission and lower rates of noneffectiveness than patients using FGAs.
A 2020 systematic review by McPhie and Kirchhof [12] similarly concluded there was no strong evidence to recommend any one antipsychotic over another, due to a low quality of evidence and study variability.
While the efficacy of both FGAs and SGAs is comparable, these agents vary in their side effect profiles. FGAs are known to produce extrapyramidal side effects, including parkinsonism, acute dystonia, akathisia, and tardive dyskinesia. While some of these side effects may be controlled with additional pharmacotherapy, extrapyramidal side effects can decrease quality of life, decrease compliance, lead to polypharmacy, and may even be permanent (eg, tardive dyskinesia) [30]. By contrast, SGAs generally have a lower incidence of extrapyramidal side effects, but their efficacy and side effect profiles vary widely based on the specific agent [31][32][33]. Given the higher rates of complete remission and lower rates of noneffectiveness that we found for SGAs compared to FGAs in this study, as well as the more variable side effect profiles of SGAs, SGAs may be more beneficial in the treatment of primary delusional infestation. However, all the studies included were case series, and in the absence of higher levels of evidence, such as that provided by randomized controlled trials, we can only draw conclusions and make recommendations with caution. Further studies should be conducted.
Risperidone is the most widely studied SGA, followed by olanzapine [12]. Although olanzapine had a higher complete remission rate and lower noneffectiveness rate compared to risperidone in our study, olanzapine is known to have a higher incidence of metabolic side effects, such as weight gain, relative to other SGAs [34]. Interestingly, we found that aripiprazole had the highest complete remission rate (11/14, 79%) compared to both risperidone (19/44, 43%) and olanzapine (12/22, 55%). Furthermore, aripiprazole is known to have a lower rate of metabolic side effects than other SGAs [35] and has the additional advantage of acting as a partial dopamine agonist [36], making it a useful adjunct in the treatment of depression, which is a common comorbidity in patients with delusional infestation. While these results are promising for the use of aripiprazole in delusional infestation, further studies are required before its use can be widely recommended.
Interestingly, the majority of patients treated with SSRIs had complete remission of delusional infestation, although this was limited to a sample size of 21 patients with comorbid depression, anxiety, or trichotillomania in 3 studies [18,24,25]. These patients were managed with fluoxetine or citalopram. This suggests that clinicians should obtain a full psychiatric history of patients with delusional infestation to identify underlying mood and anxiety disorders that might respond to SSRIs, thereby improving the management of this challenging illness.

Limitations
Due to the rarity of delusional infestation, there is a lack of clinical trials and cohort studies, and our analysis included only case series studies, all of which used subjective measures of treatment efficacy. In addition, we only assessed outcomes as complete remission, partial remission, no response, or nonadherence. Furthermore, it was challenging to separate patients with primary and secondary delusional infestation, because some studies combined analyses.

Conclusion
Delusional infestation is a rare and challenging illness to treat. While antipsychotics are considered the mainstay treatment for primary delusional infestation, we found that SGAs, such as aripiprazole and risperidone, as well as SSRIs, led to higher rates of full remission than FGAs, such as haloperidol and pimozide. We recommend that clinicians take a detailed psychiatric history of patients with delusional infestation, as comorbid depression, anxiety, and trichotillomania may be better managed with SSRIs. Larger studies, such as randomized controlled trials, are required to better evaluate the effectiveness of SSRIs, FGAs, and SGAs for the treatment of delusional infestation.