1. INTRODUCTION:

Stuttering was present among the communities for thousands of years and many historical and famous characters suffered from that disease, namely Demosthenes, Winston Churchill, Prince Albert of Monaco and King George VI. Nowadays, over 3 million of American citizens stutter and interestingly over 80% are male. First symptoms usually occur between 2 and 6 years of age. Stuttering, also known as a stammering, is the collection of problems regarding the disturbance in normal fluency and time pattering of speech, incorrect interjections in speech as well as the lack of smoothness in oral communication (Figure 1). A person, who suffers from stuttering, may experience involuntary prolongations of words, syllables and phrases, and unwitting repetition in fragments of sentences. Furthermore, the majority of patients shows abnormal pauses or blocks during speaking connected with the elongation of vowels and circumlocutions (substitutions of problematic words to avoid problems with speaking them)^1,2,3. Moreover, stuttering exerts a negative impact on the psychical comfort and relationships in society (Figure 2). It is worth emphasizing that there is no clear differentiation of level of stuttering’s intensity, which enables us to qualify patients into differentiated treatment groups. From the pharmacological point of view, an important indication is that stuttering is not related to the physical formation of tones, which are converted into speech, or the transformations of thoughts into words.

Figure 1. Characteristics of speech among the stuttering patients.

Recent research shows that stuttering is not associated with decreased intelligence or behavioral abnormalities, which offer the possibility of pharmacological intervention. Notable differences in functions of brain structures have been previously described as differences in the asymmetric scheme of the cerebral hemispheres⁴. Moreover, stuttering appears in some neurological disorders such as Parkinson’s disease, selective mutism, Asperger syndrome, and spasmodic dysphonia. There is also another evidence suggesting that stuttering is a result of brain injuries (stroke, brain tumor, and other traumatic injuries) or personal emotional trauma also known as psychogenic stuttering. However, difficulties in emotional comfort such as anxiety, chronic and acute stress, shame and, self-imposed isolation are the results of stuttering in the field of communication in society (Figure 2), and we cannot classify these mental abnormalities as a cause of stuttering^5,6. Moreover, the disorder does not occur with constant intensity but depends on many environmental as well as sociological factors and there are no reports of preventing stuttering.

Figure 2. The psychic aspect of persistent stuttering.

In spite of the widely occurrence of speech disorders in the context of fluency and smoothness, none of the pharmaceutical companies are able to offer an effective, direct, and safe pharmacotherapy for stuttering patients. What is more, the number of clinical trials is very small and usually limited to the initial phases. It is an enigmatic attitude of the pharmacological companies due to a significant number of potential patients waiting for the introduction of therapy for stuttering. The main questions are: (1) what is the major problem in discovering and introducing an anti-stuttering agent in the clinical trials and finally on the drugs market, and (2) what are the new hopes in this field of pharmacology?

2. NEW THEORIES AND HYPOTHESIS:

Studies, which focus on new approaches in a therapy of speech disorders, are fortunately still in progress and recently researchers obtained only a few new potential methods, which seem to be applicable in the treatment for these disorders. Among numerously brand new evidence concerning etiology, process, and treatment for speech disorders, we can point out the most important like: hyper-dopamine theory, genetic factors theory, questionable autoimmune component, gamma-aminobutyric acid theory and other neurophysiology relationships underlying stuttering.

The hyper-dopamine theory also known as the Dopamine Hypothesis is considered as a novel potential biological key for an effective stuttering treatment. Dopamine (DA) is a hormone and neurotransmitter synthesized from tyrosine through L-Dopa and released by dopamine neurons of the central nervous system (CNS). DA plays a crucial role in many biological pathways and may stimulate the different type of receptors. Nowadays, we differentiate five types of dopamine receptors, which belong to two families: D1-like family (D1 and D5 receptors) and D2-like family including D2, D3, and D4 receptors. Both families are a class of G protein-coupled receptors and the dopamine is a primary endogenous ligand for them. In fact, recent studies on the basis of molecular techniques provided data suggesting that every type of dopamine receptor has various biological function and impact on neurological balance⁷. For example, D2 receptors inhibit adenylate cyclase and phosphoinositide turnover, but its stimulation leads to the activation of a potassium channel and increased of arachidonic acid release. D2 receptors are particularly expressed in the nucleus accumbens septi, basal ganglia and ventral tegmental area⁸. On the other hand, D3 receptors have potential ability to mediate a positive impact of dopamine on neurotension. In turn, D4 receptors are localized especially in the hippocampus and frontal cerebral cortex and are associated with many neurological conditions like schizophrenia, Parkinson’s disease, and bipolar disorders. Interestingly, each type of receptors’ genes is positioned on separate chromosomes⁹.

