Abstract
Hypersensitivity reactions to second-generation antipsychotics and mood stabilizers are uncommon and can lead to serious complications. These medicines are generally well tolerated, but there have been reports of unusual allergic reactions, such as hives or itching, associated with these drugs. The patient is a 45-year-old woman who presented with a recurrence of a manic episode of bipolar I disorder and developed skin complications and itching after receiving valproate and levetiracetam. She subsequently experienced severe skin allergic reactions, including hives and itching, after taking various second-generation antipsychotics, including risperidone, aripiprazole, and quetiapine. These allergic reactions occurred shortly after starting the medication and resolved after discontinuing the drug. The purpose of this case report is to highlight the importance of being aware of the possibility of concomitant hypersensitivity with various antipsychotic and anticonvulsant medications, which can affect the diagnosis and treatment of the disease.
Keywords
Introduction
Drug-induced hypersensitivity reactions are a recognized but relatively unusual adverse effect of psychotropic medications.1,2 Mood stabilizers and atypical antipsychotics are generally well-tolerated medications, but there have been some reports of hypersensitivity reactions, including pruritus, urticaria, cutaneous eruptions, and, less often, angioedema.3-5
Adverse cutaneous allergic reactions have been reported with several second-generation antipsychotics (SGAs) such as olanzapine, risperidone, quetiapine, and aripiprazole.3,5,6 In addition, antiepileptic mood stabilizers, such as valproate and levetiracetam, have been associated with hypersensitivity among some patients.7,8 According to the studies, drug-induced hypersensitivity reactions can also occur even with agents that are structurally unrelated and can complicate medication management, thus restricting treatment options, especially in psychiatric populations where medications are often prescribed long term.1,9
We present a case of a 45-year-old woman who was being treated for bipolar I disorder and developed an allergic reaction to various antipsychotic and anticonvulsant medications with symptoms of urticaria and pruritus, which posed many challenges in treatment.
Case Presentation
A 45-year-old married woman with a relapse of bipolar I disorder was admitted to a psychiatric hospital with an acute manic episode. The patient’s symptoms at the time of admission included marked irritability, verbal and physical aggression, paranoid thoughts about her husband, delusions of jealousy, harm, and delusions of grandiosity, and auditory hallucinations.
Her vital signs at the time of admission were as follows: blood pressure:105/90 mmHg, respiratory rate:14, pulse rate:73 beats/minute, temperature: 36.9°C.
The patient’s laboratory test results are as follows: Creatinine (Cr): 0.9 mg/dl, Blood Urea Nitrogen (BUN): 15 mg/dl, ALT: 17 U/l, AST: 15 U/l, White Blood Cell Count (WBC): 8450, Hemoglobin (Hg): 10.5 g/dl, Platelets (Plt):178 000 /µl, TSH: 3.3 mIU/l.
The patient’s height was 162 cm and weight was 55 kg (BMI: 21 kg/m2). The patient had undergone surgical removal of a meningioma approximately 18 months before admission. Medications taken by the patient before hospitalization included valproate 500 mg at night and levetiracetam 500 mg at night. Approximately 3 months before admission, she voluntarily discontinued both medications due to severe itching and widespread skin rash. No allergy testing was performed at that time. The patient had no prior personal or family history of drug allergies. According to the patient’s wife, her psychotic episodes appeared shortly after the medication was discontinued.
The patient’s initial treatment consisted of resuming the previous regimen of tablet sodium valproate and tablet levetiracetam along with tablet olanzapine 5 mg daily. After restarting these medications, the patient developed mild pruritus. No allergy testing was performed. Four days after starting treatment, the olanzapine tablet was discontinued and replaced with a risperidone tablet 2 mg daily due to concerns about increased appetite and decreased patient compliance. Within 30 minutes of the first dose of risperidone, the patient developed an acute urticaria rash with pruritus, which resolved after discontinuation of the drug and intramuscular administration of 5 mg of promethazine.
Two days later, aripiprazole 5 mg daily was started as an alternative antipsychotic. However, within 20 minutes of administration, the patient developed hives and severe itching, which worsened after the second dose. Tablet Aripiprazole was then promptly discontinued, and promethazine 5 mg intramuscularly was restarted for symptom relief. While symptoms improved, itching persisted.
