Psychotropic medications, used to treat primary psychiatric disorders as well as psychodermatologic conditions, constitute one of the most frequently prescribed drugs in outpatients of a hospital setting given that psychiatric disorders represent a significant comorbidity in the United States (ranging from approximately 1% to 22%) ^[1][2][3][1,2,3]. Adverse reactions (ADRs) to these medications are a leading cause of discontinuations and therefore can lead to poor compliance [4]. ADRs have been broadly classified in the literature into type A—representing predictable reactions such as anticholinergic and antipyramidal signs—and type B—representing often idiosyncratic reactions such as adverse cutaneous drug reactions (ACDRs)—the latter of which has been under-reported due to the fact that most of these are benign and easily manageable [5]. Nevertheless, dermatological reactions account for the majority of side effects from drugs including psychotropic medication, with some prospective studies estimating a prevalence of approximately 4 to 7 in 1000 hospitalisations ^[6][7][6,7]. Similarly, ACDRs account for the majority (2 to 5%) of ADRs to psychotropic medication [8]. As per one report, the prevalence of dermatological symptoms in psychiatric patients was as high as 8.4%, with 50% of them having received their first treatment with psychotropic medications [9]. ACDRs have been reported in all classes of psychotropic drugs—mood stabilizers (39%), antidepressants (29%), and antipsychotics (19%) [10]. Additionally, cross-sensitivity is a concern due to the common utilization of multiple drugs to achieve remission [11]. However, most of the existing data focus on hospital settings, where multiple drugs are commonly prescribed, which can make the establishment of causal drugs difficult to interpret for an appropriate withdrawal strategy. 

Both immunogenic as well as non-immunogenic mechanisms have been described in the literature; the former accounts for 5–10% of all ACDRs and can be mediated by immunoglobulin E (IgE), circulating immune complexes, or by lymphocytes ^[12][13][13,14]. Predominantly, the expansion of T cells represents the most common immune response to a drug, recognizing it as foreign and orchestrating a delayed immune response, often manifesting as pruritic rashes affecting the skin. In the context of psychiatric medications, the immunogenic role is underscored by factors such as Human Leukocyte Antigen (HLA) subtype and viral infections, and emerging evidence suggests a strong interrelation between thoughts, emotional patterns, psychological dynamics, and the immune response in psychiatric conditions ^[14][15]. The immunogenic mechanism has been highlighted by the role of factors such as Human Leukocyte Antigen (HLA) subtype or viral infections ^[15][16]. Substance abuse, being a woman (particularly in the reproductive age group), and the use of antiepileptic drugs (AEDs) and selective serotonin reuptake inhibitors (SSRIs) were identified as independent risk factors from regression analyses ^[10][16][10,17]. Hormonal influences and a predisposition to autoimmune disease likely cause women to be at higher risk, although the exact reason remains unclear ^[17][18][18,19]. The HLA system, located on the short arm of chromosome 6p21.31, plays a pivotal role in immune recognition, and abnormalities in HLA expression can impact antigen processing and presentation ^[19][20][20,21]. The distribution of HLA genes across chromosomes is categorized into three distinct regions—class-I, class-II, and class-III ^[21][22]. Additionally, it is important to note that HLA serves as a genetic marker and remains unchanged throughout an individual’s lifespan ^[22][23]. Moreover, the classical grouping of HLA-I genes comprises three subtypes: HLA-A, HLA-B, and HLA-C ^[23][24]. The role of HLA polymorphism has been extensively studied over the years to provide an understanding of the pathogenic mechanisms of ACDRs and atopic conditions ^[24][25]. Of note is the particular HLA subtype that has been observed to impact different ethnicities based on carbamazepine (CBZ) studies (Table 1). In particular, HLA-A has been observed to be most frequently associated with SJS/TEN reactions induced by the AEDs carbamazepine, lamotrigene, phenytoin, and zonisamide, followed by HLA-B or C subtypes ^[25][26]. Furthermore, ethnicity has a role to play in the type of reaction observed ^[26][27]. Pharmacogenomic considerations such as HLA subtype can be used to guide dose adjustments or drug selections to avoid any life-threatening ACDRs ^[27][28]. A higher risk has also been observed in the elderly population, particularly those with multiple chronic medical conditions and polypharmacy ^[28][29].

The diagnosis of drug-induced dermatological reactions is a significant challenge due to factors such as multifactorial aetiology and complex presentation. A comprehensive patient history is crucial, including details about the rash’s onset, its pattern, and the patient’s medication history ^[33][34]. In some cases, confirmation of the diagnosis may necessitate skin testing or in vitro testing ^[34][35]. Exanthematous eruptions, the most common dermatological reaction, typically manifest initially on the trunk or in areas subjected to pressure or trauma ^[35][36]. Upon discontinuation of the offending drug, these eruptions tend to spread to the extremities and eventually subside. The rash commonly emerges within a few hours after the initial drug administration, although the timeline can vary for previously sensitized individuals ^[36][37]. Other dermatological presentations encompass drug-induced urticaria, characterized by erythematous wheals, and erythroderma, a generalized skin erythema ^[37][38]. Drug-induced photosensitivity is a rare phenomenon which occurs due to cellular damage caused by cross-reaction in sun-exposed areas and results in oedema and erythema ^[38][39]. Although it is considered a rare ACDR, it may have potential significance due to its association with SSRIs, which are widely prescribed globally for a variety of psychiatric conditions apart from depression. Thus, patients on these photosensitizing drugs must be aware of the potential risk and must practice sun protection. Sunlight avoidance is the ideal measure, but individuals who have to stay outdoors must use broad-spectrum sunscreens, which offer protection against both UVB and UVA; these also must contain a high sun protection factor (SPF). In addition to this, smartphone apps can alert the user about UV levels and offer personalized protection, and other measures like the use of UPF-rated clothing have also proved to be beneficial ^[38][39]. In severe cases, drug-induced dermatological reactions can escalate to conditions like Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reactions with eosinophilia and systemic symptoms (DRESS) ^[39][40][41][40,41,42]. Also, certain mood stabilizers like lithium have caused notable instances of drug induced alopecia (12–18%). Apart from this, other drugs like TCAs, benzodiazepines, and newer antidepressants are also responsible for hair loss, although the incidence remains rare ^[42][43]. Discontinuation or dose reduction usually result in complete hair regrowth, but the therapeutic value of mineral supplements remains uncertain. Such severe reactions necessitate immediate hospitalization and the prompt discontinuation of the causative drugs to mitigate further complications.

