Psychedelics in developmental stuttering to modulate brain functioning: a new therapeutic perspective?

Developmental stuttering (DS) is a neurodevelopmental speech-motor disorder characterized by symptoms such as blocks, repetitions, and prolongations. Persistent DS often has a significant negative impact on quality of life, and interventions for it have limited efficacy. Herein, we briefly review existing research on the neurophysiological underpinnings of DS -specifically, brain metabolic and default mode/social-cognitive networks (DMN/SCN) anomalies- arguing that psychedelic compounds might be considered and investigated (e.g., in randomized clinical trials) for treatment of DS. The neural background of DS is likely to be heterogeneous, and some contribution from genetically determinants of metabolic deficiencies in the basal ganglia and speech-motor cortical regions are thought to play a role in appearance of DS symptoms, which possibly results in a cascade of events contributing to impairments in speech-motor execution. In persistent DS, the difficulties of speech are often linked to a series of associated aspects such as social anxiety and social avoidance. In this context, the SCN and DMN (also influencing a series of fronto-parietal, somato-motor, and attentional networks) may have a role in worsening dysfluencies. Interestingly, brain metabolism and SCN/DMN connectivity can be modified by psychedelics, which have been shown to improve clinical evidence of some psychiatric conditions (e.g., depression, post-traumatic stress disorder, etc.) associated with psychological constructs such as rumination and social anxiety, which also tend to be present in persistent DS. To date, while there have been no controlled trials on the effects of psychedelics in DS, anecdotal evidence suggests that these agents may have beneficial effects on stuttering and its associated characteristics. We suggest that psychedelics warrant investigation in DS.

Stuttering as a spectrum disorder: A hypothesis.

Childhood-onset fluency disorder, commonly referred to as stuttering, affects over 70 million adults worldwide. While stuttering predominantly initiates during childhood and is more prevalent in males, it presents consistent symptoms during conversational speech. Despite these common clinical manifestations, evidence suggests that stuttering, may arise from different etiologies, emphasizing the need for personalized therapy approaches. Current research models often regard the stuttering population as a singular, homogenous group, potentially overlooking the inherent heterogeneity. This perspective consolidates both historical and recent observations to emphasize that stuttering is a heterogeneous condition with diverse causes. As such, it is crucial that both therapeutic research and clinical practices consider the potential for varied etiologies leading to stuttering. Recognizing stuttering as a spectrum disorder embraces its inherent variability, allowing for a more nuanced categorization of individuals based on the underlying causes. This perspective aligns with the principles of precision medicine, advocating for tailored treatments for distinct subgroups of people who stutter, ultimately leading to personalized therapeutic approaches.

Polypharmacy- Purpose, Benefits and Limitations.

With what has become increasingly common among nearly all medical specialties, the number of patients who have various comorbid diseases both psychiatrically and mentally challenges the field of psychiatry. As a result, it is not uncommon for physicians to be imposed with treatment decisions regarding polypharmacy, the use of multiple medications to treat different diseases, or even the same illness several times. In recent years, the concept of polypharmacy has been known to have a negative undertone, implying that its use is inappropriate or causes more harm than the potential benefit. Although the use of any medication should involve risk versus benefit discussion, when used with good clinical judgment and pharmacologically sound knowledge, this practice can be potentially life-altering for patients.

Case Report: Deutetrabenazine as an Adjunctive Treatment for Stuttering.

Childhood-Onset Fluency Disorder (Stuttering) is a neurodevelopmental disorder in which disturbances occur in the normal fluency and time patterning of speech. While the dopamine system has been well-described in its neurophysiology, there currently is no FDA-approved treatment for stuttering. Second-generation antipsychotics, which have been effective in the treatment of schizophrenia and bipolar disorder, act as dopamine D-2 receptor antagonists at the postsynaptic neuron and have been shown to reduce the symptoms of stuttering. However, the D-2 receptor antagonist and partial agonist agents carry the potential for metabolic side effects and can potentially lead to movement disorders. Deutetrabenazine, a VMAT-2 inhibitor indicated to treat hyperkinetic movement disorders, is a potential candidate in the treatment of stuttering, based on its mechanism of action in decreasing dopamine activity while not carrying the risk of metabolic adverse events.