The following day, tablet levetiracetam was discontinued, which resulted in a gradual resolution of the patient’s pruritus. She remained symptom-free for approximately 24 hours. Subsequently, tablet quetiapine was initiated at 25 mg/day, starting with a quarter tablet, in conjunction with hydroxyzine 10 mg nightly. Following initiation of tablet quetiapine, the patient developed a transient urticarial rash with pruritus, which resolved spontaneously within 24 hours without requiring discontinuation. After starting tablet quetiapine, the patient developed a transient urticaria rash with itching that resolved spontaneously within 24 hours without the need for discontinuation of the drug. The patient was subsequently discharged with tablet quetiapine 25 mg/day and tablet valproate 500 mg at night. Access to follow-up data after hospital discharge was not possible, as the patient was not available for follow-up assessments post-discharge.
Patient written consent for the publication of this information has been obtained.
Discussion
The 27report examines the case of a 45-year-old patient diagnosed with Bipolar I Disorder who, after the unsupervised discontinuation of her medications, experienced a relapse of psychotic symptoms and, during hospitalization, exhibited allergic reactions to several different antipsychotic medications. Allergic reactions to antipsychotic drugs are generally unusual, and in most cases where “allergy” to these drugs is reported, true immunologic allergy is confirmed in fewer than 10% of them. 10 Nevertheless, in the patient, we observed a range of hypersensitivity reactions to structurally diverse antipsychotic medications (Olanzapine, Risperidone, Aripiprazole, and Quetiapine), as well as to the anticonvulsant Levetiracetam. This unusual condition may indicate cross-sensitivity between various drugs or a Multiple Drug Hypersensitivity (MDH) syndrome. 11 See Table 1 for a summary of similar case reports.
Case Reports of Allergic Reactions to Several Antipsychotics.
Drug allergy refers to an undesirable immune-mediated reaction that occurs in response to a specific medication and is usually limited to that drug or closely related agents. Such reactions may be immediate and IgE-mediated (eg, urticaria, anaphylaxis) or non-immediate and T-cell-mediated (eg, maculopapular eruptions, DRESS, Stevens-Johnson syndrome). In contrast, multiple drug hypersensitivity, also known as Multiple Drug Hypersensitivity syndrome (MDH), is a rarer condition in which a patient develops immunologically mediated reactions to at least 2 structurally or pharmacologically unrelated drugs. 12 In other words, whereas in classic drug allergy the immune system becomes sensitized to a single drug antigen, in MDH the patient’s immune system enters a state of persistent activation after an initial drug reaction and subsequently becomes prone to reacting to other, different medications as well. An important immunological distinction between these 2 conditions is that reactions in MDH result from independent sensitizations to each drug rather than cross-reactivity to a shared allergen. This is consistent with the observation that the clinical manifestations of reactions in MDH may vary depending on the newly introduced drug, indicating that MDH represents multiple distinct drug allergies rather than a single allergy with cross-reactivity. 12 Drug allergies constitute a small but clinically significant proportion of adverse drug reactions; approximately 5% to 10% of all adverse drug reactions are immune-mediated. Nevertheless, simultaneous immune hypersensitivity to multiple unrelated drugs is considered a rarer phenomenon. Studies indicate that only a small proportion of patients with drug allergy develop true MDH; among populations referred to allergy centers, the prevalence of MDH has been reported to be approximately 0.5% to 3%. 13 A history of drug allergy itself is considered a predisposing factor for subsequent drug allergies. These data suggest that patients with a prior history of immunologically mediated drug reactions should be managed with greater caution when exposed to new medications, as they may have an increased susceptibility to MDH. 12 The diagnosis of drug allergy is generally based on clinical history and patient manifestations and, when feasible, is confirmed by complementary tests. In contrast, the diagnosis of multiple drug hypersensitivity (MDH) requires more robust evidence, as it must be demonstrated that each reaction represents a distinct immunological sensitization and is not attributable to factors such as pharmacological intolerance or structural similarity between drugs. Accordingly, experts have proposed that the term MDH should be used only when a patient has confirmed hypersensitivity reactions to at least 2 chemically unrelated drugs, supported by objective evidence such as skin testing or laboratory assays (eg, lymphocyte activation tests). 14 In our case report, in which hypersensitivity reactions to antipsychotic medications were considered, awareness of these distinctions is essential for accurate clinical interpretation. First, it must be determined whether the patient’s symptoms were due to an allergy to a single specific drug (for instance, a particular antipsychotic or closely related agents) or whether the pattern of reactions is suggestive of a multiple drug hypersensitivity syndrome. The occurrence of severe and systemic reactions to 2 dissimilar antipsychotic drugs raise the possibility of MDH. This is particularly compelling if the initial reaction was severe (such as DRESS or a widespread cutaneous reaction) and was followed, after a defined time interval, by a reaction to another unrelated drug, suggesting that the immune system remained in a sustained state of activation after the first exposure and subsequently responded to the second drug as well. Such a pattern is consistent with the mechanism of MDH and indicates that the patient may have a broader predisposition to hypersensitivity rather than 2 isolated, unrelated drug allergies. In clinical practice, identifying MDH in this patient implies that extreme caution should be exercised when prescribing new medications—whether antipsychotics or drugs from other classes—and that, whenever possible, sensitivity testing or preventive strategies should be considered to avoid the recurrence of severe reactions. If evidence does not support MDH and the patient’s reactions are limited to a single drug or structurally related drugs, a different interpretation would be warranted, and the condition could be attributed to a specific drug allergy. In all cases, emphasizing the distinction between single-drug allergy and multiple drug hypersensitivity syndrome contributes to a better understanding of the patient’s pathophysiology and to safer clinical management.