Firstly, an effect of DA on biological processes depends on the structure, where an action takes place. In extrapyramidal system (systema extrapyramidale), DA is responsible for appropriate muscle tension, coordination, and its deficiency leads to Parkinson’s disease. On the other hand, DA plays many important roles straightly associated with emotions, complex mental behaviors and other cognitive processes in the limbic system. Furthermore, in the hypothalamus, DA acts as a regulator of prolactin secretion and other hormones releasing molecules. Recent studies have shown that patients, who suffer from stuttering and other speech disorders, have an increased level of DA and its metabolites in the brain. Moreover, the neuroimaging analysis of brains structures revealed hyperactivity of mesencephalon in the area of the substantia nigra, where DA synthesis takes place. From the point of view of this paper, a role of DA in the limbic system seems to be absolutely essential in pharmacological treatment for stuttering¹⁰. The National Institute on Deafness and Other Communication Disorders is involved into a project focused on using the positron emission tomography (PET) to examine the role of DA in stuttering and measure number of dopamine receptors and their activities.

It seems that data acquisition brings on a brand new insight on the role of DA in the aspect of speech fluency. Furthermore, many psychoactive substances (cocaine, heroin, amphetamine, and nicotine), that were tested in the distant past as an alternative anti-stuttering agents, manifested the affinity to dopamine receptors and increased the striatal metabolism. Interestingly, for many years, a large number of pharmacologists attempted to treat speech fluency disorders with antipsychotic, antidepressant, and anticonvulsant medications that are also associated with DA activity. However, results of mentioned treatment were not satisfying enough due to significant adverse effects¹¹. Currently, our attention is once again directed to dopamine antagonists, which are believed to be a completely new treatment option for stuttering. The most important dopamine receptor antagonists are Asenapine, Tiapride and Pimoside. Despite the fact that these drugs are not newly synthesized molecules, their use in the treatment for stuttering may be a breakthrough.

3. NEW OPPORTUNITIES IN PHARMACOLOGICAL TREATMENT FOR STUTTERING:

3.1. Asenapine:

Asenapine (Saphris, Sycrest) is the most recent atypical antipsychotic agent, which was approved by FDA (Food and Drug Administration in US) in August 2009 after the clinical trials conducted by the Organon. The main indications for using Asenapine are acute mania and schizophrenia associated with bipolar disorders. Due to high affinity to numerous receptors, the drug may demonstrate many other properties related to its antagonism towards serotonin (exclude 5-HT_1A receptors), adrenergic, histamine and dopamine receptors¹². Scientists involved in project at the University of California - Irvine and focused on stuttering treatment, deeply believed that Asenapine owing to block DA-receptors (especially D2 and D3) inhibits bombardment of DA of brains parts responsible for the formation of fluent and smooth speech. It may be not excluded, that improvement of speech fluency may also be a result of sedation (via high affinity to H1 receptors) and relaxation, which play an important role in the elimination of speech disorders caused by stress, anxiety, and shame. Initial studies provided a promising results, which seem to give stutterers a great improvement. Generally, Asenapine is well-tolerated and has a frequency of adverse effects similar to placebo group. In rare cases, sedation, mild symptoms of Parkinson’s disease and akathisia were observed¹³. Another problem refers to oxidative metabolism by cytochrome P450 isoenzymes. Asenapine may interact with drugs metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes and then its bioavailability decreases below 2% after oral administration to 35% after sublingual application. Mentioned interactions may lead to difficulties in maintaining the drug appropriate levels in a bloodstream¹⁴. Despite these complications, Asenapine is still under clinical trials and provides an outstanding opportunity to become the absolutely new agent for the pharmacological treatment for stuttering.

