A Perspective on Neuropharmacological Agents and Stuttering: Are There Implications for a Cause as Well as a Cure?
About the presenter: Larry Molt is the director of the Neuroprocesses Research Laboratory and an assistant professor in the Communication Disorders Program at Auburn University. He holds a dual masters degree in speech-language pathology and audiology from the University of South Florida and Ph.D. in speech and hearing science from the University of Tennessee. Larry is ASHA certified in both fields and is a practicing clinician specializing in fluency disorders and central auditory processing disorders. He serves on the executive board of the International Fluency Association and as chair of the Task Force on Continuing Education for Special Interest Division 4 (Fluency Disorders) of the American Speech-Language-Hearing Association. A person who stutterers himself, he entered the field of speech-language pathology in search of a more efficacious approach to treating stuttering. He has had a long term interest in the use of drugs to treat stuttering, beginning with his participation in a haloperidal trial in 1973, and he is currently principal investigator in a double blind placebo controlled study into the effectiveness of risperidone in treating stuttering at one site of a five site nationwide field test under the direction of Gerald Maguire, M. D., from the University of California-Irvine.
A Perspective On Neuropharmacological Agents And Stuttering: Are There Implications For A Cause As Well As A Cure?
by Larry Molt
Alabama, USA
While most people think of pharmaceutical agents in terms of treating stuttering, in actuality, there are two ways that examining the relationship between neuropharmacological agents (drugs affecting nervous system functions) and stuttering can benefit the individual who stutters. We generally think first from a treatment perspective, searching for that "magic bullet", a drug that by itself cures stuttering. Additionally, however, examining how some drugs may cause, rather than cure, stuttering (known as drug-induced stuttering) may be just as important a perspective for exploring drugs and stuttering. That is, neuropharmacological agents that cause stuttering-like symptoms in previously normal-speaking individuals may provide new or additional insight into the etiology of stuttering. Interestingly, both perspectives currently suffer from the same underlying problem - the lack of knowledge of what actually causes stuttering.
TREATMENT PERSPECTIVES
Unfortunately, the history of the use of pharmacological agents in treating stuttering has had somewhat of a checkered past. Part of the problem has been the lack of knowledge concerning the cause of stuttering. Drug selection has been made on a wide variety of variables. These include choices made on the basis of theoretical assumptions of the cause of stuttering, on the nature of the symptoms, or occasionally due to serendipitous effects encountered by people who stutter when taking drugs prescribed for treatment of some other medical condition.
Etiologic Theories
Many early theories on the cause of stuttering saw it as primarily a psychological problem, with psychoanalytical models maintaining that stuttering resulted from repressed needs or unconscious expression of internal conflicts. Later theories viewed stuttering as a series of learned behaviors, possibly related to psychological factors such as excessive fear and anxiety. Other theories saw stuttering as a genetic disorder. In more recent years, various neurological-based motor and/or sensory deficits have been attributed as the causal factor. Many current theories present a multidimensional model, in which various combinations of such factors as genetic abnormalities, motor control deficits, learned behaviors and psychological deficits combine to cause the disorder. Very recently, the application of brain-imaging techniques to stuttering has yielded implications for specific areas of the brain that may be operating abnormally. Unfortunately, each of these diverse theories of causation remain just that, theories, and since pharmaceutical agents are often selected to correct, modify, or compensate for the cause of the disorder, it is little wonder that an extensive variety of agents have been tried.
Examples Of Agents Selected On An Etiologic Basis
Antipsychotics: As mentioned above, early theories saw stuttering as neurotic behavior. Early treatments included the use of carbon dioxide inhalation (Meduna, 1948). This rather radical treatment would leave the patient momentarily unconscious, which was then followed by psychomotor excitement. Carbon dioxide was used to treat a variety of conditions, including phobias, hysteria, disassociative states, as well as stuttering (Brady, 1961). Ingham (1984) provides a fascinating review of the history of this approach. What little empirical studies that were done, however, did not support the effectiveness of CO2 in treatment.