Despite the clear chemical differences among second-generation antipsychotics, there have been reports of cross-allergic reactions between them. For example, in a patient with schizophrenia, the use of Clozapine led to acute angioedema, and substitution with Olanzapine triggered the same reaction within a few days. 11 Moreover, a similar case has been reported in which, after angioedema caused by Haloperidol, the patient developed urticaria, lip swelling, and shortness of breath upon taking Iloperidone. 15 In our patient, the appearance of urticaria and generalized itching following Risperidone intake within 30 minutes, and generalized pruritus after Aripiprazole in less than 1 hour, indicate immediate reactions—possibly IgE-mediated Type I hypersensitivity—to unrelated medications. The aforementioned reports and the patient’s reaction pattern suggest that after a severe allergic reaction to one antipsychotic, the immune system may become hyper-alert and respond to other antipsychotic medications, even with differing chemical structures. 16 This phenomenon could result from broad T-cell activation and the creation of long-lasting immunological memory, leading to Multiple Drug Hypersensitivity (MDH) syndrome. In MDH, the initial reaction is typically a severe delayed hypersensitivity reaction such as widespread rash or DRESS syndrome, associated with prolonged T-cell activation; subsequently, over the following weeks or months, other unrelated drugs may provoke similar reactions (rash, DRESS, SJS/TEN, hepatitis, etc.) in the patient. 17 MDH leads to a state of “neo-sensitization” to multiple medications that may persist for years. 18 A relevant case report describes a patient with schizophrenia who, after experiencing DRESS due to Valproate, went on to develop hypersensitivity reactions over the next few years to Amoxicillin and 2 antipsychotics (Olanzapine and Quetiapine) as well. 18 Therefore, clinical experience and existing evidence emphasize that a severe reaction to one drug, such as DRESS, can sensitize an individual to other unrelated medications too.
On the other hand, true cross-reactivity caused by structural similarity among drugs is less often a concern with antipsychotics, as these medications are chemically diverse. However, certain closely related antipsychotics may share allergy patterns. For instance, the 3 drugs Clozapine, Olanzapine, and Quetiapine are all dibenzodiazepine derivatives and, in 1 patient, all 3 triggered cross-induced angioedema. 11
Furthermore, there are rare reports of angioedema induced by Risperidone, Ziprasidone, Droperidol, and even Chlorpromazine, suggesting that although the exact immune mechanism in such cases is not well understood, similar immunologic pathways—independent of the chemical structures of the drugs—are likely involved. Overall, the occurrence of hypersensitivity to multiple unrelated medications in our patient points more to an underlying predisposition of the immune system to react to various drugs, rather than to structural similarity between the agents. This underlying predisposition may be influenced by genetic and immuno-cognitive factors lowering the threshold for immune activation by drugs. 19
With regard to predisposing factors for reactions to multiple psychiatric medications, examining risk factors in such patients is of importance. Studies have shown that being female and older age are associated with a higher prevalence of being labeled with “drug allergy.” 20 Although our patient is a middle-aged male, it should be noted that reports of multiple drug hypersensitivities have been more common in older women with higher body mass index. 21 In general, polypharmacy and the presence of comorbid conditions are significant risk factors. Patients with chronic physical illnesses or concurrent psychiatric disorders—frequently engaged with the healthcare system and exposed to multiple medications—are more likely to report multiple drug allergies. 20