3.2. Tiapride:

Tiapride (Italprid, Tiapridex) is an atypical neuroleptic agent. Moreover, it is a selective antagonist of D2 and D3 receptors in brain with little propensity for causing catalepsy and sedation. This drug demonstrates anti-dopaminergic actions, which neutralize an increased level of DA in the central nervous system. Nowadays, Tiapride is widely used to treat a variety of neurological and psychiatric disorders, but the most common application is the management of alcohol withdrawal¹⁵. Interestingly, in 1994 Rothenberger et al. examined the therapeutical efficiency of Tiapride for stuttering treatment in a group of 10 patients. Despite promising results, researchers refused to continue the trials¹⁶. 20 years later, the attention of pharmacologists once again focused on this compound as a potential treatment for stuttering, however there is still no published data on the success of the research. After oral administration, Tiapride is rapidly distributed and binds preferentially to extrastriatal dopamine receptors (particularly in the hippocampus). The drug has high selectivity for limbic structures, but mechanisms underlying this property have not been fully elucidated. A significant advantage of Tiapride is the general lack of activity towards DA in normal rats and much greater activity under conditions of increased concentration of dopamine. Treatment with it improved central nervous regulatory mechanisms of speech control coordination through the elimination of extra excitation of a nervous system. Tiapride was generally well-tolerated in clinical trials. The drug does not appear to cause physical or psychological dependence¹⁷, thus seems to be safe and effective treatment for children and adolescents. As in the case of Asenapine, Tiapride requires fully clinical trials including follow-up studies with an adequate number of volunteers.

3.3. Pimozide:

Pimozide (Orap) is a pharmacological dinosaur in comparison with Asenapine because was invented by laboratories of the Janseen Pharmaceutica and brought to pharmaceutical market in the sixties of the last century. Over recent decades, researchers unexpectedly paid attention to novel receptors profile of the drug. It transpired that Pimozide has an extremely high affinity to D2 and 5-HT₇ receptors¹⁸. Blocking of D2 receptors, as it was previously described, may improve speech fluency via reversing the effect of significantly increased concentration of DA in the brain structures. Activity towards receptors for 5-HT₇ explains the antidepressant-like effect, that leads to gain self-confidence, reduce stress and anxiety, and the decrease of stuttering symptoms. In contrast to the drugs listed above, Pimozide shows extremely long time of elimination half-life (average 60 hours) and its common adverse effects include somnolence, akinesia, nocturia and spontaneously occurring QT interval prolongation in ECG (1 in 1,000 patients)¹⁹. Due to the fact that Pimozide has a number of agonistic properties of various receptors, it still reveals potential in the treatment of stuttering and other speech disorders in adolescence.

3.4. Olanzapine and Risperidone:

Another antipsychotic drugs associated with treatment for speech disorders are Olanzapine (Zyprexa) and Risperidone (Risperdal). In the present century, several studies were conducted to adapt these drugs to the pharmacological treatment for stuttering. Both of these antipsychotics are antagonists of dopamine receptors (exception: Risperidone is an inverse agonist for D3 receptors) and both block influx of DA, what lead to increased activity of the striatum and improved fluency and smoothness of speech. Additionally, Risperidone blocks the mesolimbic pathway, the prefrontal cortex limbic pathway and increases the activity of the cortical speech area. Double-blinded and multicenter studies proved that Olanzapine and Risperidone reduced stuttering symptoms such as percent of syllables stuttered, time stuttering as a percent of the total time of speaking, and a number of the pauses within words. Unfortunately, clinicians observed a large number of side-effects. Many patients suffered from vomiting, nausea, hyperprolactinemia, dizziness, and abnormalities in weight parameters^{20, 21}. The overall list of the adverse effects contains over forty components, which occurred more frequently than 1 in 100 patients. Obviously, these disqualify Olanzapine and Risperidone as medications for children and lead us to prospect another compound for the stuttering treatment.

3.5. Pagoclone – partial agonist of GABA-A receptor:

At the turn of century, expectations towards the possibility of pharmacological treatment for speech disorders (especially stuttering) were enormous but nobody realizes that the breakthrough is so close. A new hope was named Pagoclone (IP456) and it has been synthesized by the French company Rhone-Poulenc & Rorer. From the pharmacological point of view, Pagoclone is a non-benzodiazepine, selective GABA-A receptor a partial agonist. A general feature of partial agonist is a limited degree of influence on opening the ion channel. Gamma-aminobutyric acid (GABA) is the widely distributed neurotransmitter that operates primary with a GABA-A chloride-dependent channels in the brain. In contrast to DA, GABA plays an important role in the reduction of neuronal excitability, regulation of muscle tones, and activation of GABA receptors. Due to GABA neurobiological properties, people are more relaxed, calm, and optimistic. Furthermore, GABA binds to the specific transmembrane receptors, which are responsible for pre- and post-synaptic neuronal processes. The nature of that compound suggests, that a direct-acting GABA-A agents may become effective against stuttering syndromes. Interestingly, dopaminergic neurons seem to be connected with GABA-dependent synapses within areas of the brain linked to the formation of speech disorders²². The entire imbalance between excitatory and inhibitory neurotransmission may lead to the disruption of white matter fiber tracts that are responsible for junction of the Broca’s area with the motor cortex. In this case, the motor cortex is subjected to hyper excitation that leads to the appearance of stuttering symptoms. Another proof of this hypothesis is an activity of theophylline leading to hyper excitation through the increased DA level via adenosine receptors. Theophylline causes increased intensity in the occurrence of speech disorders and this fact leads us to assure that DA and GABA are involved into the mechanism underlying stuttering and other speech disorders²³.

