Senior Associate Dean, Educational Affairs. University of California, Irvine. School of Medicine .... Fox PT, et al. Nat
Advancements in the Pharmacologic Treatment of Stuttering Gerald A. Maguire, M.D. Associate Professor Kirkup Endowed Chair in Stuttering Treatment Department of Psychiatry Senior Associate Dean, Educational Affairs University of California, Irvine School of Medicine
Financial Disclosure ¾ Speaker’s Bureau: Pfizer, Eli Lilly, Merck ¾ Advisory Board: Eli Lilly, Indevus/Endo ¾ Consultant: Indevus, Eli Lilly,Teva ¾ Research Grants: Bristol-Myers Squibb, Eli Lilly, Indevus, Endo, Teva
The Pharmacologic Treatment of Stuttering
www.tomcruiseisnuts.com
The History of Stuttering
¾Stuttering has occurred throughout recorded history in every culture
Every Language Has a Word for Stuttering ¾English
stuttering
¾French
begaiement
¾Spanish
tartamudez
¾Sanskrit
Jivha Jarata
¾Chinese
hau hick
¾Japanese
domori
¾Nigerian
nsu
¾Persian
locknatezaban
Diagnostic Criteria for Stuttering DSM-IV-TR diagnostic criteria for stuttering (Code = 307.00) Axis I A. Disturbance in normal fluency and time patterning of speech (inappropriate for the individual’s age), characterized by frequent occurrences of 1 or more of the following: (1) Sound and syllable repetitions (2) Sound prolongations (3) Interjections
Current Diagnostic Criteria for Stuttering (cont.) (4) Broken words (e.g., pauses within a word) (5) Audible or silent blocking (filled or unfilled pauses in speech) (6) Circumlocutions (word substitutions to avoid problematic words) (7) Words produced with an excess of physical tension (8) Monosyllabic whole-word repetitions (e.g., “I-I-I-I see him”)
Current Diagnostic Criteria for Stuttering (cont.) B. The disturbance in fluency interferes with academic or occupational achievement or with social communications C. If a speech-motor or sensory deficit is present, the speech difficulties are in excess of those usually associated with these problems
Potential Revised Criteria for DSM-V
•
¾ Adding a ninth criterion: Avoidance and/or anxiety around feared speaking situations or words ¾ Remain in Axis I but revised placement near other speech disorders/movement disorders (Maguire, Huang, Huffman. Current Psychiatry. March 2009) (Ranter, Maguire. IFA presentation. 2009)
Potential Revised Criteria for DSM-V
•
¾ Adding a ninth criterion: Avoidance and/or anxiety around feared speaking situations or words ¾ Remain in Axis I but revised placement near other speech disorders/movement disorders (Maguire, Huang, Huffman. Current Psychiatry. March 2009) (Ranter, Maguire. IFA presentation. 2009)
Historical Stuttering Theories and Treatments ¾Believed to be caused by abnormalities of the tongue or larynx • Cauterizing or cutting the tongue • Botulinum toxin injections into the larynx • Both without efficacy
Orton and Travis: A Brain Theory of Stuttering ¾Stuttering may arise from abnormal cerebral activity/stuttering viewed as a brain disorder (cross dominance with handedness) ¾Believed to be brought about by an incomplete dominance of the speech centers
Orton ST. Arch Neurol Psychiatry. 1927;18:671-672. Travis EE. Speech pathology; A dynamic neurological treatment of normal speech and speech deviations; 1931.
Psychoanalytic Theory ¾Unconscious neurotic need fulfillment ¾Unresolved oral conflict ¾“Stuttering results from thoroughly unresolved pregenital oral sadistic conflict”
Dominic Barbra
Stuttering is… ¾“That disorder that can cause a great deal of suffering for those affected, but is largely ignored by the medical community” ¾Stuttering treatment in the medical community largely based on one single case study…….
Maguire GA. Presented at: XXIInd CINP Congress; July 9-13, 2000; Brussels, Belgium.
Famous Persons Who Stutter(ed) ¾ Alexander the Great ¾ Aristotle ¾ Winston Churchill ¾ Charles Darwin
¾ Somerset Maugham ¾ Marilyn Monroe ¾ Moses
¾ King George VI
¾ Carly Simon
¾ James Earl Jones
¾ Bill Walton
¾ Bo Jackson
¾ Bruce Willis
Etiology of Stuttering (Likely Multifactorial) ¾Genetics ¾Abnormal development of basal ganglia and/or white matter tracts (Maguire et al; Neumann et al; Sommer et al) ¾Questionable autoimmune Component (i.e. PANDAS) ¾Environmental stressors
Stuttering Shows Many Similarities With Tourette’s Syndrome Both associated with tic motions Both follow a waxing and waning course Made worse under anxiety or stress 4:1 male to female ratio Begins in childhood Symptoms worsened by dopamine agonists and improved with dopamine antagonists ¾ Related to abnormalities in the basal ganglia ¾ Genetic linkage postulated1 ¾ ¾ ¾ ¾ ¾ ¾
1. Comings DE. J Am Acad Child Adolesc Psychiatry. 1995;34(4):401-402.
Approaches to the Medical Treatment of Stuttering ¾Top down (determine what is wrong with the brain and develop targeted medication/treatment to correct it) ¾Bottom up (determine empirically which medications/therapy work and utilize this knowledge to elucidate brain abnormalities underlying the disorder)
PET and SPECT Imaging ¾Allow measurement of the metabolism of the living functioning brain
Brain Imaging Studies of Stuttering (cont.) ¾Wood, Stump 1980 investigated the effects of haloperidol on brain activity in stuttering utilizing SPECT • Stuttering symptoms improve with haloperidol with resulting improved fluency associated with increased brain activity in speech areas
Wood F, et al. Brain Lang. 1980;9(1): 141-144.
