The aim of this article is to discuss the use of the serotonin-dopamine antagonists (SDAs) in those who stutter. 

Stuttering, like nausea, schizophrenia, and Tourette syndrome, is associated with increased activity of the neurotransmitter dopamine.   Neuroimaging and pharmacological research has revealed that, in part, hyperactivity of the dopaminergic system exacerbates or induces stuttering speech.  This observation has promoted the study of medications that decrease dopaminergic activity in stuttering.

The first dopamine antagonist used in stuttering was Haloperidol (Haldol®).   Haloperidol is a synthetic compound that was developed by the Belgian physician Paul Janssen in the late-1950s, and a precursor to the serotonin-dopamine antagonists.  Haloperidol works by blocking dopamine receptors in the brain, specifically targeting the dopamine-2 receptor, which is one of the five different dopamine receptors in the brain.   By blocking dopamine-2 receptors, haloperidol prevents the binding of dopamine to its receptor in the synaptic cleft, which is the space between brain cells (neurons) where neurotransmitters modulate communication within the brain.  Thus haloperidol stops the effects of dopamine in the synaptic cleft and decreases dopaminergic transmission between neurons.

The initial use of haloperidol in stuttering was not based on its mechanism of action, as the association of dopamine and stuttering was not known at the time.  Haloperidol is a FDA approved treatment for the symptoms of Tourette syndrome and other tic disorders.  As Tourette syndrome shares many characteristics with developmental stuttering, physicians began to systematically evaluate haloperidol in the treatment of developmental stuttering. 

Throughout the 1970s, many double-blind, placebo-controlled studies – the gold standard in evaluating the efficacy of a medication – were conducted and revealed that haloperidol was more effective than placebo in promoting fluency.  By the end of the decade the consensus was that haloperidol is an effective treatment for stuttering speech.  

However, efficacy is not the only consideration when one makes treatment recommendations, and haloperidol never proved to be of any clinical use in stuttering due to side effects, which are more troublesome than stuttering.  Haloperidol, because it is such a strong blocker of dopamine, causes side effects that resemble Parkinson’s disease.  Parkinson’s disease is caused by a depletion of dopaminergic neurons, and has symptoms such as tremors, muscle stiffness, slow movements, and gait difficulties.  Side effects of medications that resemble Parkinson’s disease are commonly termed “extrapyramidal side effects” (EPS), as they are mediated by the extrapyramidal motor system found in the basal ganglia – a cluster of neurons deep within the brain involved in the regulation of motor movements.  EPS are noted with haloperidol, and have been observed in individuals treated with haloperidol for their stuttering.  In addition, haloperidol causes akathisia, a motor restlessness that can range from an urge to move about to actual random movements.  EPS and akathisia are side effects that can be treated by the addition of other medications.  However, haloperidol – if given over many years – may cause tardive dyskinesia, a rare, permanent condition characterized by involuntary movements of the tongue and facial muscles.  There is no effective treatment for tardive dyskinesia, and fortunately, it has not been reported in any of the individuals who received haloperidol for their stuttering.  The risk of tardive dyskinesia and the other side effects of haloperidol outweigh the benefits of fluency, and it is not currently recommended for those who stutter.  In fact, many of the individuals recruited for haloperidol studies dropped out secondary to the side effects.

Even though haloperidol has side effects that limit its use, the study of its effect on brain function stimulated the development of a new generation of medications that retain the efficacy of haloperidol, while decreasing the side effects.  These medications have shown promise in the treatment of developmental stuttering, and are termed “serotonin-dopamine antagonists.”

In the 1990s, Serotonin-dopamine antagonists (SDAs) emerged as a new generation of medications for brain-based conditions that simultaneously block serotonin and dopamine receptors.  Like dopamine, serotonin is a neurotransmitter.  As serotonin relates to the SDAs, its blockage provides a major clinical benefit as it significantly decreases the risk of the side effects found with haloperidol while maintaining efficacy.

SDAs have a low incidence of akathisia, EPS, and tardive dyskinesia because they were specifically designed to block the serotonin-2 receptor, more commonly written as an abbreviation of its chemical name, 5HT-2 (5-hydroxytryptamine).

Currently, six SDAs are available: aripiprazole (Abilify®); clozapine (Clozaril®); olanzapine (Zyprexa®); risperidone (Risperdal®); quetiapine (Seroquel®); and ziprasidone (Geodon®).  Of the available SDAs, risperidone and olanzapine have undergone double-blind, placebo-controlled trial, both of which occurred at the University of California, Irvine under the direction of Gerald Maguire, M.D.

Risperidone

In a pilot study presented in 2000, 16 adults (12 men and 4 women aged 20 to 74 with a mean age of 41 years) with developmental stuttering were evaluated for 6 weeks.  Eight individuals received placebo and eight received risperidone at 0.5 mg once daily at night, increased to a maximum of 2 mg per day.  After 6 weeks of treatment, statistically significant improvements in percentages of syllables stuttered and stuttering severity were noted in the risperidone treated group.  There was no difference between the groups in the duration of stuttering.  

None of the individuals receiving risperidone acquired the worrisome side effects observed with haloperidol, such as, EPS and akathisia.  However, sedation was noted in about three of the individuals in the risperidone treated group.  This sedation resolved with a decrease of the risperidone.  In addition to sedation, there was another side effect observed in the study that, while quite rare, is associated with risperidone.

One of the female individuals reported galactorrhea (secretion of breast milk) and amenorrhea (absence of menstruation).  These symptoms are normally observed in women during lactation, which is the period after birth when mothers’ breast-feed their child.  However, this woman was not breast-feeding, and her symptoms were attributed to the risperidone. 

