By Mary V. Seeman MD (biography, no disclosures)
What frequently asked questions I have noticed
Fellow psychiatrists often ask whether their patients with schizophrenia are aging prematurely. They point to the fact that several of their patients seem slowed down, forgetful, fidgety, and that they garble their words and stutter. These are, of course, all side effects of antipsychotic medication. Frequently attributed to stress and usually not recognized as a drug side effect, stuttering can occur in psychiatric patients as a result of treatment with a variety of psychotropic drugs. These include antidepressants, memantine, mood stabilizers, propranolol, stimulants, and antipsychotics. Out of the many published case reports on drug-induced stutter, clozapine emerges as the most common culprit (1-3). Because clozapine is typically only used after two or more other drug trials have failed to produce results, clozapine-treated patients cannot simply be switched to another similar antipsychotic. There is no similar antipsychotic. Patients characteristically present with severe psychotic symptoms so neither can the clozapine dose be safely reduced. Because such patients have been on a number of prior antipsychotic drugs, usually at high doses, they have accumulated a variety of tics and grimaces and idiosyncratic manners of speaking and moving. in this context, acquired stuttering can easily be overlooked by the treating physician. Sometimes the patient will complain about it, but sometimes not. Should the physician notice the stutter and recognize that it wasn’t present earlier, the clozapine dose is often paradoxically raised, on the assumption that the stutter is stress-induced.
Data that answers these questions
Patients with schizophrenia can, in fact, age prematurely, but many of the outward signs of aging can be prevented or buffered. With respect to stuttering, it is defined in DSM-5 (the diagnostic and statistical manual of the American Psychiatric Association) as the involuntary, sometimes spasmodic, repetition of speech sounds, usually the consonants at the beginning of words. Syllables are often prolonged and speech flow is often interrupted by short periods of silence (4). When whole words are repeated, the speech disfluency is called palilalia (5). A spasmodic quiver of the mouth often accompanies the disfluency. When stutter emerges in adult life, it is referred to as acquired stuttering. When it begins within a few days after a drug dose increment or the initiation of a new drug, it is referred to as drug-induced acquired stuttering. When drug-induced stuttering occurs with clozapine, it sets in at an average dose of 200-250mg/day (2), but can start at as a low a dose as 50mg (1).
While stuttering in childhood is quite common, its lifetime prevalence is below 1% because children lose their stutter before puberty 80% of the time (6). Like most neurodevelopmental disorders, stuttering affects more boys than girls. By adulthood, the prevalence ratio of stuttering is approximately four males to every female because, not only are there more boys to start with, but, in addition, proportionally more girls overcome childhood stuttering (6).
When stuttering emerges de novo in adulthood, the cause can be psychogenic, a reaction to a significantly stressful event (7,8). It can also be neurogenic, secondary to cerebrovascular accident, brain tumor, brain injury, dementia, or Parkinson’s disease (9), although the two forms, psychogenic versus neurogenic, are often difficult to distinguish. Drug-induced stutter is considered a subcategory of neurogenic stutter. While its prevalence has not been established, a retrospective study in Ireland estimated clozapine-induced stuttering at 0.92%, 6 out of 654 patients (3), with no significant sex difference.
Neurogenic stuttering has been associated with lesions in the left supplementary motor area, the putamen and internal capsule, the striatum, thalamus, and cerebellum (10), not necessarily linked to structural impairment of these structures but, rather, to interruption of brain networks (11). The main network thought to be involved is the cortico-striato-cortical loop, which includes the inferior frontal cortex, the superior temporal cortex, the intraparietal cortex, the basal ganglia, and their white matter connections (12).
The drugs that have been reported to induce stuttering target several different neurotransmitter systems: the cholinergic systems (tricyclic antidepressants), dopaminergic systems (bupropion, methylphenidate, antipsychotics), noradrenergic systems (propranolol, theophylline), serotonergic systems (selective serotonin reuptake inhibitors) and NMDA systems (memantine). This means that theories of causation need to take into account the properties of the drug that triggers the stutter. Because clozapine is known to be active at many brain neurochemical receptors (13), clozapine-induced stuttering could potentially be triggered in a number of different ways.
As do all antipsychotics, clozapine lowers the seizure threshold (14) and can, therefore, lead to focal seizures that manifest as stuttering. This is a mechanism frequently discussed in the literature (15), although EEGs in most reported cases are considered normal. A further problem with the seizure theory is that anticonvulsant drugs can also sometimes induce stuttering.
As mentioned, clozapine is prescribed after several other antipsychotic drugs have failed to produce benefits. While symptoms have not benefited, the earlier drugs have very frequently produced extrapyramidal side effects (EPS) including tardive dyskinesia (TD). Many case reports of clozapine-induced stuttering note that, prior to clozapine, the patient had had severe EPS and/or TD (1), which disappeared when clozapine was started. Clozapine has a well-recognized ability to reverse these adverse effects. This raises the possibility that it is not clozapine alone that is responsible for clozapine-induced stutter but, rather, the combination of clozapine and a prior extrapyramidal disorder.
Risk factors for developing drug-induced stuttering in psychiatric patients include: a history of disfluency problems in the family (1) or a personal history of childhood stuttering, as has frequently been reported in the case of Parkinson’s disease-induced stuttering (16). The type of drug is an important risk factor, as is the dose of the drug, and, finally, the prior presence of EPS/TD.
What I recommend (practice tip)
When drug-induced stuttering is suspected, it needs first to be differentiated from psychogenic stuttering and other potential causes of neurogenic stuttering (17). Speech language pathologists should be consulted, but classical stuttering reduction techniques are known to not work well for drug-induced stuttering. Clozapine doses can also be distributed over the day so that a large bolus does not suddenly arrive at vulnerable brain sites. If this does not work, the offending drug should be discontinued. While many drugs, including those that are known to induce stuttering (18) sometimes relieve it, the addition of anti-convulsant drugs is probably the best first approach.
