Clozapine-induced stuttering: an estimate of prevalence in the west of Ireland

Abstract

Objectives:

Clozapine is the most effective treatment available for treatment-resistant schizophrenia; however, it is also associated with a large array of adverse effects that limits its tolerability. A number of previous case reports have noted an association between clozapine and stuttering, however the rate of this possible adverse effect is yet to be established.

Methods:

In this paper, we present six cases of patients treated with clozapine who developed stuttering.

Results:

Clozapine was associated with stuttering in 0.92% of individuals treated with clozapine in the region. Clozapine-induced stuttering was associated with an increase in treatment dose or with dose titration at initiation of clozapine in five individuals, with dose reduction or slower dose titration associated with a cessation of stuttering in these cases.

Conclusions:

This is the largest case series to date examining clozapine-induced stuttering and indicates that clozapine-induced stuttering is a relatively common adverse effect that can be managed by a slower titration of clozapine dosage or a modest reduction in dose in most cases.

Introduction

Clozapine is the most effective antipsychotic agent available for treatment-resistant schizophrenia [McEvoy et al. 2006], and has beneficial effects, not just for positive and negative symptoms, but also for cognitive deficits [Burton, 2006], and functioning [Wheeler et al. 2009]. However, clozapine is associated with a wide array of adverse effects that require constant monitoring and management to minimize morbidity and improve treatment adherence, particularly as adverse effects together with nonadherence to essential serum monitoring, often due to limited insight, are frequent reasons for clozapine discontinuation [Taylor et al. 2009].

We are aware of 12 previous case reports that have demonstrated an association between clozapine and the development of stuttering [Kumar et al. 2013; Grover et al. 2012; Horga et al. 2010; Krishnakanth et al. 2008; Abdelmawla and Frost, 2007; Lyall et al. 2007; Hallahan et al. 2007; Begum, 2005; Bar et al. 2004; Duggal et al. 2002; Supprian et al. 1999; Ebeling et al. 1997]. Stuttering is a condition in which the flow or fluency of speech is disrupted by involuntary motor events, resulting in the production of repetitive sounds, syllables and/or fragmented or prolonged words and includes both developmental and neurogenic/iatrogenic subtypes [Krishnakanth et al. 2008]. Neurogenic or acquired stuttering is infrequent in presentation and has been associated with either neurological disease or specific pharmacological intervention including selective serotonin reuptake inhibitors, tricyclic antidepressants, lithium, benzodiazepines and antipsychotics including chlorpromazine, fluphenazine, olanzapine, risperidone and aripiprazole [Kumar et al. 2013; Yadav, 2010; Rocha, 2009; Bar et al. 2004; Netski and Piasecki, 2001; Messiha, 1993; Elliott and Thomas, 1985; Numberg and Greenwald, 1981; Quader, 1977].

Despite numerous case reports suggesting an association between clozapine and stuttering, there remains limited data in relation to the cause or prevalence of this potential adverse reaction. An association with treatment dose [Hallahan et al. 2007], and epileptic activity [Horga et al. 2010; Abdelmawla and Frost, 2007; Lyall et al. 2007; Begum, 2005; Duggal et al. 2002; Supprian et al. 1999; Ebeling et al. 1997; Thomas et al. 1994], has been postulated.

We undertook a retrospective audit of case files of all 654 individuals treated with clozapine in the west of Ireland mental health services to ascertain the prevalence and identify cases of clozapine-induced stuttering (n = 6). All geographical areas provided input and follow up to patients prescribed clozapine from the same clozapine nurse specialist, together with regular review and follow up by the patients named Consultant Psychiatrist. All data from such medical and nursing involvement were recorded into patient-specific medical case files. Potential clinical correlates of stuttering and strategies utilized to ameliorate this adverse effect were examined. Medical and nursing case files were assessed to ascertain any documented evidence of clozapine-induced stuttering, associated speech dysfluency or seizure activity. We also interviewed consultant psychiatrists responsible for the care of clozapine patients, the clozapine nurse specialist and other multidisciplinary team members involved in each patient’s clinical management (i.e. community mental health nurses) to confirm the presence of stuttering and evaluate other demographic and clinical data. Informed consent was attained from identified individuals presented in the case series. For clarity, we present the six cases in Table 1.

Table 1.

Demographic and clinical data.