Risperidone, as it effectively blocks dopamine-2 receptors, inhibits the dopaminergic pathway projecting to the pituitary gland, and this can affect the regulation of prolactin secretion.  Prolactin induces lactation and ovulation, and its release from the pituitary gland is inhibited by dopamine.  Risperidone, via the inhibition of dopamine, can induce prolactin secretion and thus cause these side effects.  Fortunately, risperidone rarely causes these side effects and when it does, the side effects resolve with discontinuation of the medication.  This was the case with this woman.

Olanzapine

Olanzapine was the second SDA after risperidone to pass clinical trials, and was approved for use in late-1996.  Olanzapine blocks a number of different receptors with a varying degree of strength, but its mechanism of action is related to its ability to bind dopamine receptors and 5HT-2 receptors.  Like risperidone, olanzapine is associated with a low risk of akathisia, EPS, and tardive dyskinesia.  Unlike risperidone, and following the observation that the individual members of SDAs differ slightly in their respected side effect profile, olanzapine is not associated with increased prolactin secretion.  However, olanzapine is associated with sedation and weight gain.  In addition, olanzapine – possibly because of its side effect of weight gain – must be used with caution with diabetics, as it is associated with an increase in blood sugar in these individuals.

In 2004, a double-blind, placebo-controlled study of olanzapine was presented.   This study included more individuals than the risperidone study in that 23 adults (20 men and 3 women aged 18 to 56 with a mean age of 33 years) were evaluated.   Initially twelve individuals were in the placebo group, but one subject was dropped from the study secondary to the onset of depression.  The other twelve individuals received 2.5 mg of olanzapine a day for the first four weeks, which was increased to 5 mg a day for the last eight weeks.  After conclusion of the 3-month study, the olanzapine treated group showed statistically significant improvements in stuttering severity via the three measures used: the stuttering severity instrument (SSI-3), self-assessment of stuttering severity (SSS), and clinical global impression (CGI). 

As in the risperidone study, there were no observations of akathisia, EPS, or tardive dyskinesia.  Though, as is commonly found with olanzapine, side effects of mild sedation and weight gain were noted.  The average weight gain was 3.5 kg (7.7 lbs) with a range of 0.5 kg (1.1 lbs) to 9.5 kg (20.9 lbs).  Due to the association of diabetes with olanzapine, individuals were monitored for changes in blood sugar, and no subjects had an elevation in fasting blood glucose during the study. 

These two studies show promise for the use of SDAs in stuttering.  Despite the sedation found with both medications, the one case of transient lactation with risperidone, and weight gain with olanzapine, the medications were tolerated and found to be superior to placebo in inducing fluency.  These observations distinguish the use of haloperidol in stuttering as no subjects in the SDA studies dropped out due to side effects.

Interestingly, the SDAs appear to be an effective intervention in decreasing the severity of stuttering speech, but do not end stuttering.  All of the individuals in these two studies still stuttered to some degree.  This type of observation is common in symptom-based treatment, and is analogous to the use of anti-inflammatory medications in arthritis, which alleviate the symptoms of arthritis, but do not affect the underling etiology.  Hence the promise for SDAs is alleviation of some symptoms, but they will not provide a cure for stuttering.

The good results of these two studies needs to be tempered with the fact that they are of small size, limited in the duration of study, and not replicated.  To gain acceptance, longer-term, multi-center studies with larger sample sizes are needed.  This type of scrutiny is necessary, as the SDAs are not benign medications.  For example, the weight gain and the possibility of elevated blood sugar associated with olanzapine, is not a side effect one would like to experience if suffering from diabetes. 

While the SDAs require further research before inclusion in the armament of stuttering treatments, they can decrease the severity of stuttering speech.  Time and study will reveal the usefulness of these medications in stuttering.  No matter what the final analysis of the SDAs in stuttering reveals, they are an advancement in the pharmacological approach to stuttering. 

References

Abwender DA, Trinidad KS, Jones KR, Como PG, Hymes E.  Features resembling Tourette’s syndrome in developmental stuttering.  Brain and Language 1998; 62: 455-464.

Brady JP.  The pharmacology of stuttering: a critical review. The American Journal of Psychiatry 1991; 148: 1309-1316.

Coffey BJ, Biederman J, Geller DA, Spencer T, Park KS, Shapiro SJ, Garfield SB.  The course of Tourette’s disorder: a literature review.  Harvard review of psychiatry 2000; 8: 192-198.

Flake ZA, Scalley RD, Bailey AG.  Practical selection of antiemetics.  American Family Physician 2004; 69: 1169-1174.

Maguire GA, Riley GD, Franklin DL, Gottschalk LA.  Risperidone for the treatment of stuttering.  Journal of Clinical Psychopharmacology 2000; 20: 479-482.

Maguire GA, Riley GD, Franklin DL, Maguire ME, Nguyen CT, Brojeni PH.  Olanzapine n the treatment of developmental stuttering: a double-blind, placebo-controlled trial.  Annals of Clinical Psychiatry 2004; 16: 63-67.

Robertson MM, Stern JS.  Gilles de la Tourette syndrome: symptomatic treatment.  European Child and Adolescent Psychiatry 2000; 9 Suppl 1: I60-75.

Wells PG, Malcolm MT.  Controlled trial of the treatment of 36 stutterers.  The British Journal of Psychiatry 1971; 119: 603-604.

Wood F, Stump D, McKeehan A, Sheldon S, Proctor J.  Patterns of regional cerebral blood flow during attempted reading aloud by stutterers both on and off haloperidol medication: evidence for inadequate left frontal activation during stuttering.  Brain Language 1980; 9: 141-144.

Wu JC, Maguire G, Riley G, Lee A, Keator D, Tang C, Fallon J, Najafi A.  Increased dopamine activity associated with stuttering.  Neuroreport 1997; 8: 767-770.

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