Does treatment with antidepressants, antipsychotics, or benzodiazepines hamper allergy skin testing?

Abstract Background Treatment with commonly used drugs such as antidepressants (ADs), antipsychotics (APs), and benzodiazepines (BDs) may hamper the use of allergy skin testing due to possible antihistaminic effects. Objective To examine the antihistaminic effect of AD, AP, and BD as measured by the ability of these drugs to suppress the normal wheal reaction caused by skin prick test (SPT). Methods Skin prick test was performed in patients receiving treatment with AD, AP, and/or BD. Double SPT was performed with histamine solutions of 10, 30, and 100 mg/ml and mean wheal diameter calculated. Results A total of 313 patients were included. 236 (75%) patients were treated with one of the examined drugs and 77 (25%) patients with more than one of these drugs. Drugs most frequently used was sertraline (n = 65), citalopram (n = 63), mirtazapine (n = 36), venlafaxine (n = 33), and quetiapine (n = 32). Treatment with mirtazapine and/or quetiapine was associated with negative SPTs in 30/36 (83%) and 22/32 (69%), and the antihistaminic effect of these drugs was dose‐dependent. For patients treated with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin norepinephrine reuptake inhibitors (SNRIs), or BD alone, almost all SPTs were positive (94%, 95%, 100%, and 100%, respectively). Negative SPTs in patients treated with SSRI, TCA, SNRI, or BD and ≥1 other of the examined drugs were associated with simultaneous treatment with mirtazapine or quetiapine in 39/44 (89%) patients. Conclusion Skin testing has little meaning in patients treated with mirtazapine or quetiapine. Treatment with SSRI, SNRI, and BD does not seem to affect the results of SPTs, whereas skin tests in patients treated with TCA should be interpreted with caution.


| INTRODUCTION
Treatment with antidepressants (ADs), antipsychotics (APs), and/or benzodiazepines (BDs) is very common, and many patients referred for allergy evaluation are in ongoing treatment with these drugs. In Denmark with a total population of 5.8 million people (4.5 million adults), the number of patients treated with AD, AP, or BD in 2019 was 420,000, 130,000 and 258,000. 1 Since up to 40% of the general population suffer from allergic diseases, the overlap between treatment with these drugs and need for allergy evaluation is large. 2 Ongoing treatment with AD, AP, or BD can complicate the diagnostic work-up for allergy due to the potential antihistaminic effect of these drugs. Skin prick tests (SPTs) are based on interpretation of wheal and flare reactions caused by the release of histamine in the skin to allergens the patient do not tolerate. 3 The test can however not be used if treatment with ongoing drugs suppresses this histamine release. A very important part of evaluation for food-and drug allergy is allergen challenges. These challenges should however not be performed if the patient receives drugs with antihistaminic effect since this hampers interpretation of the challenge outcome.
Suppression of skin test reactivity has been studied for different drugs such as oral antihistamines, 4,5 oral steroids, [6][7][8] topical steroids, and calcineurin inhibitors 9,10 as well as other drugs. 3 The very few published studies on AD, AP, and BD are small, rather old and retrospective. [11][12][13] As such, the knowledge on the degree of the specific antihistaminic effect of different ADs, APs, and BDs used nowadays is sparse.
The aim of this study was to examine the antihistaminic effect of different ADs, APs, and BDs as measured by the ability of the drug to suppress the normal wheal and flare reaction caused by SPT with histamine in patients using these drugs.

| METHODS
Adult patients (age ≥ 18 years) referred to the Allergy Centre, Odense University Hospital, Denmark for allergy evaluation were asked to participate in this observational, cross-sectional study provided they received ongoing treatment with AD, AP, or BD. The inclusion period was from November 2017 to April 2019. All drugs (including doses) received by the patient were recorded by the doctor, and it was verbally assured that the patient was actually compliant in taking these drugs. All patients referred to our Allergy Centre receive a letter before their visit asking them to discontinue any use of oral antihistamines at least 72 h before their visit. At the visit, it was reassured that the patient had followed these instructions on discontinuation of oral antihistamines-and that the patient did not use oral steroids-or potent topical steroids on the forearms. An SPT with a histamine solution of 10, 30, and 100 mg/ml (twice for each concentration) and a negative control with saline was performed on the forearm of the patient. The size of the resulting wheals was recorded after 15 min, and the wheal size was measured on the longest and the midpoint orthogonal diameter; the numbers were added and divided by two to calculate the mean wheal diameter. 14 Finally, the mean from the two tests on each concentration was recorded. The antihistaminic effect of specific drugs was determined from these readings. In addition to patients fulfilling the above-specified inclusion criteria, 10 healthy participants not using any drugs (nurses/doctors working in the department) were also skin prick tested. Median wheal size and quartiles (Q1: first quartile, Q3: third quartile) as well as significance testing between the control group and different drug groups were performed in STATA/SE 16.0 (Stata Corporation), the latter analyses using the two sample Wilcoxon rank-sum (Mann-Whitney U) test.

| Ethics
The study was approved by the Regional Committees on Health Research Ethics for Southern Denmark (project ID S-20160141) and the Danish Data Protection Agency (no. 18/54980). Oral and written informed consent was obtained from all patients.