Dopamine, vocalization, and astrocytes.

Dopamine, the main catecholamine neurotransmitter in the brain, is predominately produced in the basal ganglia and released to various brain regions including the frontal cortex, midbrain and brainstem. Dopamine's effects are widespread and include modulation of a number of voluntary and innate behaviors. Vigilant regulation and modulation of dopamine levels throughout the brain is imperative for proper execution of motor behaviors, in particular speech and other types of vocalizations. While dopamine's role in motor circuitry is widely accepted, its unique function in normal and abnormal speech production is not fully understood. In this perspective, we first review the role of dopaminergic circuits in vocal production. We then discuss and propose the conceivable involvement of astrocytes, the numerous star-shaped glia cells of the brain, in the dopaminergic network modulating normal and abnormal vocal productions.

Investigation of Risperidone Treatment Associated With Enhanced Brain Activity in Patients Who Stutter.

Stuttering is a childhood onset fluency disorder that leads to impairment in speech. A randomized, double-blinded placebo-controlled study was conducted with 10 adult subjects to observe the effects of risperidone (a dopamine receptor 2/serotonin receptor 2 antagonist) on brain metabolism, using [18F] deoxyglucose as the marker. At baseline and after 6 weeks of taking risperidone (0.5-2.0 mg/day) or a placebo pill, participants were assigned to a solo reading aloud task for 30 min and subsequently underwent a 90-min positron emission tomography scan. Paired t-tests were performed to compare the pre-treatment vs. post-treatment in groups. After imaging and analysis, the blind was broken, which revealed an equal number of subjects of those on risperidone and those on placebo. There were no significant differences in the baseline scans taken before medication randomization. However, scans taken after active treatment demonstrated higher glucose uptake in the specific regions of the brain for those in the risperidone treatment group (p < 0.05). Risperidone treatment was associated with increased metabolism in the left striatum, which consists of the caudate and putamen, and the Broca's area. The current study strengthens previous research that suggests the role of elevated dopamine activity and striatal hypometabolism in stuttering. We propose that the mechanism of risperidone's action in stuttering, in part, involves increased metabolism of striatal astrocytes. We conclude that using neuroimaging techniques to visualize changes in the brain of those who stutter can provide valuable insights into the pathophysiology of the disorder and guide the development of future interventions.

Can Na18F PET/CT bone scans help when deciding if early intervention is needed in patients being treated with a TSF attached to the tibia: insights from 41 patients.

PURPOSE: To demonstrate the usefulness of positron emission tomography (PET)/computed tomography (CT) bone scans for gaining insight into healing bone status earlier than CT or X-ray alone. METHODS: Forty-one prospective patients being treated with a Taylor Spatial Frame were recruited. We registered data obtained from successive static CT scans for each patient, to align the broken bone. Radionuclide uptake was calculated over a spherical volume of interest (VOI). For all voxels in the VOI, histograms and cumulative distribution functions of the CT and PET data were used to assess the type and progress of new bone growth and radionuclide uptake. The radionuclide uptake difference per day between the PET/CT scans was displayed in a scatter plot. Superimposing CT and PET slice data and observing the spatiotemporal uptake of 18F- in the region of healing bone by a time-sequenced movie allowed qualitative evaluation. RESULTS: Numerical evaluation, particularly the shape and distribution of Hounsfield Units and radionuclide uptake in the graphs, combined with visual evaluation and the movies enabled the identification of six patients needing intervention as well as those not requiring intervention. Every revised patient proceeded to a successful treatment conclusion. CONCLUSION: Numerical and visual evaluation based on all the voxels in the VOI may aid the orthopedic surgeon to assess a patient's progression to recovery. By identifying slow or insufficient progress at an early stage and observing the uptake of 18F- in specific regions of bone, it might be possible to shorten the recovery time and avoid unnecessary late complications.