Neuroleptics: Many researchers who believed in a neurotic etiology for stuttering selected antipsychotic agents, and among these were a family of drugs known as neuroleptics. Neuroleptics are antipsychotic drugs that primarily affect psychomotor activity and generally do not have hypnotic effects (are not sleep-inducing). They may, however, produce extrapryamidal effects, such as the appearance of undesired movements (e. g., twitches, tics). Neuroleptics that have been utilized in the treatment of stuttering include thioridazine (Mellaril) (Goldman, 1968), trifluoperazine (Stelazine) (Aron, 1965), and haloperidol (Haldol) (e. g., Gattusco & Leocata, 1962; Tapia, 1969; Wells & Malcolm, 1971; Andrews & Dozsa, 1977; Prins, Mandelkorn, & Cerf, 1980; see Brady, 1991, for a thorough review). These and other researchers reported that thioridazine and trifluoperazine resulted in a decrease in the severity, but not the frequency of stuttering, possibly reflecting a reduction in secondary symptoms (Brady, 1991). Haloperidol was tested in a variety of studies, and to date has been one of the most successful drugs in terms of ameliorating stuttering symptoms, although it too has the greatest effects on the secondary symptoms rather than the primary or core symptoms. Unfortunately, it also yields many undesired side effects, including dizziness, a feeling of being "drugged", and the occurrence of extrapyramidal effects. Especially due to risk of these effects (a condition known as tardive dsykinesia), haloperidol is seldom prescribed for stuttering today. The side effects were so unpleasant that in many of the studies, even the subjects who exhibited the greatest improvement would not remain on the drug, often dropping out before the clinical trials were completed (Wells & Malcolm, 1971). Also, for the majority of the subjects, it was necessary that they remain on the drug to retain their gains in fluency.
Sedatives and Tranquilizers: Another popular theory saw fear and anxiety as a precipitating and maintaining cause, and so various forms of sedatives and other tranquilizing agents were utilized. Antihistamine drugs, which have mild anxiolytic (anti-anxiety) and hypnotic effects, such as hydroxyzine (e. g., Atarax, Vistaril) have been tried (Yannatos, 1960), and appear to have little effect when used as the sole form of treatment.
Other minor tranquilizers that were used include reserpine (e. g., Diupres, Hydropres, Diutensen) and meprobamate (e. g., Miltown, Equanil), both thought to be effective in reducing anxiety and excessive physical tension. Early uncontrolled studies (e. g., Drake & Ebaugh, 1955; Maxwell & Patterson, 1958) reported promising results, however, later studies using placebo (identical-looking "sham" medications) and double blind experiments (both patient and researcher are unaware of whether the patient is receiving the actual pharmaceutical agent or the placebo) did not demonstrate the drug to have any greater effect than the placebo (Kent & Williams, 1959; Kent, 1963). These early anxiolytic agents such as meprobamate also carried somewhat lethal risks, including respiratory and/or central depression. More recent studies have utilized some of the safer benzodiazepines (e. g., Librium, Valium). Once again, placebo-controlled studies failed to demonstrate their effectiveness in reducing stuttering (Leanderson & Levi, 1967).
Examples Of Agents Selected On A Symptomatic Basis
Some pharmaceutical agents have been selected because they are effective in treating a symptom of stuttering, rather than necessarily the underlying etiology. For example, Schaubel and Street (1949) used neostignine (e. g., Prostigmin), on the basis that it was effective in treating spastic conditions, and that stuttering appeared to be a "in the form of a spasm". They reported favorable results in an uncontrolled trial.
