Key words
adverse events · - antipsychotic treatment - · inflammation - · second generation
antipsychotics - · side effects
Introduction
Quetiapine hemifumarate (QF), that is available as a non-retarded as well as a retarded
preparation, is a common agent in psychiatry with a wide spectrum of indications ranging
from schizophrenia to bipolar disorder [1]. It has been assessed to be effective for its main indication in schizophrenia and
is frequently associated with side effects such as dizziness, dry mouth, weight gain
and sleepiness [2]. Apart from these typical adverse events there are anecdotal reports of rare adverse
events related to quetiapine such as dependence [3], rhabdomyolysis [4], priapism [5], cholestasis [6], and hypothyroidism [7] that expand the knowledge of treatment-dependent risks. In the following we report
the first case of QF-associated aseptic gingivitis.
Case Report
The 34-year-old female patient was treated at regular intervals in our outpatient
department for agitation and severe psychomotor arousals related to moderate mental
retardation accompanied by generalized idiopathic epilepsy. Following impaired psychomotor
and speech development and a first generalized tonic clonic seizure at the age of
3 years the patient was hospitalized in several neurological and later on psychiatric
departments for diagnostic reasons. Considering normal pregnancy and delivery as well
as unremarkable findings regarding several magnetic resonance imagings of the brain,
the patient’s phenotype, examination of cerebrospinal fluid and chromosome analysis,
the etiology of the patient’s syndrome was finally classified as unidentified. Further
anamnesis revealed absence of other psychiatric or neurological diseases and there
was no history of alcohol, nicotine or illicit drug use. The patient’s family history
was unremarkable. Subsequent to frequently occurring severe agitation and aggressiveness
due to the patient’s high irritability, a psychiatric treatment was established in
order to particularly ameliorate these events. At the time of the first treatment
in our outpatient department, 4 years prior to the reported episode, the patient was
treated with valproic acid (1 000 mg per day), oxcarbazepine (1 500 mg per day), haloperidol
(5 mg per day), mirtazapine (15 mg per day), prothipendyl (40 mg per day) and biperiden
(4 mg per day). Anticonvulsive therapy with valproic acid and oxcarbazepine was present
for approximately 7 years resulting in complete suppression of epileptic seizures
and without the occurrence of adverse events. In the further course we modified the
medication and could achieve a substantial improvement regarding agitation and paroxysmal
arousals with QF (400 mg per day, retarded preparation), haloperidol (3 mg per day)
and valproic acid (1 000 mg per day). Termination of oxcarbazepine treatment did neither
result in worsening of electroencephalographic findings nor in an occurrence of seizures.
After approximately 1 year of stable remission regarding psychomotor target symptoms,
the patient’s legal guardian reported restlessness and increase of agitation. Thus,
QF (retarded preparation) was slowly titrated up to 800 mg per day within 2 weeks
until the patient presented a sufficient improvement. After approximately 1 week of
treatment with elevated QF (800 mg per day) the patient developed painful gingivitis
discontinuously affecting the gingiva of the maxilla and mandible, which was primarily
not connected with the dose escalation. There was no previous hypertrophy of the gum
tissue. Considering the unremarkable blood examination (including inflammatory parameters,
differential blood count, liver enzymes, serum vitamin C levels, no pregnancy by means
of blood human chorionic gonadotropin levels) and dental examination, hygiene measures
(antimicrobial mouth rinses and thorough dental care after food intake) were performed
for another 2 weeks without amelioration of the gingival inflammation. There was no
temporal link between the onset of gingivitis and the patient’s menstrual cycle and
the patient did not take any oral contraception. Clinical signs indicating an oral
fungal infection were absent. Since gingivitis developed subsequent to increased QF
dose and all other relevant parameters (unchanged dosages of haloperidol and valproic
acid, unaltered nutritional habits) remained unchanged QF was reduced probatorily
down to 400 mg per day. Within 1 week the gingival inflammation subsided completely
but the patient relapsed regarding psychomotor agitation as expected and lorazepam
was administered temporarily. As a second probatory intervention QF was increased
again up to 800 mg per day and gingival inflammation reoccurred. Hence we kept QF
(retarded preparation) at a dosage of 400 mg per day and established an additional
medication with promethazine (50 mg thrice per day) with which we achieved an improvement
of agitation. Again gingival inflammation ceased within 1 week and has not relapsed
since the last 6 months.
Discussion
In the presented case the gingival inflammation occurred with a close temporal relation
to elevated QF doses. This phenomenon subsided after dose reduction and reoccurred
after rechallenge with the increased dose. Application of the Naranjo adverse drug
reaction probability scale [8] to this constellation reveals a score of at least 5, indicating a probable causation
of the observed gingivitis by QF. Since other conclusive factors that could explain
our observation are lacking, we think that QF might have contributed to the development
of gingivitis in a causal way. Gingivitis and gingival enlargement are known as side
effects of a treatment with antiepileptic drugs (especially carbamazepine, valproic
acid and phenytoin) [9]. However, the pathomechanisms underlying these phenomenona are not completely elucidated
[10]. Taking into account that gingivitis did not occur under a 7-year treatment with
oxcarbamazepine and valproic acid, it is not plausible to hypothesize that gingivitis
is a consequence of continued treatment with valproic acid, particulary in consideration
of the observed dose dependence. Considering that other reports regarding similar
observations are lacking, the etiology of this phenomenon remains fairly speculative.
In the present case, the absence of a detectable systemic inflammation and unremarkable
differential blood count suggest an aseptic reaction that seems to be dose-dependent
and potentially idiopathic since gingivitis did not occur under lower doses of QF.
