Abstract
Adverse cutaneous reactions are one of the most frequent types of adverse drug reactions, and have been reported with a wide range of psychotropics including typical and atypical antipsychotics. However the majority of adverse cutaneous reactions are relatively minor, and severe reactions are relatively rare. Aripiprazole is a third-generation atypical antipsychotic that has been available in the UK for over seven years. Here the author reports the first reported case of a lichenoid drug reaction to aripiprazole, a severe and potentially life-threatening adverse cutaneous reaction that required medical and surgical intervention.
Introduction
Adverse cutaneous reactions are one of the most frequent types of adverse drug reactions [Svensson et al. 2000], and have been reported with a wide range of psychotropics including both typical and atypical antipsychotics [Lange-Asschenfeldt et al. 2009]. As a group, antipsychotics are thought to induce adverse cutaneous reactions in approximately 5% of those for whom they are prescribed [Warnock and Morris, 2002a]. The incidence is lower than reported with antiepileptic mood stabilisers (10%) [Warnock and Morris, 2002b; Lange-Asschenfeldt et al. 2009; Svensson et al. 2000] and antidepressants [Lange-Asschenfeldt et al. 2009], and is not influenced by gender [Lange-Asschenfeldt et al. 2009].
The types of adverse cutaneous reactions reported with antipsychotics vary widely [Warnock and Morris 2002a], from very mild to severe and life threatening [Lange-Asschenfeldt et al. 2009]. These are type B adverse reactions, i.e. rare and bizarre reactions that could not be predicted and are unrelated to the medicines’ pharmacology [Pirmohamed et al. 1998]. However, in keeping with the range of reactions, the mechanisms vary widely and commonly are unknown, with only approximately 10% of such reactions being immunological in nature, particularly the more severe ones [Svensson et al. 2000; Valeyrie-Allanore et al. 2007; Vervloet and Durham, 1998].
Overall rates of adverse cutaneous reactions are thought to be under reported, as most reactions are relatively benign and easily treated [Lange-Asschenfeldt et al. 2009]. The adverse cutaneous reactions most frequently reported with antipsychotics are exanthematous eruptions, photosensitivity reactions and skin pigmentation changes. Fixed drug eruptions are also relatively common adverse cutaneous reactions with several atypical and some typical antipsychotics as well as with other psychotropics [Bhattacharjee and El-Sayeh, 2008]. The onset is usually within a few days of ingestion, affects any part of the body, and may involve the mucosal membranes [Valeyrie-Allanore et al. 2007]. Severe cutaneous eruptions, such as erythema multiforme, have been reported much less frequently with several atypical and some typical antipsychotics [Warnock and Morris, 2002a]. The onset is slower, typically 1–3 weeks after initiation [Svensson et al. 2000], but this may potentially develop into a more serious reaction such as Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis [Warnock and Morris, 2002a]. When a severe cutaneous reaction develops the suspected causal agent should be immediately withdrawn [Kimyai-Asadi et al. 1999; Svensson et al. 2000; Warnock and Morris, 2002a].
Here the author presents a case of a severe and potentially life-threatening adverse cutaneous reaction following initiation of oral aripiprazole.
Case presentation
A 61-year-old Moroccan gentleman with a long-standing diagnosis of schizophrenia had been treated with flupentixol decanoate depot since 1976. Over the years this had been prescribed at varying doses and at times with the addition of other antipsychotics, such as trifluoperazine. Throughout this time he regularly suffered with extrapyramidal side-effects (EPSs) for which he took oral procyclidine. He had residual but manageable psychotic symptoms and no psychiatric admissions. He was obese, had type 2 diabetes for which he took metformin and had no known drug allergies.
He was prescribed flupentixol decanoate 150 mg fortnightly. At lower doses the psychotic symptoms became more problematic although the EPS lessened; at this dose the ongoing EPS included pill rolling tremor in his left hand, poverty of facial expression, festinating gait and oculogyric crises. The latter were described and verified by both him and his wife, although not observed during clinic appointments; they appeared independently of time, location and setting, and happened several times a week. Both he and his wife found these very distressing. He was already taking procyclidine 5 mg usually twice a day but often more, and carried these tablets with him in his pocket. An additional 5–10 mg of procyclidine was effective at treating an oculogyric crisis.
A suggestion was made to try an alternative antipsychotic. He had only previously taken typical antipsychotics, and in view of his physical health, comorbidities and concurrent medication, a limited range of atypicals were considered. Following discussions between the pharmacist, the patient and his wife, a mutual decision was made to change to aripiprazole. The patient was given written information about aripiprazole and a very gradual change over was recommended from the depot to aripiprazole in order to minimize the risk of relapse. No further doses of depot were given: when the depot would next have been due aripiprazole 5 mg was started. A fortnight later, as there were no adverse effects, the dose was increased to 10 mg with the plan to increase further to 15 mg if tolerated. After starting on aripiprazole 10 mg daily there was no immediate change in mental state, and no initial side effects (such as nausea or insomnia), and he slept much better. He had pre-existing neurological pain in his left arm for which he was not specifically taking any treatment, which had previously disturbed his sleep significantly. After 2 weeks on this dose it was increased to the therapeutic dose of 15 mg a day. One day later his wife reported that ‘the skin fell off his legs’ when she removed his socks (he was unable to do this for himself due to poor mobility), and described fluid exuding through the skin of his abdomen. There was no mucosal involvement. On presentation to his GP he was immediately referred to the local accident and emergency department, from where he was admitted to an acute surgical ward.