COVID-19, ferrosenescence and neurodegeneration, a mini-review.

Exacerbation of cognitive, motor and nonmotor symptoms have been described in critically ill COVID-19 patients, indicating that, like prior pandemics, neurodegenerative sequelae may mark the aftermath of this viral infection. Moreover, SARS-CoV-2, the causative agent of COVID-19 disease, was associated with hyperferritinemia and unfavorable prognosis in older individuals, suggesting virus-induced ferrosenescence. We have previously defined ferrosenescence as an iron-associated disruption of both the human genome and its repair mechanisms, leading to premature cellular senescence and neurodegeneration. As viruses replicate more efficiently in iron-rich senescent cells, they may have developed the ability to induce this phenotype in host tissues, predisposing to both immune dysfunction and neurodegenerative disorders. In this mini-review, we summarize what is known about the SARS-CoV-2-induced cellular senescence and iron dysmetabolism. We also take a closer look at immunotherapy with natural killer cells, angiotensin II receptor blockers ("sartans"), iron chelators and dipeptidyl peptidase 4 inhibitors ("gliptins") as adjunct treatments for both COVID-19 and its neurodegenerative complications.

How and when to treat the most common adverse effects of antipsychotics: Expert review from research to clinical practice.

OBJECTIVE: As most treatment guidelines for antipsychotics focus on clinical efficacy, we will instead focus on adverse effects and how to manage them. In this review, we aim to provide an up-to-date clinical resource for providers who prescribe antipsychotics and have included here "what's new" and "what to do" for numerous antipsychotic-induced adverse effects. METHODS: A review was performed of relevant literature, studies, randomized clinical trials, and systematic reviews. This information was combined with the clinical experience of the authors to formulate a practical guide for treating adverse effects of antipsychotics with an emphasis on metabolic and movement disorder adverse effects and brief mention of some others (sedation and sexual dysfunction). CONCLUSIONS: Antipsychotics are an integral part of psychiatric care and are often prescribed lifelong. When choosing an antipsychotic, special consideration must be given to adverse effects which have an undeniable impact on quality of life and can often be the deciding factor in patients' medication compliance. While patients may respond well to one specific medication, they may still experience adverse effects that lead them to discontinue it or switch to a more tolerable but less effective option. However, strategies do exist for managing and treating adverse effects, especially metabolic and movement adverse effects, allowing better personalization of antipsychotic choice.

The Other Obesity Epidemic-Of Drugs and Bugs.

Chronic psychiatric patients with schizophrenia and related disorders are frequently treatment-resistant and may require higher doses of psychotropic drugs to remain stable. Prolonged exposure to these agents increases the risk of weight gain and cardiometabolic disorders, leading to poorer outcomes and higher medical cost. It is well-established that obesity has reached epidemic proportions throughout the world, however it is less known that its rates are two to three times higher in mentally ill patients compared to the general population. Psychotropic drugs have emerged as a major cause of weight gain, pointing to an urgent need for novel interventions to attenuate this unintended consequence. Recently, the gut microbial community has been linked to psychotropic drugs-induced obesity as these agents were found to possess antimicrobial properties and trigger intestinal dysbiosis, depleting Bacteroidetes phylum. Since germ-free animals exposed to psychotropics have not demonstrated weight gain, altered commensal flora composition is believed to be necessary and sufficient to induce dysmetabolism. Conversely, not only do psychotropics disrupt the composition of gut microbiota but the later alter the metabolism of the former. Here we review the role of gut bacterial community in psychotropic drugs metabolism and dysbiosis. We discuss potential biomarkers reflecting the status of Bacteroidetes phylum and take a closer look at nutritional interventions, fecal microbiota transplantation, and transcranial magnetic stimulation, strategies that may lower obesity rates in chronic psychiatric patients.

Scientists, society, and stuttering.

More than 70 million people worldwide are affected by developmental stuttering. It is important to reach out to the public, scientific and medical communities, and those who stutter with a goal to raise awareness about stuttering. In this short perspective, we argue that to educate, advocate, and spread awareness about stuttering, we need role models, support, and opportunities.

