Cenesthopathy, first described by Dupré and Camus,1 is characterized by idiopathic bizarre bodily sensations. The oral area is one of the most frequently affected regions. There are various complaints of oral cenesthopathy. Some patients complain of unusual oral sensations, such as excessive mucus secretion or a slimy sensation, and others complain of a bizarre oral sensation, such as a feeling of coils or wires being present within the oral region. Patients commonly have an unshakable conviction that some foreign body is existing in their mouths. They often spend hours each day examining their mouth and sometimes try to catch the foreign body.2

Previously, we reported that right brain perfusion asymmetry within a broad brain area, including the frontal and temporal lobes, is related to oral cenesthopathy.3 In addition, brain perfusion asymmetry is attenuated after electroconvulsive therapy4 and pharmacotherapy using low-dose aripiprazole.5 Some researchers have suggested treatment options for oral cenesthopathy. These included antidepressants such as amitriptyline, milnacipran, paroxetine, and mianserin, and antipsychotic drugs such as haloperidol, pimozide, tiapride, sulpiride, risperidone, perospirone, and aripiprazole.6

Herein, we report a case of oral cenesthopathy that was successfully treated with mirtazapine and brexpiprazole, a recently approved antipsychotic medication.

CASE DESCRIPTION

A 57-year-old female homemaker was referred to our clinic by an oral surgeon. The patient complained that her incisors were “softened and flaccid.” She also reported, “all of my mouth is bitter, and there is a sticky sensation in my mouth.” Her oral symptoms spontaneously developed 5 years before presentation. She visited a dentist in the Department of Oral Surgery at a university hospital and was prescribed ethyl loflazepate and Chinese herbal medicine, which did not alleviate her symptoms.

Our patient denied depressed mood and did not display signs of depression or cognitive decline on presentation. The patient did not have psychiatric history. The patient denied any psychotic symptoms, that is, auditory or visual hallucinations, or delusions. The patient had no history of physical or sexual trauma. The patient had no history of alcohol, prescription, or illicit substance use. Her Mini-Mental State Examination score was 29. Her face was symmetry, and no tenderness or enlargements of lymph nodes was detected with extraoral examination. No ulcer or any other inflammation of intraoral area was detected with visual examination (Fig. 1). The result of the Saxon test was 3.2 g/2 min, meaning that her salivary flow was within normal limit. Because no medical etiology could explain our patient's symptoms, we diagnosed her with oral cenesthopathy. Owing to her oral symptoms, she had trouble performing housework, eating, and talking. On the oral Dysesthesia Rating Scale (oral DRS),7 the symptom severity score (SSS) was 6 and the functional impairment score (FIS) was 7. The visual analog scale (VAS) score for uncomfortable oral symptoms was 90/100. See Figure 2 for the scores and descriptions of these scales.

FIGURE 1:

Intraoral photograph of the patient at the time of first visit. Although the patient complained of “softened incisors,” no abnormal findings were detected.

FIGURE 2:

Visual analog scale and oral DRS scores at the first visit and after 17 months of treatment. The bars on the left of each graph (hatched bars) indicate scores at the first visit. The right-side bars of each graph (black bars) indicate the scores 17 months after the first visit. VAS is 100 mm long, where 0 mm is “no symptoms” and 100 mm is “extremely severe” In the oral DRS, the severity was rated on a scale of 0 to 5 (0, none; 1, subtle or suspected; 2, mild; 3, moderate; 4, severe; 5, extremely severe). At the first visit, exudation (A2) was “moderate,” and spontaneous thermal sensation or taste (A7) was “mild” according to the SSS. According to the FIS, impairment of eating (B1) and articulation (B2) were “mild,” and that of work (B3) was “moderate.” The patient had enjoyed drinking coffee previously but discontinued because of her symptoms. The VAS score and A2, A7, B2, and B3 oral DRS scores improved after 17 months of treatment.

We prescribed aripiprazole (0.5 mg/d) and gradually increased the dose to 3 mg/d, which resulted in no change. Mirtazapine (7.5 mg/d) was then added 5 months after the first visit. The combination of mirtazapine and aripiprazole did reduce the patient's symptoms, such that her oral DRS score and the VAS score decreased to 85/100. Subsequently, she reported a decrease in the “bitter taste” in her mouth. The VAS score decreased to 85/100. Further increase in mirtazapine did not further decrease our patient's symptoms; however, the patient was not satisfied with the improvement. We tapered aripiprazole and then began brexpiprazole.

Brexpiprazole 0.5 mg/d was initiated 10 months after the first visit. Brexpiprazole 0.5 mg/d was initiated 10 months after the initial visit and, within the first week, resulted in a decrease of the patient's report of “softened teeth.” The patient reported a VAS score of 75. The patient could perform housework without noticing any oral symptoms. However, the “slightly sticky sensation” persisted for an additional month. Hence, we increased the brexpiprazole dosage to 1 mg/d for 6 months. However, the symptoms did not improve further, and the dosage was decreased to 0.5 mg/d. Although the symptoms did not resolve completely, they were stable for a year after the addition of brexpiprazole, and we attempted to taper the medication. After tapering of both mirtazapine and brexpiprazole, there was a recurrence of the “softened incisor” sensation. Therefore, the patient continued to take mirtazapine 7.5 mg/d and brexpiprazole 0.5 mg/d to maintain symptomatic control.