Brain Imaging Studies of Stuttering (cont.) ¾Pool, Devous, et al. in a large SPECT study showed stuttering to be associated with no abnormalities in brain structure (MRI), but associated with abnormally low brain activity in left-sided speech cortical areas
Pool KD, et al. Arch Neurol. 1991;48(5):509-512.
Brain Imaging Studies of Stuttering (cont.)
¾Left hemispheric speech areas less active than analogous areas of right hemisphere ¾Now confirmed with structural (MRI) studies (Foundas et al; Sommer et al) ¾Is the increase in right-sided structures a compensatory effect/therapy effect? May explain gender differences. De Nil LF, et al. J Speech Lang Hear Res. 2000;43(4):1038-1053. Fox PT, et al. Nature. 1996;382(6587):158-161. Sommer et al. Lancet 2002
Brain Imaging Studies of Stuttering (cont.) ¾Wu, Maguire, Riley, et al. utilized FDG to measure glucose metabolism in stuttering • Stuttering associated with abnormal low activity of speech cortical areas (Broca’s and Wernicke’s) and striatum • During induced fluency, cortical speech areas increase to normal or high normal areas, but striatum remains low Wu JC, et al. Neuroreport. 1997;8(3):767-770.
Two “Loops” of Speech ¾An inner or medial system • Abnormal in stuttering
¾An outer or lateral system • Can be activated in stuttering through induced fluency
Riley G, et al. PET scan evidence of parallel cerebral systems related to treatment effects. In: Hulstijn W, Peters HFM, eds. Speech production: motor control, brain research, and fluency disorders; 1997.
Possible Neurologic Pathway of Stuttering Involved in Pharmacologic Treatment Dopamine-GABA
Broca’s Area
–
“Inner loop”
“Outer loop”
¾ Dopamine lowers activity of striatum ¾ Olanzapine/ risperidone block dopamine, leading to increased activity of the striatum and improved fluency Left ¾ GABA can reduce dopamine function (Pagoclone)
Dopamine blocker/ Pagoclone
Right Wernicke’s Area
Dopamine Theory of Stuttering ¾ Striatal hypometabolism=elevated dopamine1 ¾ Dopamine antagonists increase striatal metabolism1 ¾ Dopamine antagonists improve stuttering1 ¾ Dopamine activity elevated in persons who stutter1 ¾ Dopamine agonists worsen stuttering2 1. Maguire GA. Lancet-Neurology. 1(7) November 2002. 2. Burd L, Kerbeshian J. J Clin Psychopharmacol. 1991;11(1):72-73.
Pharmacologic Treatment of Stuttering ¾Numerous medications have been studied but until recently, only those with dopamine blocking activity have shown confirmed efficacy ¾Pagoclone, a GABA selective agonist, has shown efficacy as well in the largest pharmacologic trial of stuttering ever conducted
Haloperidol ¾First-Generation Dopamine Antagonist ¾Associated with improved fluency ¾However, poor long-term compliance secondary to disabling side effects (e.g., dysphoria, sexual dysfunction, extrapyramidal symptoms, tardive dyskinesia) Rosenberger PG, et al. Am J Psychiatry. 1976;133:331-334.
Pimozide/Paroxetine Study ¾Positive clinical response in those on pimozide (dopamine antagonist) ¾Paroxetine (serotonin reuptake inhibitor) exhibited no clinical response ¾However, Pimozide associated with limiting sideeffects such as EPS, TD, dysphoria, prolactin elevation and cardiac conduction concerns Stager S, et al. A double-blind trial of pimozide and paroxetine for stuttering. In: Hulstijn W, et al., eds. Speech Production: Motor Control, Brain Research, and Fluency Disorders; 1997:379-382.
New Generation Dopamine Blockers Studied in Stuttering ¾Risperidone ¾Olanzapine ¾These agents have a much lower risk of motor system side-effects (e.g. tardive dyskinesia) and are much better tolerated than first generation agents
Risperidone Study ¾n=16 ¾Double-blind, placebo-controlled ¾6-week duration
Maguire GA, et al. J Clin Psychopharmacol. 2000;20(4):479-482.
Risperidone Study (cont.) ¾Ages 20-74 (mean 40.75) ¾12 males/4 females ¾Dose 0.5-2.0 mg ¾Ratings (% SS, duration, % TS, SSI-3) Maguire GA, et al. J Clin Psychopharmacol. 2000;20(4):479-482.
% Reduction in Severity Scores
Reductions in Severity Scores at best time-point in Subjects Receiving Risperidone or Placebo
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