Clozapine-Induced Stuttering: Case Report and Literature Review

To the Editor,

Clozapine is an atypical antipsychotic with proven efficacy in the management of treatment-resistant schizophrenia. It has well-documented side effects, including agranulocytosis, myocarditis, epileptic seizures, and secondary metabolic disturbances. Additionally, it is known to have rare secondary side effects, such as stuttering, which has been documented in several case reports. This case highlights the importance for clinicians to be aware of clozapine-induced stuttering, even in the absence of known risk factors, and emphasizes the necessity for future research to investigate the pathophysiology of clozapine-induced stuttering [1].

Stuttering is a rare side effect of clozapine. The pathophysiologic mechanisms underlying stuttering are not yet elucidated, but dopamine dysregulation, genetic mechanisms, and structural and functional changes in the brain have been hypothesized [2].

Here we report the first Tunisian case of a patient with ultra-resistant schizophrenia, who developed stuttering when treated with a high dose of clozapine. A 29-year-old Caucasian woman was first hospitalized for psychiatric reasons. Except from breast surgery, breast repair and hymenoplasty, which were found to have been performed secondary to delusional experiences, the patient was without notable organic medical history or known medication allergies. According to the anamnesis based on interviews with the patient and members of her family, the psychotic symptoms had developed during the last five years and included delusions of kinship and corporal transformation. These symptoms brought the patient to drop out of university studies, to be physically violent to her mother and to get breast and gynecological operations. She had not any contact with policlinic psychiatry before the hospitalization. Moreover, she hadn’t any previous psychiatric contact and she didn’t receive any treatment. The patient was diagnosed to fulfil criteria for schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

Pretreatment Brief Psychiatric Rating Scale (BPRS) score was 88 (score range 0–168) and the Clinical Global Impression (CGI) therapeutic index score was 11 (the best score at 0, the lowest at 16).

The patient was initially treated with haloperidol up to 60 mg/d. Then olanzapine up to 20 mg/d was added and the patient received this combination for eight weeks ([Fig. 1]), however with no clinical response. BPRS after this treatment trial was 82 (initially was 88) and CGI was 10 (initially was at 11).

Fig. 1 Timeline of adapting clinical pharmacology during hospitalization.

At this point we decided to start treatment with clozapine. Pretreatment investigations included electrocardiogram (ECG), electroencephalography (EEG) and blood sampling for hematology with normal results. The initial clozapine dose was 12.5 mg/d for the first week, followed by 25 mg/d for the second week, and thereafter the dose was increased with 25 mg/d or 50 mg/d each week according to international reference protocols. To evaluate the effect of the treatment psychomotor scales and occupational therapy activity tracking scales were used: Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) therapeutic index [3].

Two days after reaching a total clozapine dose of 650 mg/d (300 mg in the morning and 350 mg in the evening), and with her last clozapine blood concentration of 364 ng/ml, the patient started to stutter: she repeated whole words or parts of words, such as “my, my, my, my” or “my na-na-name”. The stuttering progressively increased over 48 hours.

An emergent EEG showed a normal background rhythm with paroxysmal abnormalities of spike waves and bilateral frontal slow waves. Cerebrospinal fluid analysis and ECG were normal. All physical, neurological, laboratory and brain magnetic resonance imaging (MRI) examinations were also normal.

In collaboration with our neurological colleagues and referring to the Maudsley prescribing guidelines in psychiatry, we opted for a quick decrease of the clozapine dose with a careful monitoring of the neurological state considering the risk of epileptic seizure. At the dose of 300 mg/d, which was obtained with strict supervision of neurological states, a total clearance was observed, without any stuttering sequelae and a new EEG investigation did not show any abnormalities.

After a multidisciplinary conference and a literature review in this context [4], we were compelled to restart raising the dose of clozapine, very carefully up to 600 mg/d under cover of sodium valproate, along with the adjunction of a second antipsychotic drug. We obtained consent from the family and the patient herself for this approach ([Fig. 1]).

First, the patient received sodium valproate 1500 mg/d reaching a blood concentration equal to 79 mg/L. Thereafter, clozapine doses were gradually increased until reaching 600 mg/d. In third step, taking into account the available pharmacological compounds in Tunisia, we added risperidone 2 mg/d considering its pharmacodynamics and pharmacokinetic properties.

With this treatment combination for 2 months, the patient became calmer, less delusional, and free of severe dissociative syndrome with a Clinical Global Impression (CGI) therapeutic index score of 4/16 (the best score at 0, the lowest at 16) and a BPRS score of 12, thus a considerable improvement. The patient was discharged for further management by the rehabilitation and social reintegration unit.

The extrapyramidal side effects induced by antipsychotic such as clozapine have been widely discussed in the literature.