New Medications for Neuropsychiatric Disorders.

This article seeks to summarize the mechanisms of action, clinical trials, and FDA approval status of several psychiatric medications that are either newly available or in the FDA approval process. This article highlights medications that demonstrate novel mechanisms of action, examines nonpsychiatric medications that are being used to augment existing psychiatric treatments, and elucidates treatments for illnesses that have not previously received FDA indications.

The Pharmacologic Treatment of Stuttering and Its Neuropharmacologic Basis.

Stuttering is a DSM V psychiatric condition for which there are no FDA-approved medications for treatment. A growing body of evidence suggests that dopamine antagonist medications are effective in reducing the severity of stuttering symptoms. Stuttering shares many similarities to Tourette's Syndrome in that both begin in childhood, follow a similar male to female ratio of 4:1, respond to dopamine antagonists, and symptomatically worsen with dopamine agonists. In recent years, advances in the neurophysiology of stuttering have helped further guide pharmacological treatment. A newer medication with a novel mechanism of action, selective D1 antagonism, is currently being investigated in FDA trials for the treatment of stuttering. D1 antagonists possess different side-effect profiles than D2 antagonist medications and may provide a unique option for those who stutter. In addition, VMAT-2 inhibitors alter dopamine transmission in a unique mechanism of action that offers a promising treatment avenue in stuttering. This review seeks to highlight the different treatment options to help guide the practicing clinician in the treatment of stuttering.

Accuracy and precision of a CT method for assessing migration in shoulder arthroplasty: an experimental study.

BACKGROUND: Radiostereometric analysis (RSA) is the gold standard to measure early implant migration which is a predictive factor for implant survival. PURPOSE: To validate an alternative computed tomography (CT) technique to measure implant migration in shoulder arthroplasty. MATERIAL AND METHODS: A cadaver proximal humerus and a scapula, which had tantalum beads incorporated within them, were prepared to accept a short-stemmed humeral component and a two-pegged glenoid component of a commercial total shoulder arthroplasty (TSA) system. A five degree of freedom micrometer and goniometer equipped rig was used to translate and rotate the implant components relative to the respective bone to predetermined positions. Double CT examinations were performed for each position and CT motion analysis software (CTMA) was used to assess these movements. The accuracy and precision of the software was estimated using the rig's micrometers and goniometers as the gold standard. The technique's effective dose was also assessed. RESULTS: The accuracy was in the range of 0.07-0.23 mm in translation and 0.22-0.71° in rotation. The precision was in the range of 0.08-0.15 mm in translation and 0.23-0.54° in rotation. The mean effective dose for the CT scans was calculated to be 0.27 mSv. CONCLUSION: In this experimental setting, accuracy, precision, and effective dose of the CTMA technique were found to be comparable to that of RSA. Therefore, we believe clinical studies are warranted to determine if CTMA is a suitable alternative to traditional RSA for migration measurements in TSA.

Ecopipam as a pharmacologic treatment of stuttering.

BACKGROUND: Stuttering, also known as childhood-onset fluency disorder, is a chronic neurodevelopmental disorder that affects 1% of the population and can greatly impact an individual's social, occupational, and academic functioning. Prior research has shown dopamine D2 antagonists are effective in reducing the severity of stuttering symptoms, but these compounds can be associated with metabolic and movement disorder adverse effects. Ecopipam is an investigational medication that acts as a selective dopamine D1 receptor antagonist. This mechanism should reduce the likelihood of metabolic and movement disorder adverse effects of D2 antagonists. METHOD: This open-label pilot study investigated ecopipam in the treatment of adults who stutter. RESULTS: The results showed that a majority of participants demonstrated improvement in their stuttering. The medication was well tolerated. CONCLUSIONS: These positive, preliminary findings suggest that a doubleblind, randomized controlled clinical trial to examine the efficacy of ecopipam in the treatment of stuttering is warranted.