He was seen by two dermatology teams and diagnosed with a lichenoid drug reaction, which was attributed to the newly initiated antipsychotic aripiprazole. He was found to have extensive skin peeling on his right hand with evidence of pus. In theatre he underwent several surgical procedures including debridement of the skin on several parts of his body including his hands and soles of his feet, and fluid collected under the epidermis was aspirated. He was treated with intravenous antibiotics and fluids, and discharged after 6 days.
Discussion
Aripiprazole is an atypical antipsychotic that was licensed in the UK in June 2004 in its oral formulations. It has been described as a third-generation antipsychotic due to its slightly different mode of action. Unlike other antipsychotics which antagonize dopamine D2 receptors in the mesolimbic area of the brain, aripiprazole is a partial agonist at D2 dopamine and 5HT1a serotonin receptors, and an antagonist at 5HT2 serotonin receptors. It has been postulated that through this combination of actions it stabilizes the dopamine and serotonin system. However, despite this alternative mechanism of action a Cochrane review [Bhattacharjee and El-Sayeh, 2008] concluded that aripiprazole was as equally effective as other typical and atypical antipsychotics.
Until January 2012 a total of 110 skin disorders associated with the use of aripiprazole (oral or intramuscular) have been reported to the Medicines and Healthcare products Regulatory Agency (MHRA) via the voluntary Yellow Card Scheme [Commission on Human Medicines/Medicines and Healthcare products Regulatory Agency, 2012]. None of the cutaneous adverse reactions were fatal, the majority were either hyperhidrosis and cold sweats (n = 30) or rashes (n = 23). The remaining reactions (n = 57) were varied and there were only a handful of cases of each, including three cases of erythema multiforme. Our case was coded as a fixed drug eruption and is the only one reported.
Lichenoid drug eruptions are hypersensitivity reactions; they are usually symmetrical on the trunk and extremities, and exclude the mucosa [Kimyai-Asadi et al. 1999], as in this case. They are characterized by damage and infiltration between the epidermis and dermis. They generally occur months after the initiation of a drug, although in this case it was just over 2 weeks; reactions take months to resolve after discontinuing the offending agent. Even then, postinflammation hyperpigmentation may be seen. Such reactions have been reported with various psychotropics including phenothiazine antipsychotics [Kimyai-Asadi et al. 1999].
The Summary of Product Characteristics for aripiprazole [Otsuka and Bristol-Myers Squibb, 2011] does not suggest that dermatological reactions were noted during clinical trials. It lists ‘rash, photosensitivity, reaction, alopecia and hyperhidrosis’ as adverse reactions that have been noted during postmarketing surveillance, but the incidence cannot be determined.
A literature search (using Medline) identified case reports of three severe adverse cutaneous reactions in patients prescribed aripiprazole [Hilas and Charneski, 2007; Shen et al. 2007]. All were cases of SJS; although the patients were taking aripiprazole they had all been recently initiated on lamotrigine which was thought to be the more likely causal agent as this is well known to be associated with SJS [Warnock and Morris, 2002b]. These cases raise the question of whether the presence of aripiprazole increases the likelihood of SJS with lamotrigine [Shen et al. 2007].
In our case aripiprazole was immediately stopped on presentation of the reaction, and with surgical and pharmacological treatment this resolved. A few weeks later the patient was started on oral flupentixol as a short-term measure as this was known to be a reasonably effective antipsychotic for him. In light of this extreme and frightening adverse reaction the patient was very reluctant to try an alternative antipsychotic. In view of the patient’s preference when weighing up the relative risks, and after several further discussions between the doctors, patient and his wife, and the pharmacist, a joint decision was made to continue oral flupentixol. His skin continued to heal and the oculogyric crises (which had been the presenting difficulty) did not return. It was presumed that this was because the oral dose was relatively lower than that cumulative depot dose. Ten months later he remains on oral flupentixol, he is the same mentally (symptomatic, but manageable), his skin has healed and the oculogyric crises have not returned.
Summary
Severe side-effects from a very long-standing antipsychotic treatment prompted a change to a new atypical antipsychotic, with the expectation that this would minimize the patient’s significant existing side-effect burden and so improve his quality of life. However, this well-intended change led to a significantly worse outcome and a life-threatening cutaneous adverse drug reaction that has never been reported in the literature before with aripiprazole.
Covering statements
This adverse drug reaction was reported to the MHRA via the Yellow Card Scheme, and to the manufacturer.
The patient and the consultant psychiatrist have seen this report and have consented to its publication.