A history of prior allergic reaction is, in itself, a notable risk factor for reaction to a new drug. Classically, individuals with a history of drug allergy have up to 9 times the risk of reacting to a different drug compared to those without such a history. The exact mechanism is unclear but may involve a genetic predisposition or specific immuno-cognitive state, which is sometimes observed in family members as well. Interestingly, about 10% of family members of individuals with drug allergies also experience some form of drug reaction, indicating a possible genetic component. 22 From an immunologic standpoint, HLA system genes play a key role in drug allergy susceptibility. Although no specific associations between HLA alleles and antipsychotics have yet been identified, genetic polymorphisms in drug metabolism or immune regulation pathways may still be involved. 23 Impaired hepatic enzyme function in drug metabolism—whether due to liver failure or genetic makeup—can lead to the accumulation of active metabolites and increased likelihood of immune reactions. Both childhood and old age are associated with a higher risk of drug reactions due to differences in metabolic pathways. Moreover, concurrent viral infections may act as cofactors, increasing the risk of DRESS syndrome in predisposed individuals. Another important medical history consideration is that of atopic allergy (such as allergic rhinitis, asthma, or eczema); although findings are mixed, some studies have shown that people with an atopic background or a family history of allergy are more likely to experience drug reactions. 23 Overall, any form of autoimmune disorder or immune deficiency can render the immune system more “error-prone” in reacting to medications. For example, patients with systemic lupus erythematosus (SLE) have been shown to have a higher prevalence of drug-related rashes, 24 and individuals with HIV are approximately 100 times more likely than the general population to experience hypersensitivity reactions to medications. 25 Although our patient had no history of the aforementioned conditions, the broad range of her reactions to multiple drugs suggests the presence of an underlying, unrecognized genetic or immunologic background that has made her prone to these responses.
Managing a patient who shows allergic reactions to multiple medications is highly challenging. The first step is to avoid re-prescribing the medications that have previously caused reactions, and to select alternative drugs from different classes. In this case, all 4 problematic antipsychotics were second-generation agents. Therefore, a rational strategy would be to use a first-generation (typical) antipsychotic with a completely different chemical structure. 11 Clinical experience has shown that, for example, haloperidol, with a butyrophenone structure, can be tolerated without allergic response in patients who have reacted to atypical antipsychotics. 11 In a case report, after angioedema occurred with 3 atypical antipsychotics, cautious administration of haloperidol followed by loxapine (a first-generation antipsychotic) proved successful and controlled psychotic symptoms as well. 11 A similar approach could be considered for our patient, particularly loxapine, which is a dibenzoxazepine derivative (structurally similar to clozapine) and has antipsychotic properties, making it a candidate for trial under close monitoring. Besides, chlorpromazine, an older phenothiazine, may be considered if no cross-allergy exists. It is crucial to note that any new medication for this patient must be initiated in a hospital setting with full readiness to manage possible acute reactions. From the perspective of bipolar disorder treatment, fortunately, non-pharmacological options are also available. Electroconvulsive Therapy (ECT) is an effective and approved method for treating mania and acute psychosis. Clinical guidelines from the American Psychiatric Association (APA) and the World Federation of Societies of Biological Psychiatry (WFSBP) affirm that ECT can be employed in manic episodes, particularly those resistant to treatment or accompanied by prominent psychotic symptoms. Evidence shows that the response rate to ECT in mania is substantial; in some reports, around 80% of manic patients responded favorably to ECT. 17 Therefore, for our patient, who is unable to tolerate most antipsychotics, ECT may serve as a highly effective second-line treatment, particularly if alternative pharmacologic measures are insufficient. Of course, ECT requires thorough medical evaluation and informed consent, but when feasible, it can rapidly control manic/psychotic symptoms and reduce reliance on multiple medications.