4. Morphology and Diagnosis

4.1. Morphology and Basics of Skin Lesions

Drug-induced cutaneous reactions pose a significant challenge in diagnosis and management. Among the enhanced spectrum of skin lesions seen, 51–95% of them are exanthematous eruptions ^[43][44]. Exanthematous eruptions typically manifest as diffuse erythematous macules and papules, predominantly on the upper half of the body. They often emerge within ten days of initiating the offending drug but can also appear after drug discontinuation. The notorious agent attributed to this kind of skin eruption is phenothiazine neuroleptics. Notably, CBZ can induce a similar eruption that tends to initiate on the face and spread throughout the body ^[44][45]. Barbiturates have also been implicated in causing exanthematous eruptions, typically manifesting as macular lesions ^[44][45]. Urticarial reactions are another type of drug-induced cutaneous response which can appear anywhere on the body, often within minutes to hours of drug intake, and usually resolve within 24 h ^[34][35]. They potentially impact the airway and necessitate urgent medical intervention because of their association with anaphylaxis and angioedema. Fixed drug eruptions present as well-defined, solitary, red to purple lesions, sometimes with bullae or erosions. These eruptions typically occur within 30 min to 8 h after drug ingestion ^[45][46]. Barbiturates are commonly associated with fixed drug eruptions, and they have also been reported with certain antidepressants ^[44][45]. Drug Reaction with Eosinophilia and Systemic Symptoms (DIHS) is characterized by a macular exanthematous eruption, fever, lymphadenopathy, and multiorgan involvement, with the liver being most affected. About 25% of DIHS sufferers have significant facial oedema, and about 30% have eosinophilia ^[46][47]. Usually occurring two to six weeks after starting medication, CBZ and aromatic anticonvulsants such as phenytoin and phenobarbital are most commonly linked to this condition’s symptoms. DIHS can result in a 10% death rate, mostly from hepatic necrosis and fulminant hepatitis ^[46][47]. Erythema multiforme is characterized by well-defined erythematous macules or papules with central bullae or crusts, often forming “target” lesions. Typically, this condition affects the extremities and palmoplantar surfaces, with the potential involvement of mucous membranes. Erythema multiforme is commonly linked to infections, with drug-induced cases primarily associated with AEDs ^[47][48]. Cutaneous pseudolymphoma is a benign condition that mimics cutaneous lymphoma. It typically presents as red to violaceous smooth papules, nodules, or plaques, often accompanied by an exanthem. A dermatology consult and biopsy may be necessary to differentiate this condition from malignancy.

4.2. Diagnosis

Diagnosing cutaneous side effects can be a challenging endeavour due to the involved complexities of the interplay of etiologic factors and complex cross-reactions due to multiple therapeutic agents prescribed to the patient. The burden of antipsychotic side effects is estimated using validated tools such as the Glasgow Antipsychotic Side Effect Scale (GASS) or the Udvalg for Kliniske Undersøgelser (UKU) SE scale, which could provide clues about any dermatological side effects from antipsychotics. Physical examination is pivotal in understanding the pattern, distribution, and characteristics of the cutaneous eruption, offering essential diagnostic information. A high level of suspicion is warranted given the fact that ACDRs are non-specific and mimic any skin lesions. Numerous algorithms have been devised to assess the likelihood that a drug is responsible for a cutaneous manifestation. One such example is the algorithm of drug causality for EN (ALDEN) scale, which can be helpful in determining drug causality and has been found to be more sensitive than general methods ^[48][49]. Constructing a timeline that includes the drug’s initiation, duration of use, the last time it was taken, and when the cutaneous symptoms appeared can aid in diagnosis. Drugs initiated within the previous three months, particularly within the last six weeks, are often the primary suspects, as are drugs used intermittently ^[49][50]. Therefore, a comprehensive drug history with proper information regarding dosage and duration must be obtained before starting a new agent. Prior ACDRs in a patient’s history should be considered as a potential diagnostic clue. Moreover, the response of cutaneous symptoms to reduced drug dosages or discontinuation is a valuable indicator of a drug-induced reaction. Exploring the patient’s family history for instances of hypersensitivity reactions to drugs may provide additional context for diagnosis ^[50][51]. In cases where drug-induced skin reactions raise concerns, certain clinical findings should be closely monitored ^[49][50]. Identifying these symptoms may necessitate immediate discontinuation of the offending drug and a consultation with a dermatologist. Moreover, it is crucial to differentiate between ACDRs caused by psychotropic drugs and self-inflicted skin lesions, often resulting from psychiatric conditions like trichotillomania ^[51][52]. Therefore, comprehensive documentation of cutaneous findings during psychotropic medication treatment, including detailed descriptions, the timing of onset, and the progression of the skin eruption, plays a significant role in achieving an accurate diagnosis and ensuring appropriate management.