Dopamine hypothesis of stuttering

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The dopamine hypothesis of stuttering attributes to the phenomenon of stuttering a hyperactive and disturbed dopaminergic signal transduction in the brain. The theory is derived from observations in medical neuroimaging and from the empirical response of some antipsychotics and their antagonistic effects on the dopamine receptor. However, it is important to outline that the hypothesis does not consider the excessive dopaminergic activity as the direct cause of stuttering; instead, this synaptic dysregulation is a symptom of a greater disorder that affects other brain pathways and structures.

Contents

Introduction

Following the comparative analysis of brain imaging of stuttering and non-stuttering speakers, people who stutter seem to display a heightened dopaminergic activity in striatal regions of the brain. [1] This has been described during a PET study using fluoro-L-DOPA as a marker of presynaptic dopaminergic activity [2] and an MRI study of brain activation patterns. [3] Since dopamine acts as an inhibitor of striatal metabolism, striatal hypometabolism can be explained by the recorded increased levels of presynaptic dopamine in people who stutter as compared to controls groups. There was a significantly higher dopamine reuptake activity in the cortex and subcortical regions associated with speech in people who stuttered, further supporting the hypothesis that dopaminergic pathways within the mesocortical and limbic systems may be more elevated than the norm in people who stutter. [2]

Arguments in favour of a dopamine hypothesis

Haloperidol

The typical antipsychotic haloperidol has been the most used drug in treatment trials for stuttering. In double-blind placebo-controlled trials with objective speech measures, the group receiving haloperidol displayed significant improvement after a 8-week trial. However, the mechanism of action of this first generation antipsychotic bore important side effects that affected the tolerability in patients and maintaining the improved speech required that subjects keep taking the drug. Moreover, the trial was conducted before the full extent of the risks of using neuroleptics was appreciated; the extrapyramidal symptoms and the possible permanent tardive dyskinea that could result now qualify the drug as dangerous and possibly disproportionate in the treatment of stuttering. Taking into account Haloperidol's mechanism of action that specifically targets dopamine receptors (through silent antagonist for D1, D5 and inverse agonist for D2, D3, D4) unlike other neuroleptics as well as its effectiveness over a placebo, the dopaminergic pathway seems to be correlated to the symptoms of stuttering since the drug normalised to some extent the dopaminergic hyperactive state. [4]

Aripiprazole

Aripiprazole's mode of action differs from other atypical antipsychotics in its selectivity with dopamine receptors (partial agonist activity on postsynaptic D2 receptor and partial agonist activity on presynaptic D2, D3 and partially D4 [5] ) and serotonin receptors (partial agonist of 5-HT1A and antagonist of 5-HT2A. Aripiprazole's main antagonist action on the dopamine D2 postsynaptic receptor is believed to decrease excessive dopaminergic activity and may also decrease the synthesis and release of dopamine through its presynaptic D2 antagonist action. [6] Furthermore, the drug's agonist activity on seretonin receptor 5-HT1A is believed to possess an anxiolytic effect, providing a possible explanation for the decreased social anxiety patients noticed. [7]

Antipsychotic-induced stuttering

Concomitantly, it is of interest to note that dopamine antagonist have also been reported to cause stuttering in some individuals and speech disorder has been characterised as a proper but uncommon side effect of aripiprazole during the premarketing trials of the drug (Abilify). [8] This effect further corroborates the dysregulated dopaminergic character stuttering ensues from.

Similarities with other pathologies

Motor tics and Tourette's syndrome share important characteristics with stuttering; they all initially manifest in childhood, affect more males than females, obey a waxing and waning course, and increase in intensity under emotional stress. The treatment of tic disorders in children has been efficient with the administration of aripiprazole, namely single or multiple motor or vocal tics, [9] alluding to similar mechanisms the disorder share with stuttering. Given that these other two conditions seem to respond to the same drug and given the symptomatic similarities, these three disorders not only share common features but maybe a very similar cause.

Related Research Articles

<span class="mw-page-title-main">Haloperidol</span> Typical antipsychotic medication

Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations from alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks by people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.

<span class="mw-page-title-main">Atypical antipsychotic</span> Class of pharmaceutical drugs

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.

<span class="mw-page-title-main">Aripiprazole</span> Atypical Antipsychotic

Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressive disorder, tic disorders and irritability associated with autism. It is taken by mouth or injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.

<span class="mw-page-title-main">Dopamine antagonist</span> Drug which blocks dopamine receptors

A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

<span class="mw-page-title-main">Progabide</span> Pharmaceutical drug

Progabide is an analogue and prodrug of γ-aminobutyric acid (GABA) used in the treatment of epilepsy. Via conversion into GABA, progabide behaves as an agonist of the GABAA, GABAB, and GABAA-ρ receptors.