Stuttering shares similar symptoms with Tourette's Syndrome and with motoric tics. All three disorders appear in childhood and follow somewhat of a cyclic pattern of occurrence with symptoms worsening under conditions of emotional stress. In addition, all three disorders are more prevalent in boys than in girls. Brady (1991), also suggests that the sudden temporary "freezing" of articulators observed in patients with parkinsonism shares similarities with stuttering. Pharmacological agents that affect the dopaminergic systems (those utilizing dopamine, a chemical compound in the brain that affects the transmission of messages between neurons/nerve cells) of the brain often have beneficial effects on the symptoms of Tourette's, motor tics, and parkinsonism. Since stuttering shares similar symptoms, dopaminergic agents have been utilized to treat stuttering, with some favorable results. Haloperidol, discussed earlier, blocks the neurochemical transmission through some types of dopamine receptors in the neurons. In fact, haloperidol demonstrates a high degree of selectivity towards certain types of dopamine receptors, to a much greater extent than the majority of the other neuroleptics, which may explain why it is more effective in treating stuttering.
Interestingly, some of the recent positron emission tomography research in stuttering (Wu, Maguire, Riley, Fallon, LaCasse, Chin, Klein, Tang, Caldwell, & Lottenberg, 1995; Wu, Maguire, Riley, Lee, Keator, Tang, Fallon, & Najafi, 1997) implicates abnormalities in activity levels in certain regions of the brain in people who stutter, where hyperactivity of dopaminergic receptors is a distinct possibility. Maguire, Riley, Wu, Franklin, & Potkin (1997) have reported very good results in open clinical trials using risperidone to treat stuttering. Risperidone works similarly to haloperidol in blocking specific dopamine receptors, thus negating the dopaminergic hyperactivity. An advantage, however, is that risperidone does not have the same serious side effects seen in haloperidol.
Examples Of Agents Selected On A Serendipitous Basis
Occasionally, when a stutterer is being treated pharmaceutically for another disorder or disease, they will experience a decrease or cessation of stuttering when placed on that drug. This rather serendipitous occurrence often sparks interest in that drug as a new treatment approach for stuttering. A good example is the drug verapamil (e. g., Calan, Verelan), a calcium channel blocker used in the treatment of cardiac arrhythmia. Zachariah (1980) reported a case in which a patient of his who stuttered showed a marked improvement in his speech when going on the drug for a heart condition. In further trials on 70 adult stutters, Zachariah reported very favorable results, although detailed examination of its effect of speech behaviors was not conducted. Ensuing studies have demonstrated a smaller, but still somewhat consistent effect. Zachariah speculated that verapamil may work by reducing spasm in the muscles of articulation, as it does in the cardiac muscles. In a 1991 summary article, however, Brady questioned the effect that verapamil would have on the striated muscles of the articulators, as opposed to the smooth cardiac muscles. Brady did report that other calcium channel blockers, specifically nifedipine (e. g., Adalat, Procardia) and diltiazem (e. g., Cardazem, Dilacor), did appear to have similar favorable effects on stuttering as reported with verapamil, at least in early open clinical trials.
Interestingly, other types of cardiac medications also have been said to have favorable effects on stuttering. A family of drugs known as beta-andrenergic antagonists (beta-blockers) are used to help control blood pressure and cardiac contraction and are known to have anxiolytic properties. Propranolol (e. g., Inderal) and betaxolol (Kerlone) have been utilized in open, non-placebo trials and are reported to have beneficial effects on stuttering (Cocores, Dackis, Davies, & Gold, 1986; Burris, Riggs, & Brinkley, 1990), however, in a double-blind placebo controlled study, Rustin, Kuhr, Cook, & James (1981) found no beneficial effects for a similar beta-blocker (oxprenolol).
Comments on Neuropharmacological Treatment Perspectives
There are two important factors to consider in closing the discussion on the use of neuropharmacological agents in treating stuttering. First, no one drug approach has been proven to be clearly superior. While beneficial effects have been noted, it is important to remember than much of the research has employed very "weak" science, such as open clinical trials, extremely small numbers of subjects, and little empirical pre- and post- treatment measures of stuttering. Double-blind, placebo-controlled research has been limited, and when it has been employed, favorable treatment effects are seen much less frequently. Ludlow and Braun (1993) in an article reviewing the use of neuropharmacological agents to treat stuttering, provide an excellent discussion of many of the problems in the current research base, and provide suggestions for future research.