Figure 2 shows the VAS and oral DRS scores at the first visit and 17 months after treatment. On oral DRS, the SSS was 1 and FIS was 2, 17 months after the first visit. In particular, exudation (A2) and spontaneous thermal sensation or taste (A7) disappeared. Based on the FIS, impairment in eating (B1) disappeared, with considerable improvement in articulation (B2) and work (B3). The VAS score decreased to 61/100. No adverse reactions were observed during the clinical course.

DISCUSSION

To our knowledge, this is the first report on the use of brexpiprazole for oral cenesthopathy. Brexpiprazole could be a new option for oral cenesthopathy, a clinically refractory oral symptom. In summary, the combination of aripiprazole and mirtazapine partially improved the oral symptoms, and mirtazapine augmentation with brexpiprazole resulted in further improvement. In contrast, no symptomatic change was observed with aripiprazole monotherapy.

Oral cenesthopathy, sometimes called oral somatic delusion, may be managed using antidepressants and antipsychotic drugs. Some antidepressants including amitriptyline, and antipsychotic drugs, such as haloperidol, risperidone, and aripiprazole, have been reported to be effective in single case reports. However, the response to any therapy seems to be <50%.8

The role of neurotransmitters in the pathophysiology of oral cenesthopathy remains unclear. However, 5-hydroxytryptamine (5-HT), adrenergic, muscarinic, histaminergic, and dopaminergic receptors, or their imbalance, may be related to medication reactivity.6 Aripiprazole and its combination with the aforementioned drugs have been commonly reported to treat this condition. In our patient, aripiprazole monotherapy was not effective. Conversely, the combination of mirtazapine and aripiprazole was effective, and the combination of mirtazapine and brexpiprazole was more effective. This might indicate the variability in the pathophysiology of oral cenesthopathy and/or its response to proposed treatments.

One of the most interesting points of this case was that the symptoms respond to brexpiprazole more than aripiprazole. No head-to-head studies compare the efficacy or the safety of brexpiprazole versus aripiprazole, so comparisons can only be made on the basis of their pharmacologic properties. Both aripiprazole and brexpiprazole are potent D2 partial agonists, 5-HT2A antagonists, 5-HT1A partial agonists, and Alpha1B antagonists.9Brexpiprazole has less intrinsic activity as a D2 agonist and has greater potency with regard to 5-HT2A, 5-HT1A, and Alpha1B receptors than aripiprazole.10Brexpiprazole may have the added advantage of being effective for oral cenesthopathy in this case, owing to its unique profile.

Oral cenesthopathy in this case with intact reality testing and insightfulness could be categorized into the clinical concept of “pseudohallucinations,”11 which has also been explained as an “illusion or sensory error.”12 Pseudohallucinations are induced by psychedelics, such as lysergic acid diethylamide, psilocybin, and dimethyltryptamine.13 In previous clinical studies, administering lysergic acid diethylamide to normal volunteers and psychiatric patients14 led to the development of paresthesia, especially in the circumoral region, and to an indescribable “unpleasant” taste, which is very similar to the symptoms of oral cenesthopathy in this case. As exemplified, psychedelics cause not only typical visual hallucinations but also sensory flooding15 and somatic hallucinations14 via 5-HT2A receptor activation. Although the symptoms of cenesthopathy in this case are not identical to those of psychedelic-induced hallucinations, the effectiveness of brexpiprazole due to its more potent binding at 5-HT2A receptors compared with aripiprazole could imply, at least partially, a common pathway.

Looking back at the clinical course of this case, the first effective drug was mirtazapine. The pharmacological profile of mirtazapine also includes potent antagonism of the 5-HT2A receptors. The efficacy of the combination of mirtazapine and brexpiprazole in this case suggests the importance of the 5-HT2A receptor system in oral cenesthopathy. Interestingly, the dose increase of these medicines with 5-HT2A blockade activities did not provide further symptomatic improvement, which may suggest the involvement of other receptor systems and/or multiple neuronal circuits. The pathogenesis of cenesthopathy is not homogeneous across patients. Hence, a detailed consideration of drug efficacy for oral cenesthopathy is necessary.

CONCLUSIONS

Oral cenesthopathy is the experience of abnormal pains and unusual sensations in the mouth without a somatic basis. Our patient's symptoms of oral cenesthopathy did not improve with monotherapy aripiprazole but did demonstrate partial improvement with adjunctive mirtazapine. Her symptoms further diminished when brexpiprazole was substituted for aripiprazole while mirtazapine treatment was ongoing. We recommend that this medication combination be further evaluated in larger, randomized trials.

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