<span class="mw-page-title-main">Amisulpride</span> Atypical antipsychotic and antiemetic medication

Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold under the brand names Barhemsys and Solian, Socian, Deniban and others. At very low doses it is also used to treat dysthymia.

Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side effects (EPSE). The symptoms can be acute (short-term) or chronic (long-term). They include movement dysfunction such as dystonia, akathisia, parkinsonism characteristic symptoms such as rigidity, bradykinesia, tremor, and tardive dyskinesia. Extrapyramidal symptoms are a reason why subjects drop out of clinical trials of antipsychotics; of the 213 (14.6%) subjects that dropped out of one of the largest clinical trials of antipsychotics, 58 (27.2%) of those discontinuations were due to EPS.

<span class="mw-page-title-main">Bifeprunox</span> Experimental dopamine D2 receptor partial agonist researched as an antipsychotic agent

Bifeprunox (INN) (code name DU-127,090) is an atypical antipsychotic which, similarly to aripiprazole, combines minimal D2 receptor agonism with serotonin receptor agonism. It was under development for the treatment of schizophrenia but has since been abandoned.

Dopamine receptor D<sub>2</sub> Main receptor for most antipsychotic drugs

Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.

5-HT<sub>1A</sub> receptor Serotonin receptor protein distributed in the cerebrum and raphe nucleus

The serotonin 1A receptor is a subtype of serotonin receptor, or 5-HT receptor, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarisation and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.

The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms of schizophrenia linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.

<span class="mw-page-title-main">Amperozide</span> Chemical compound

Amperozide is an atypical antipsychotic of the diphenylbutylpiperazine class which acts as an antagonist at the 5-HT2A receptor. It does not block dopamine receptors as with most antipsychotic drugs, but does inhibit dopamine release, and alters the firing pattern of dopaminergic neurons. It was investigated for the treatment of schizophrenia in humans, but never adopted clinically. Its main use is instead in veterinary medicine, primarily in intensively farmed pigs, for decreasing aggression and stress and thereby increasing feeding and productivity.

<span class="mw-page-title-main">Tiapride</span> Drug

Tiapride is a drug that selectively blocks D2 and D3 dopamine receptors in the brain. It is used to treat a variety of neurological and psychiatric disorders including dyskinesia, alcohol withdrawal syndrome, negative symptoms of psychosis, and agitation and aggression in the elderly. A derivative of benzamide, tiapride is chemically and functionally similar to other benzamide antipsychotics such as sulpiride and amisulpride known for their dopamine antagonist effects.

<span class="mw-page-title-main">Blonanserin</span> Atypical antipsychotic

Blonanserin, sold under the brand name Lonasen, is a relatively new atypical antipsychotic commercialized by Dainippon Sumitomo Pharma in Japan and Korea for the treatment of schizophrenia. Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension. As with many second-generation (atypical) antipsychotics it is significantly more efficacious in the treatment of the negative symptoms of schizophrenia compared to first-generation (typical) antipsychotics such as haloperidol.

<span class="mw-page-title-main">Roxindole</span> Dopaminergic & serotonergic drug developed for schizophrenia treatment

Roxindole (EMD-49,980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produce potent and rapid antidepressant and anxiolytic effects. As a result, roxindole was further researched for the treatment of depression instead. It has also been investigated as a therapy for Parkinson's disease and prolactinoma.

<span class="mw-page-title-main">Piquindone</span> Chemical compound

Piquindone (Ro 22-1319) is an atypical antipsychotic with a tricyclic structure that was developed in the 1980s but was never marketed. It acts as a selective D2 receptor antagonist, though based on its effects profile its selectivity may be considered controversial. Unlike most other D2 receptor ligands, piquindone displays Na+-dependent binding, a property it shares with tropapride, zetidoline, and metoclopramide.

<span class="mw-page-title-main">Cariprazine</span> Atypical antipsychotic medicine

Cariprazine, sold under the brand names Vraylar and Reagila among others, is an atypical antipsychotic originated by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. It is taken by mouth.

<span class="mw-page-title-main">F-15063</span> Chemical compound

F-15,063 is an orally active potential antipsychotic, and an antagonist at the D2/D3 receptors, partial agonist at the D4 receptor, and agonist at the 5-HT1A receptors. It has greater efficacy at the 5-HT1A receptors than other antipsychotics, such as clozapine, aripiprazole, and ziprasidone. This greater efficacy may lead to enhanced antipsychotic properties, as antipsychotics that lack 5-HT1A affinity are associated with increased risk of extrapyramidal symptoms, and lack of activity against the negative symptoms of schizophrenia.