The second factor to consider is that even where favorable responses to neuropharmacologic agents were seen, none eliminated the stuttering. In many cases, the frequency remained the same as seen before beginning the drug regimen. Beneficial effects involved either the reduction of secondary/associated symptoms, or a reduction in anxiety towards the speaking situation even though a concomitant reduction in stuttering was not seen. Brady (1991) has suggested that neuropharmacological treatment, at least at this point, remains part of a more comprehensive approach that also involves behavioral treatment utilizing conventional speech therapy, and/or psychological treatment.
PERSPECTIVES ON DRUG-INDUCED STUTTERING
One of the problems facing the literature base on drug-induced stuttering is that the term stuttering has been applied loosely or inaccurately across the research reports. Some drugs induce a disfluency pattern that reflects difficulty in retrieving the words to use. Once the words are retrieved, speaking goes forward with little or no difficulty in producing the utterance. This pattern is unlike that of the traditional "developmental stuttering" model, in which the speaker knows what words he/she wishes to convey, but is unable to easily initiate the act of speaking or produce the words without repetitions or prolongations of the sounds, and other similar production difficulties. A third type of drug-induced dysfluency is a result of dysarthria, which is difficulty in producing the words due to weakness, paralysis, or incoordination within the muscles used for speaking. A fourth type of disfluency, known as acquired or "neurogenic stuttering" usually appears later in life following some form of brain injury, such as stroke, head trauma, brain tumor, etc. Both dysarthria and word retrieval problems can be drug-induced, however, their symptomology is very different from that of stuttering. and will not be considered in this paper. The exact nature of induced stuttering in many of the published reports do not provide adequate information to differentiate whether the disfluencies resemble those seen with developmental stuttering or with acquired stuttering.
The neuropharmacological agents that induce stuttering come from a variety of drug classes. They include members of the neuroleptics, the tricyclic antidepressants (TCAs), antihistamines and bronchodialators, tranquilizers, and the selective serotonin reuptake inhibitor (SSRIs) type of antidepressants.
As the reader may have noticed from the list above, some of the drugs that induce stuttering in non-stuttering speakers are ones that lessen stuttering in many people who stutter. A good example are the neuroleptics discussed in the treatment section of this paper. Nurnberg and Greenwald (1981) reported a single subject case in which both trifluoperazine and chlorpromazine induced stuttering in a previously normal speaker. Several of the tricyclic antidepressants have been linked to drug-induced stuttering. Masand (1992) reported a drug induced stuttering resulting from desipramine. Paradoxically, however, Stager, Ludlow, Gordon, Cotelingham, & Rapoport (1997) reported desipramine to be more effective than placebo in treating stuttering.
Brady (1998), in a review of drug-induced stuttering, theorized that there may four possible mechanisms that underlay which particular drug tends to alleviate stuttering versus resulting in drug induced stuttering. One relates to the cholinergic system and its reaction to the TCAs (Adler, Leong, & Delgato, 1987), possibly due to their antimuscarinic properties (affecting neuronal firing patterns). The second mechanism relates to dopaminergic mechanisms, with a link to the cholinergic system. Menkes and Ungvari (1993) have speculated that the balance between dopamine and acetylcholine may be as important to whether stuttering is induced or alleviated as the reactivity to either chemical alone. Brady (1998) suggests that this feature may explain the diversity of the response to the neuroleptic drugs.
The third system discussed by Brady is the noradrenergic system. The neuroleptic phenothiazines are known to play a role in both provocation and reduction of stuttering. Adler, et. al. (1987) speculate that the provocative effects on stuttering may be related to the presence of akathisia symptoms (motor restlessness and inability to sit or lie quietly or sleep). Not all individuals are as susceptible to akathisic symptoms. The fourth mechanism is the serotonergic system. The prevalent type of drug with provocative effects on fluency are the SSRIs. These tend to have even higher akathisic effects than the other antidepressants, and three of the six SSRI studies that Brady reviewed reported much higher levels of restlessness in their subjects who were experiencing drug-induced stuttering. Serotonin may be the culprit in this case via its effects on dopaminergic pathways (Hamilton and Opler, 1992).