	Patient 1	Patient 4	Patient 2	Patient 3	Patient 5	Patient 6
	JS	PM	DB	MB	TG	MF
Age	32 years	43 years	33 years	46 years	67 years	63 years
Gender	Male	Male	Male	Female	Male	Female
Diagnosis	Paranoid schizophrenia	Schizoaffective disorder	Paranoid schizophrenia	Delusional disorder	Schizoaffective disorder	Paranoid schizophrenia
Daily dose of clozapine	650 mg	400 mg	450 mg	300 mg	325 mg	650 mg
Plasma level of clozapine	3.9 nmol/L	Not available	1.0 nmol/L	1.0 nmol/L	0.75 nmol/L	Not available
Association of stuttering with alteration of dose of clozapine	Became noticeable when dose increased from 600 mg	Became noticeable when dose increased from 350 mg	Developed during treatment initiation and titration	Developed during treatment initiation and titration	Developed during treatment initiation and titration	No
Description of stuttering	Expressive speech dysfluency with hesitancy and frequent pauses	Expressive speech dysfluency	Intermittent stuttering of speech	Hesitancy with specific syllables	Expressive speech dysfluency	Expressive speech dysfluency with hesitancy
Association with movement disorder or seizures	Involuntary twitching of muscles of jaw	None	None	Orofacial dyskinesia	Orofacial twitching and upper limb jerking	None
Investigations	Electroencephalography – normal	None	None	Speech and language therapy assessment – no abnormalities detected	Electroencephalography – normal	None
Other psychotropic medications – daily dose	Sertraline 300 mgLamotrigine 500 mgHaloperidol 4 mgClonazepam 1 mg	Paroxetine 20 mg	None	None	Duloxetine 60 mgHyoscine 30 mgAripiprazole 10 mg	Amisulpride 200 mgAmitriptyline 25 mgParoxetine 20 mgZopiclone 3.75 mg
Past medical history	Nil of note	Nil of note	Nil of note	Nil of note	Hearing impairment	Nil of note
					Hypertension
Hypersalivation	No	No	No	No	Yes	No
Strategy to alleviate stuttering	Dose reduced by 25 mg	Dose reduced by 50 mg	Slower treatment titration	Dose reduced to 50 mg	Slower treatment titration	Dose reduced by 50 mg
Effect on reducing stuttering	Yes	Yes	Yes	Yes	Yes	Nil
Effect on psychosis	No	No	No	No	Recurrence of psychotic symptoms when dose reduced (clozapine increased again)	Recurrence of psychotic symptoms when dose reduced (clozapine dose increased again)

Case series: findings

Six individuals (four males and two females) out of the 654 individuals treated with clozapine (0.92%) suffered from clozapine-induced stuttering (see Table 1). All individuals suffered from treatment-resistant psychotic disorders with three individuals diagnosed with paranoid schizophrenia (JS, DB and MF), two with schizoaffective disorder (PM and TG), and one with delusional disorder (MB). All individuals to our knowledge were adherent with clozapine treatment.

Two individuals (JS and PM) developed stuttering upon dose increases, with three others (DB, MB and TG) developing stuttering during dose titration and initiation. These five individuals noted significant improvement in their stuttering symptoms on dose reduction or slower titration of clozapine dose. The other individual (MF) had been treated on a stable dose of clozapine (650 mg) when she developed stuttering, however treatment reduction was not associated with any amelioration of her stuttering but was associated with a deterioration in her psychosis, and consequently in collaboration with her clinical team she agreed to recommence 650 mg of clozapine.

No association was determined between speech symptoms and either hypersalivation or seizure activity. Three individuals (JS, MB and TG) displayed orofacial dyskinesia with one individual also displaying upper limb jerking (TG).

Discussion

To the best of our knowledge, this is the largest case series of clozapine-induced stuttering to date and the first to look at the prevalence of clozapine in a relatively large sample of individuals. Clozapine-induced stuttering occurred in approximately 1% of individuals treated with clozapine in the west of Ireland. Consistent with previous reports, this case series demonstrated an association between clozapine-induced stuttering and either dosage increase or initiation and titration of clozapine, with a resolution of stuttering with either dose reduction or slower titration of clozapine at initiation.

Previous reports have suggested an association between clozapine-induced stuttering and seizure activity including abnormal micro-electrical activity [Supprian et al. 1999; Thomas et al. 1994]. However, none of the individuals in this study demonstrated any seizure activity and the two individuals who underwent electroencephalography demonstrated no abnormalities. In addition, none of the five individuals who demonstrated an amelioration of their symptoms required the initiation (or increase in one case) of an antiepileptic agent. Consequently, we cannot confirm this association, although there are reports of anticonvulsants demonstrating benefit for stuttering associated with clozapine [Weiss et al. 1989; Lyall et al. 2007; Begum, 2005; Supprian et al. 1999; Horga et al. 2010]. In three cases, stuttering was associated with a movement side effect including orofacial twitching, which similarly ameliorated with dose reduction or slower dose titration and thus it is possible in these individuals that clozapine-induced stuttering may in part be related to a movement side effect [Horga et al. 2010; Begum, 2005; Supprian et al. 1999]. However, of note no individuals in this study required treatment trials of agents such as tetrabenazine in an effort to ameliorate movement side effects.

The limitations of this study are that two individuals had no recent clozapine plasma level and that only two individuals had undergone electroencephalography.

Conclusion

This case series, in addition to previous case reports, suggest that clinicians need to be aware that speech symptoms such as stuttering are a potential adverse effect of clozapine treatment. Stuttering is associated with significant morbidity affecting adversely an individual’s self-image and ability to engage in social interaction, and consequently requires monitoring and aggressive management. Dose reduction or slower clozapine titration at initiation of clozapine is sufficient in most cases, with evaluation for associated neurological or movement disorders required where this strategy is either not possible or ineffective.