According to M.Kurz and coll. comparing the incidence of extrapyramidal effects of clozapine with other antipsychotic: clozapine is not totally free of extrapyramidal side effects, but that they are generally less severe and of a different quality from the side effects induced by typical antipsychotics (e. g. Haloperidol). In fact, this study evaluating 92 patients treated with clozapine for the first time and 59 patients treated with haloperidol revealed that the cumulative incidence rate of tremor was 24.4% in the clozapine group and 39.3% in the haloperidol group. There was no statistically significant difference between groups. Bradykinesia was observed in 21.8% of clozapine-treated patients and 47.7% of haloperidol-treated patients. In the clozapine group, the incidence rate of akathisia was 5.6%, whereas patients on haloperidol had a higher rate of 31.7%.

According to Nikvarz and coll., The low level of Extrapyramidal sides effects (EPS) with clozapine may be related to the special receptor-binding profile of this medication: during treatment with therapeutically high doses, the level of D2 receptor blockade is too low (40% to 50% occupancy by positron emission tomography) to induce Extrapyramidal sides effects, and the D1 receptor blockade (also 40% to 50% occupancy) has a lower EPS potential than D2 blockade. This binding profile may at the same time contribute to the special antipsychotic properties of clozapine [5].

Stuttering is the frequent repeating or prolonging of sounds, syllables or words, or frequent hesitations or pauses that disrupt the rhythmic flow of speech. Stuttering can affect academic, professional performance and impact social functioning by disrupting self-image [6].

Stuttering is generally developmentally related, but incidental causes of stuttering due to neurological or psychological insults have also been described in any age range. Drug-induced stuttering, known as “secondary stuttering”, is a type of neurogenic stuttering. Although it has not been reported commonly in the literature, it is not a marginal adverse effect of medications and can significantly affect quality of life. Moreover, a study of drug-induced stuttering by Nikvarz et al., revealed that, in 55.8% of cases, the implicated drug was withdrawn to manage the stuttering, resulting is significant improvement or complete relief of the stuttering in all cases [5] [7].

Regarding iatrogenic causality of secondary stuttering, the antipsychotics such as risperidone and aripiprazole has been widely discussed by several authors. In this context, rarely, clozapine has also been reported as a cause of stuttering. A retrospective study from Ireland, estimated the prevalence of stuttering to 0.92% (6 of 654) in patients treated with clozapine. The mechanism of stuttering is complex and poorly understood. Studies have shown that psychological stressors, genetic links and lingual and laryngeal muscle pathologies underlie stuttering. However, evidence widely suggests a lack of integration of somatosensory, language, and motor regions, involving fronto-temporo-parietal networks and subcortical structures [7] [8].

Some studies suggest an association between stuttering and seizure-like activity in the EEG and improvement with antiepileptic drugs. Our patient presented stuttering associated to pathological EEG pattern at the dose of 650 mg/day that could be explained as orofacial dyskinesia. One case, reported by Horga et al. and cited by Murphy R, the patient developed speech diffluence with myoclonus on clozapine 350 mg/day and clomipramine 225 mg/day and then had generalized tonic-clonic [7].

In another case reported by Duggal et al. cited by Krishnakanth, a patient developed stuttering when the dose of clozapine was raised to 300 mg/day and subsequently developed tonic-clonic seizures when the dose of clozapine was further increased to 425 mg/day [9].

Rissardo et al. revealed that for pregabalin-associated dystonia, stuttering can be explained by inhibition of the surrounding muscles, which can be assessed by alterations in the potential of the somatosensory cortex. In this context, Vreeswijk and al cited by Rissardo studied somatosensory evoked potentials in people who stutter and matched non-stutters, and did not find any differences between the groups. These results in the stuttering group showed that inhibition was normal, so what is probably occurring is compensatory facilitation of the surrounding muscles. Therefore, this disorder may be linked to impaired inhibition of the surrounding muscles that can be assessed by somatosensory cortex potential alterations, but we think it is more likely that a piece of the puzzle is missing. One hypothesis that may explain stuttering and dystonia could be the gamma-amino-butyric acid (GABA) density involved in high-frequency myoclonus; in susceptible individuals, there is a putative increase in GABAergic transmission in a specific area [2] [10].

Antipsychotic-induced stuttering is not conclusive. It has been linked to the duration of antipsychotic treatment and to extrapyramidal side effects, including dopaminergic hypersensitivity states such as tardive dyskinesia and dystonia. In addition to dopamine, multiple neurotransmitter systems, including muscarinic and Dopaminergic receptors, on which clozapine acts have also been implicated [10].

This side effect of orofacial dyskinesia also seems to be contingent on the increase being too quick and on the dose itself, and a modest decrease in dose may be the only strategy needed to manage the stutter. This was noted in our case, in which the stuttering disappeared after a dose reduction with the combination of an effective dose of an antiepileptic drug [8].

The role of antiepileptic therapy in clozapine-induced stuttering is not yet fully understood, although antiepileptic therapies may have a contribution in preventing tonic-clonic seizures. It would certainly be beneficial for the patient to be followed up for any emerging signs of seizures. For our patient, we were obliged to add sodium valproate because clozapine was an inevitable choice. The addition of a second antipsychotic could exacerbate the side effects but was deemed essential in the management [9] [10].

Publication History

Article published online:
09 November 2023

• References

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