Another important pharmacological strategy is to maximize the use of classical mood stabilizers, such as lithium and valproate. According to guidelines, lithium or valproate are recommended as first-line treatments for mania, with antipsychotics added mainly for aggressive behavior or severe psychosis.26,27 Fortunately, our patient previously tolerated valproate, making it feasible to use valproate or lithium, with serum level monitoring, to manage manic symptoms and prevent relapse. Although the presence of psychotic symptoms in this patient initially suggested a need for antipsychotics, in the absence of tolerable second-generation antipsychotics due to allergy, low-dose haloperidol with gradual titration, combined with a mood stabilizer, may be an effective regimen. 11 In some cases of severe mania, a combination of lithium and valproate has been used, too, and it may help reduce the required antipsychotic dose. Furthermore, benzodiazepines (such as clonazepam or lorazepam) can be employed for short-term control of agitation and insomnia in mania, thus helping to minimize reliance on antipsychotics. 28
Another important consideration in the management of this patient is consultation with an allergy and immunology specialist. Specialized allergy evaluation may include skin or blood tests to confirm the type of hypersensitivity to each drug, particularly IgE-mediated type I reactions. Although there are no standardized skin tests for antipsychotics, patch testing or graded drug challenge under specialist supervision may, in the future, help to identify safe alternatives. 29 In some reported cases, patients with multiple drug hypersensitivities have undergone drug challenge tests or desensitization protocols and were eventually able to tolerate essential medications. Drug desensitization is a method in which very small and gradually increasing doses of a drug are administered to temporarily induce tolerance. This approach is typically reserved for situations where no viable alternative exists and the benefits of continuing the drug outweigh the risks. In our patient, given the broad range of triggering medications, it remains unclear which drug would be the most appropriate candidate for desensitization. However, if no first-line antipsychotic is tolerated, and clozapine remains the only effective option, a cautious desensitization protocol with clozapine, under the cover of antihistamines and corticosteroids could be considered. Nevertheless, it is essential to note that clozapine itself carries a high risk of severe reactions such as DRESS, and there are case reports of fatal outcomes in clozapine-induced DRESS. Limitations of this study include the absence of therapeutic drug monitoring and clinical photographs, the latter due to strict adherence to patient confidentiality protocols. Hence, such an approach should only be pursued in cases of absolute treatment resistance and under the supervision of an expert allergy team. A summary of case reports of allergic reactions to several antipsychotics is shown in Table 1.
Strengths
The current report presents a rare and clinically significant pattern of hypersensitivity reactions to multiple psychotropic medications. A major strength is the precise chronological timeline and the very close temporal association between drug exposure and symptom onset, together with improvement following drug discontinuation that strengthens the likelihood of a causal relationship. Besides, the occurrence of symptoms after exposure to several structurally distinct agents enhances the value of the report and has important implications for drug safety and therapeutic decision-making in patients with bipolar disorder. The inclusion of a brief literature review and a comparative table of similar cases also help contextualize the findings within the existing body of evidence.
Limitations
First, this is a single case report; therefore, the generalizability of the findings is limited, and no estimates of prevalence or risk can be derived. Second, the diagnosis of immune mediated allergy and hypersensitivity is largely based on the clinical presentation and the timing of events, while confirmatory allergy testing (such as skin tests, specific laboratory assays, or supervised drug provocation/challenge tests under an allergist’s supervision) was not performed. Consequently, definitive differentiation between true allergy, drug intolerance, or non-immune mechanisms remains limited. Third, the presence of concomitant medications may confound attribution of symptoms to a single causative drug, and the possibility of synergistic effects or underlying predisposing factors cannot be entirely excluded. Fourth, the absence of clinical photographs, lack of therapeutic drug monitoring, and the unavailability of some complementary data such as long term follow up after discharge or standardized causality assessment tools represent practical limitations of this report. Despite these limitations, this case may increase clinical awareness regarding the potential for simultaneous hypersensitivity to multiple psychotropic agents and highlights the need for specialized allergy evaluation and caution when selecting and initiating alternative therapies. In future studies and case reports, comprehensive allergy and immunology assessments, confirmatory testing, and, where feasible, the use of standardized causality assessment instruments are recommended.
Conclusion
Our case represents a rare instance of multiple hypersensitivity reactions to psychiatric medications, posing significant challenges from both immunological and psychiatric perspectives. This condition may be considered a manifestation of Multiple Drug Hypersensitivity Syndrome (MDHS), where patients develop reactions to various unrelated drugs following a severe initial hypersensitivity event. Multidisciplinary management is essential. On the one hand, collaboration with allergy specialists is needed to develop an avoidance plan for offending agents, and if necessary, to conduct controlled drug challenges for essential medications. On the other hand, from a psychiatric standpoint, the underlying disorder should be treated with minimal reliance on high-risk medications. To this end, the use of alternative treatments such as ECT, maximization of classical mood stabilizers (eg, lithium, valproate), and even the judicious use of older antipsychotic agents (if tolerated) are recommended. Fortunately, in many cases, these strategies allow for successful symptom control without recurrence and without the need for triggering drugs. Finally, the reporting of such cases and systematic research in the field of psychopharmacological immunology is critical. They may contribute to the identification of genetic or clinical predictors of hypersensitivity and help design safer treatment protocols for vulnerable patients.
Footnotes
Ethical Considerations
The patient information kept being confidential to the researchers.
Author Contributions
MP contributed in case selection, study design, and manuscript revision. FS and MM contributed in database searches and extraction of clinical studies and patient paraclinical information. All authors wrote the original draft and have read and approved the final version of the manuscript.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.