What I recommend for clozapine-induced stutter is the addition of a low dose of clonazepam. Because switching to another drug or lowering the dose is not usually possible for clozapine-treated patients, adjunctive clonazepam is probably the safest and most effective management strategy. Clonazepam has anti-convulsant properties, which is helpful if the stuttering is partly or wholly caused by focal seizures. It is also a calming agent, which is important for patients with schizophrenia and helps with the stress-induced component when that is present. I found out recently that clonazepam interacts with clozapine to reduce its serum level (19), so the decrease in the amount of clozapine reaching the brain may also be a therapeutic factor.
In conclusion, when patients with schizophrenia garble their words, it is not that they have suddenly become old. Their drugs, especially if one of them is clozapine, may be at fault. Language disfluency is a major social handicap and requires clinical attention, especially so in psychiatric patients, who are already socially stigmatized. After all potential causes are investigated, the existing pharmacological and psychological management of the patient needs to be carefully evaluated, and appropriate treatment strategies put into effect.
- Grover S, Verma AK, Nebhinani, N. Clozapine-induced stuttering: a case report and analysis of similar case reports in the literature. Gen Hosp Psychiatry. 2012;34(6):703.e1–703.e3. DOI: 10.1016/j.genhosppsych.2012.02.010. (View with CPSBC or UBC)
- Krishnakanth M, Phutane VH, Muralidharan K. Clozapine-induced stuttering: a case series. PrimCareCompanionJClinPsychiatry. 2008;10(4): 333-334. DOI: 10.4088/pcc.v10n0411e. (View)
- Murphy R, Gallagher A, Sharma K, et al. Clozapine-induced stuttering: an estimate of prevalence in the west of Ireland. Ther Adv Psychopharmacol. 2015; 5(4):232–236. DOI: 10.1177/2045125315590060. (View)
- American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association: Washington, D.C. 2013: 1-947.(View with CPSBC or UBC)
- Magnin E, de Bustos EM, Moulin T. Pali and echo phenomena: symptoms of persistence and perseveration. Front Neurol Neurosci. 2018; 41: 28-39. DOI: 10.1159/000475692. (Request with CPSBC or view with UBC)
- Yairi E, Ambrose N. Epidemiology of stuttering: 21st century advances. J Fluency Disord. 2013;38(2): 66–87. (View)
- Baizabal-Carvallo JF, Jankovic J. The wide spectrum of functional movement disorders. JAMA Neurology. 2019;76(2):235-236. DOI: jamaneurol.2018.3905. (Request with CPSBC or view with UBC)
- Ward D. Sudden onset stuttering in an adult: Neurogenic and psychogenic perspectives. J Neurolinguistics. 2010; 23(5): 511–517. DOI: 10.1016/j.jneuroling.2009.06.001. (View with CPSBC or UBC)
- Lundgren K, Helm-Estabrooks N, Klein R. Stuttering following acquired brain damage: a review of the literature. J Neurolinguistics. 2010; 23(5): 447–454. (View)
- Cruz C, Amorim H, Beca G, Nunes R. Neurogenic stuttering: a review of the literature. Rev Neurol. 2018; 66(2): 59-64. DOI: 10.33588/rn.6602.2017151. (Request with CPSBC or view with UBC)
- Neumann K, Foundas AL. From locations to networks: Can brain imaging inform treatment of stuttering? J Fluency Disord. 2017; 55: 1-5. DOI: 10.1016/j.jfludis.2017.08.001. (View with CPSBC or UBC)
- Theys C, De Nil L, Thijs V, van Wieringen A, Sunaert S. A crucial role for the cortico-striato-cortical loop in the pathogenesis of stroke-related neurogenic stuttering. Hum Brain Mapp. 2013; 34(9): 2103–2112. DOI: 10.1002/hbm.22052. (Request with CPSBC or view with UBC)
- Ashby Jr CR, Wang RY.Pharmacological actions of the atypical antipsychotic drug clozapine: a review. Synapse. 1996; 24(4): 349-394. DOI: 10.1002/(SICI)1098-2396(199612)24:4<349::AID-SYN5>3.0.CO;2-D. (Request with CPSBC or view with UBC)
- Bhatti M, Dorriz P, Mehndiratta P. Impact of psychotropic drugs on seizure threshold. Neurology. 2017; 88(16 Supplement). (View)
- Varma S, Bishara D, Besag FMC, Taylor D. Clozapine-related EEG changes and seizures: Dose and plasma-level relationships. Ther Adv Psychopharmacol. 2011;1(2): 47–66. (View)
- Shahed J, Jankovic J. Re-emergence of childhood stuttering in Parkinson’s disease: A hypothesis. Movement Disord. 2001;16(1): 114-118. DOI: 10.1002/1531-8257(200101)16:1<114::aid-mds1004>3.0.co;2-2. (Request with CPSBC or view with UBC)
- Jiang P, Lin Z, Jin Y, Ren J, Liu H, Cui H, et al. Effect of clonazepam co-administered with clozapine on the serum clozapine and norclozapine concentration of patients with schizophrenia: a retrospective survey. Shanghai Arch Psychiatry. 2016; 28(6): 318-325. (View)
- Penttilä N, Korpijaakko-Huuhka A-M. New guidelines for assessing neurogenic stuttering. Procedia-Soc Behav Sci. 2015;193:310–313. (View)
- Maguire GA, Yu BP, Franklin DL, Riley GD. Alleviating stuttering with pharmacological interventions. Expert Opin Pharmacother. 2004; 5(7):1565-1571. DOI: 10.1517/146565126.96.36.1995. (View with CPSBC or View with UBC)
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