Comments on Drug-Induced Stuttering Perspectives
As was also seen when examining the effects of various pharmacological agents in treating stuttering, there is no one single neuropharmacological agent that plays a primary role in inducing stuttering symptoms in normal speakers. Various types of drugs have induction effects, and the effects are inconsistent across individuals (as were treatment effects on developmental stuttering). One interpretation is that this inconsistency indicates that stuttering, both from a developmental perspective as well as a drug-induced perspective, may reflect the interaction of several neurotransmitter systems, rather than any one single mechanism. Brady has proposed that such a model would explain the inconsistency of reactions across individuals in the case of drug-induced stuttering. Such a theory would also account for the inconsistency seen in treatment effects, as well as explaining the seemingly paradoxical effect for some drugs between alleviating and provoking stuttering.
There are several significant implications of such a model. Further exploration of the effects of neuropharmacological agents is necessary, and it is vital that this include double blind placebo controlled studies. Additional studies such as the Wu, et. al. (1997) PET scan study that examined dopamine activity associated with stuttering are vital to better define the mechanisms at work. Additionally, further exploration into the effects of combinations of neuropharmacologic agents is warranted.
Finally, it is important to note that there are alternative explanations for the inconsistencies seen from both perspectives. One such explanation is the nature of the current literature base. As Ludlow and Braun (1993) and others have pointed out, much of the research has involved single case or very small population research, many of the studies are the result of open trials, and there has been a lack of systematic evaluation of treatment effects not only in speech performance, but also relating to secondary and associated symptoms and psychological effects. Much of the inconsistency may result from errors in the data rather than true performance effects.
References
Adler, L., Leong, S., & Delgato, R. (1987). Drug-induced stuttering treated with propanolol (letter). Journal of Clinical Psychopharmacology. 7, 115-116.
Andrews, G. & Dozsa, M. (1977). Haloperidol in the treatment of stuttering. Journal of Fluency Disorders, 2, 214-224.
Aron, M. L. (1965). The effects of the combination of trifluoperazine and amylobarbitone on adult stutterers. South African Journal of Medical Science, 11, 227-233.
Brady, J. P. (1991). The pharmacology of stuttering: A critical review. American Journal of Psychiatry, 148, 1309-1316.
Brady, J. P. (1998). Drug-induced stuttering: A review of the literature. Journal of Clinical Psychopharmacology, 18, 50-54.
Burris, J., Riggs, M. C., & Brinkley, R. (1990). Betaxolol and stuttering (letter). Lancet, 335, 223.
Cocores, J. A., Dackis, C., Davies, R. K., & Gold, M. (1986). Propranolol and stuttering (letter). American Journal of Psychiatry, 1443, 1071-1072.
Drake, F. & Ebaugh, F. G. (1955). The use of reserpine in office psychiatry. Annals of the New York Academy of Science, 61, 198-205.
Gattuso, R. & Leocata, A. (1962). Haloperidol in the treatment of stuttering. La Clinica Otorinolaringoiatrica (Sicily), 14, 227-234.
Goldman, R. (1968). The effects of psychotherapeutic drugs on stuttering. Proceedings of the IV World Congress of Psychiatry, Madrid, 1966. Amsterdam: Excerpta Medica.
Hamilton, M. S. and Opler, L. A. (1992). Akathisia, suicidality, and fluoentine. Journal of Clinical Psychiatry, 58, 401-406.
Ingham, R. (1984). Stuttering and Behavior Therapy. San Diego: College-Hill Press, pp 416-418.
Kent, L. R. (1963) . The use of tranquilizers in the treatment of stuttering. Journal of Speech & Hearing Disorders, 28, 288-294.