Recent data suggest that Pagoclone may be Panaceum for speech difficulties due to enhanced activity in the GABA neuro-circulation. Over hundred volunteers were involved in the largest clinical trial in the field of stuttering treatment named EXPRESS (the EXamining Pagoclone for peRsistent dEvelopmental Stuttering Study). This trial lasted 8 weeks and was followed by a 1-year open label extension. The results of the trial were satisfying during the treatment with doses of 0.30 to 0.60 mg/bw/day of Pagoclone. The drug was effective in reducing symptoms of stuttering. Pagoclone-treated patients demonstrated improvement of speech parameters (their speech was more „natural”) and the compound was well-tolerated. In addition, Pagoclone showed 19.2% reduction (in percentage) of incorrectly pronounced syllables in comparison with 5.1% among a placebo group²⁴. It may be not excluded that beneficial effects in speech fluency may be present as the results of sedation and abolition of stress accompanying speech in stressful conditions. However, despite the good results and grand plans for bringing Pagoclone to the drug market, FDA has stopped all efforts and now the future of Pagoclone is absolutely unclear. Although the allocation of Pagoclone in pharmacology is still an enigma, it seems that medical world noticed problems regarding stuttering. Another promising hypothesis is to combine Pagoclone with dopamine receptors antagonist in order to ensure synergistic pharmacological effects. The future is open and we should not forget about this compound.

4. DISCUSSION:

Dynamic growth of genetic sciences and possibilities to carry out inexpensive analysis of human genes provide another tool in studies of mechanisms underlying speech disorders, which may contribute to simplify drugs research. Recent studies revealed the connection of GNPTAB, GNPTG and NAGPA genes with stuttering²⁵. These findings allow supposing that further studies based on genomics, proteomics and metabolomics high throughput analysis methods may indicate a novel ways to pharmacological or genetic treatment for stuttering.

Everyone may ask the question: “Why in the century of a brand new technologies and molecular biology, the treatment for stuttering is still unresolved query?” The reasons underlying this problem seem to have a wide range of obstacles. Firstly, stuttering and speech disorders have been not clearly understood in the meaning of brain chemistry, audiology dependences, and psychoanalytic theories. Obviously, it is much harder to discover the cure, when the etiology of disorders remains unknown. Another problem refers to the lack of ability to observe effects of treatment for stuttering per se without a patient’s mental impact. In each clinical trial, researchers observed compositions of behavioral changes, different adverse effects, and great variability of personal habits. Diseases of the central nervous system are also unpredictable, dynamic, and dependent on many environmental factors. Nobody makes sure that observed effect of therapeutical agents is the result of their high affinity to receptors instead of introducing patient into comfortable condition leading to decreased stress, fear, insecurity, and anxiety that result in the improvement of speech fluency. Furthermore, it is not recommended to use drugs, which were designed for a serious mental disease in treatment for stuttering. Adverse effects and complications of using these drugs may cause more health problems than as it may seem. In other words, treatment for stuttering requires a targeted therapy, although its introducing is impossible without knowledge about mechanisms causing stuttering. At the present, treatment for stuttering consists mainly of behavioral exercises and speech therapy. Unfortunately, mental training, which requires a long time, is still insufficient support for stuttering people.

Knowledge of the mechanisms of action, adverse effects, interactions, and potential clinical implications of above-listed drugs is essential for pharmacologists in order to find safe, effective and accurate treatment for stuttering. We should hopefully look into the future, because medical and technological progress is unstoppable and everyday it provides new discoveries, which may resolve our queries in the near future.

5. ACKNOWLEDGMENTS:

Non-applicable

Declarations of interest: The authors report no declarations of interest.

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Received on 20.03.2018 Accepted on 28.04.2018

Asian J. Pharm. Res. 2018; 8(2):104-109.

DOI: 10.5958/2231-5691.2018.00018.7