<span class="mw-page-title-main">Brexpiprazole</span> Atypical antipsychotic

Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic. It is a dopamine D2 receptor partial agonist and has been described as a "serotonin–dopamine activity modulator" (SDAM). The drug was approved by the U.S. Food and Drug Administration (FDA) on 10 July 2015, for the treatment of schizophrenia, and as an adjunctive treatment for depression. It has been designed to provide improved efficacy and tolerability (e.g., less akathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).

<span class="mw-page-title-main">Brilaroxazine</span> Experimental atypical antipsycotic

Brilaroxazine, also known as oxaripiprazole, is an investigational atypical antipsychotic which is under development by Reviva Pharmaceuticals for the treatment of schizophrenia and schizoaffective disorder. Reviva Pharmaceuticals also intends to investigate brilaroxazine for the treatment of bipolar disorder, major depressive disorder, psychosis/agitation associated with Alzheimer's disease, Parkinson's disease psychosis, attention deficit hyperactivity disorder (ADD/ADHD), and autism. As of August 2022, it is in phase III clinical trials for schizophrenia.

References

  1. ↑ Blomgren, Michael; Nagarajan, Srikantan S.; Lee, James N.; Li, Tianhao; Alvord, Lynn (2003). "Preliminary results of a functional MRI study of brain activation patterns in stuttering and nonstuttering speakers during a lexical access task". Journal of Fluency Disorders. 28 (4): 337–356. doi:10.1016/j.jfludis.2003.08.002. PMID   14643069.
  2. 1 2 Wu Joseph C.; Maguire, Gerald; Riley, Glyndon; Fallon, James; LaCasse, Lori; Chin, Sam; Klein, Eric; Tang, Cheuk; Cadwell, Stephanie; Lottenberg, Stephen (February 1995). "A positron emission tomography [18F]deoxyglucose study of developmental stuttering". NeuroReport. 6 (3): 501–505. doi:10.1097/00001756-199502000-00024. PMID   7766852.
  3. ↑ Blomgren, Michael; Nagarajan, Srikantan S.; Lee, James N.; Li, Tianhao; Alvord, Lynn (2003). "Preliminary results of a functional MRI study of brain activation patterns in stuttering and nonstuttering speakers during a lexical access task". Journal of Fluency Disorders. 28 (4): 337–356. doi:10.1016/j.jfludis.2003.08.002. PMID   14643069.
  4. ↑ Brady, J. P. (1991). "The pharmacology of stuttering: a critical review". American Journal of Psychiatry. 148 (10): 1309–1316. doi:10.1176/ajp.148.10.1309. ISSN   0002-953X. PMID   1680295.
  5. ↑ Mailman, Richard; Roth, Bryan L.; Sibley, David R.; Li-Xin Liu; Chiodo, Louis A.; Arrington, Elaine; Renock, Sean; Shapiro, David A. (August 2003). "Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology". Neuropsychopharmacology. 28 (8): 1400–1411. doi: 10.1038/sj.npp.1300203 . ISSN   1740-634X. PMID   12784105.
  6. ↑ Tran, Nancy L.; Maguire, Gerald A.; Franklin, David L.; Riley, Glyndon D. (August 2008). "Case Report of Aripiprazole for Persistent Developmental Stuttering". Journal of Clinical Psychopharmacology. 28 (4): 470–472. doi:10.1097/JCP.0b013e31817ea9ad. ISSN   0271-0749. PMID   18626285.
  7. ↑ Carson, William H.; Kitagawa, Hisashi (2004). "Drug development for anxiety disorders: new roles for atypical antipsychotics". Psychopharmacology Bulletin. 38 (1): 38–45. ISSN   0048-5764. PMID   15278017.
  8. ↑ Murphy, Ruth; Gallagher, Anne; Sharma, Kapil; Ali, Tariq; Lewis, Elizabeth; Murray, Ivan; Hallahan, Brian (August 2015). "Clozapine-induced stuttering: an estimate of prevalence in the west of Ireland". Therapeutic Advances in Psychopharmacology. 5 (4): 232–236. doi:10.1177/2045125315590060. ISSN   2045-1253. PMC   4535049 . PMID   26301079.
  9. ↑ Yoo, Hanik K.; Lee, Joong-Sun; Paik, Kyoung-Won; Choi, Soon-Ho; Yoon, Sujung J.; Kim, Jieun E.; Hong, Jin Pyo (March 2011). "Open-label study comparing the efficacy and tolerability of aripiprazole and haloperidol in the treatment of pediatric tic disorders". European Child & Adolescent Psychiatry. 20 (3): 127–135. doi:10.1007/s00787-010-0154-0. ISSN   1018-8827. PMC   3046348 . PMID   21188439.
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