Kent, L. R. & Williams, D. E. (1959). Use of meprobamate as an adjunct to stuttering therapy. Journal of Speech & Hearing Disorders, 24, 64-69.
Leanderson, R. & Levi, L. (1967). A new approach to the experimental study of stuttering and stress. Acta Otolaryngologica (Supplement), 224, 311-316.
Ludlow, C. L., & Braun, A. (1993). Research evaluating the use of neuropharmacological agents for treating stuttering: Possibilities and problems. Journal of Fluency Disorders, 18, 169-182.
Maguire, G., Riley, G., Wu, J. C., Franklin, D., & Potkin, S. (1997). PET scan evidence of parallel cerebral systems related to treatment effects: Effects of risperidone in the treatment of stuttering. In W. Hulstijn, H. Peters, & P. H. H. M. Van Lieshout (Eds.) Speech Production, Motor Control, Brain Research, and Fluency Disorders. Amsterdam: Elsevier Science. pp 379-382.
Masand, P. (1992). Desipramine-induced oral-pharyngeal disturbances: Stuttering and jaw myoclonus (letter). Journal of Clinical Psychopharmacology, 12, 444-445.
Maxwell, R. D., & Patterson, J. W. (1958). Meprobamate in the treatment of stuttering. British Medical Journal, 5075, 873-874.
Meduna, L. J. (1948). Alteration of neurotic pattern by use of CO2 inhalations. Journal of Nervous and Mental Diseases, 108, 373-374.
Menkes, D. B. & Ungvari, G. S. (1993). Adult-onset stuttering as a presenting feature of schizophrenia: Restoration of fluency with trifluoperazine. Journal of Nervous and Mental Diseases, 181, 64-65.
Nurnberg, H. G. & Greenwald, B. (1981). Stuttering: An unusual side effect of phenothiazines. American Journal of Psychiatry, 138, 386-387.
Prins, D., Mandelkorn, T., & Cerf, F. A (1980). Principal and differential effects of haloperidol and placebo treatments upon speech disfluencies in stutterers. Journal of Speech & Hearing Research, 23, 614-629.
Rustin, L., Kuhr, A., Cook, P. J., & James, I. M. (1981). Controlled trial of speech therapy versus oxprenolol for stammering. British Medical Journal, 283, 517-519.
Schaubel, H. J. & Street, R. F. (1949). Prostigmin and the chronic stutterer. Journal of Speech & Hearing Disorders, 14, 143-146.
Stager, S., Ludlow, C. L., Gordon, C. T., Cotelingham, M., & Rapoport, J. (1997). Fluency changes in people who stutter following a double blind trial of clomipramine and desipramine. Journal of Speech & Hearing Research, 38, 516-525.
Tapia, F. (1969). Haldol in the treatment of children with tics and stutterers. Behavioral Neuropsychiatry, 1, 28-32.
Wells, P. G. & Malcolm, M. T. (1971). Controlled trial of the treatment of 36 stutterers. British Journal of Psychiatry, 119, 603-604.
Wu, J. C., Maguire, G., Riley, G., Fallon, J., LaCasse, L., Chin, S., Klein, E., Tang, C., Caldwell, S., & Lottenberg, S. (1995). A positron emission tomography [18F] deoxyglucose study of developmental stuttering. NeuroReport 6, 501-505.
Wu, J. C., Maguire, G., Riley, G., Lee, A., Keator, D., Tang, C., Fallon, J., & Najafi, A. (1997). Increased dopamine activity associated with stuttering. Clinical Neuroscience and Neuropsychology (NeuroReport), 8, 767-770.
Yannatos, G. (1960). L'hydroxyzine dans la therapeutique des begaiements. Journal Francais d'Oto-Laryngologie et Chirurgie Maxillo-Faciale, 9, 293-296.
Zachariah, G. (1980). Verapamil in the management of stammering. The Antiseptic (India), 77, 87-88.
September 29, 1998