| RESULTS
A total of 313 patients receiving treatment with AD, AP, and/or BD were included. All patients were skin prick tested. Table 1 (drugs with ≥5 patients treated) and Table 2 (drugs with <5 patients treated) list specific drugs and number of treated patients. Of the 313 patients, 236 (75%) patients were treated with one of the examined drugs and 77 (25%) patients with more than one of these drugs. Of the latter, 60 patients were treated with two drugs, 16 with three drugs, and 1 patient with four drugs. Median age of participants was 55 years with an age span of 20-90 years.
To begin with, we looked at the AD, AP, and BD most frequently used (≥5 patients treated). SPTs were evaluated separately for patients receiving only one of these drugs ("alone") as opposed to patients receiving more than one of these drugs ("combination"). The result of the SPT (wheal size) was categorized into "no wheal," 0 < SPT < 3 mm, 3 ≤ SPT < 5 mm, and SPT ≥ 5 mm. An SPT < 3 mm is hereafter referred to a "negative." The two latter categories were also combined (see Tables 1 and 2) since an SPT ≥ 3 mm is defined as a positive SPT provided the saline control is negative. All saline controls were negative.   Chlorprothixen combination 6 2 (33%) Abbreviations: NaSSA, noradrenergic and specific serotonergic antidepressants; SNRIs, serotonin norepinephrine reuptake inhibitors; SPT, skin prick test; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.
T A B L E 2 Skin prick test results (histamine solution of 10 mg/ml) for drugs with <5 patients treated Abbreviations: NaSSA, noradrenergic and specific serotonergic antidepressants; SPT, skin prick test.
In the drug groups where monotherapy very rarely resulted in negative SPTs, combined therapy did so to a much higher degree. We ine + venlafaxine + lorazepam, and these three patients were negative also in 30 and 100 mg/ml. As such, apart from treatment including mirtazapine or quetiapine, we did not find significant evidence that specific combinations of other drugs suppressed the histamine response in any pattern.
Mirtazapine was also a highly significant suppressor of the histamine response when evaluating median wheal size for monotherapy compared to controls (p = 0.0004) ( Table 3). Median wheal size for quetiapine (4.4 mm) and amitriptyline (4.9 mm) was also reduced compared to the control group, but the differences did just not reach a significance level of p < 0.05 (p = 0.06 and 0.07, respectively). Median wheal size for the drug groups of SSRI, SNRI, and BDs was not reduced compared to the control group, but for zopiclone it was actually increased. Median age differed somewhat between the groups, whereas the gender ratio was comparable.

| DISCUSSION
Although some limitations have to be taken into account, our study were able to block more than 60% of brain H 1 receptors. 17 In our study, the antihistaminic effect of both mirtazapine and quetiapine was clearly dose-dependent. The vast majority of patients having a positive SPT, despite ongoing treatment with these drugs, study. 13 In our study, all 24 participants on BD monotherapy (mainly oxazepam, zopiclone, and zolpidem) had a positive skin test response, moreover with mean wheal sizes larger than our control group and in conclusion therefore not suggestive of any suppression of the histamine response.
Since all participants tested did receive ongoing treatment with the specified drugs, we do not know what results the SPTs would have revealed for each individual if these drugs were discontinued.
As such, in this study, patients do not serve as their own controls.
This is of course a limitation when evaluating the direct influence of the medication in detail; on the other hand, discontinuation of these kind of drugs would be quite a challenge in a study setting, in some cases even unethical.
T A B L E 3 Age, sex, median wheal size (for histamine 10 mg/ml) and quartiles for drugs used in monotherapy (≥5 treated patients) and healthy controls (*p < 0.05, **p < 0.01, ***p < 0.001 for comparison with healthy controls)  20 Age was significantly higher in monotherapy groups of mirtazapine, amitriptyline, and nortriptyline compared to controls and represents a possible confounder, but age was also significantly higher in monotherapy groups of citalopram, oxazepam, and zopiclone with higher median wheal values than the control group.
Although not specifically evaluated in this study, allergen challenges should not be performed if the patient receives ongoing antihistaminic drugs, since this hampers interpretation of the challenge result. Since discontinuation of the examined drugs was not part of our study, our data cannot be used to recommend for how many days mirtazapine or quetiapine should be discontinued before an interpretable SPT or allergen challenge could be per- In conclusion, this study presents clinical data from a large cohort describing the association between treatment with different ADs, APs, and/or BDs and SPT results. Based on our results and the associated pharmacologic knowledge, we suggest that SPTs (and allergen challenges) have little meaning if the patient is treated with mirtazapine or quetiapine due to the antihistaminic effect of these drugs. SPT might be considered in patients treated with very low doses of mirtazapine and quetiapine, but results should be interpreted very carefully. SPTs in patients receiving TCA can, according to our results, be performed, but interpretation should be done with caution, since these drugs may well partially suppress the wheal response. For AP other than quetiapine and a number of older BD, the groups were too small to draw conclusions, but crude data have been presented. Our data suggest that treatment with SSRI, SNRI, and most of the BD used nowadays is unlikely to interfere with allergy skin testing (and/or allergen challenges)-meaning these procedures can be performed without discontinuation of these drugs.