Duloxetine for <scp>PSP</scp> ‐Related Speech Disorders

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy characterized by an akinetic-rigid syndrome, postural instability, and supranuclear vertical gaze palsy.1 Among its most disabling features are axial motor symptoms, including speech disturbances such as slurring, hypophonia, stuttering, harsh voice, echolalia, and palilalia which significantly impact communication and quality of life.2 While dopaminergic and cholinergic deficits are well-documented in PSP, emerging evidence suggests noradrenaline depletion plays an important role in motor and speech dysfunction.3-5 The locus coeruleus, the primary source of cerebral noradrenergic innervation, undergoes early and severe degeneration in PSP, disrupting noradrenaline-dependent modulation of motor planning, arousal, and postural stability.3 Previously, several medications with noradrenergic effects (selegiline, idazoxan, L-threodihydroxyphenylserine, methylphenidate, atomoxetine, and duloxetine) have shown promising improvement in parkinsonian axial symptoms like freezing of gait (FOG),4 suggesting a potential role of these agents in the managing axial symptoms. We present three patients diagnosed with PSP according to MDS clinical diagnostic criteria1 whose speech difficulties improved significantly with duloxetine. All patients demonstrated remarkable speech improvements within weeks of treatment initiation, characterized by reduced pauses, enhanced fluency, clearer articulation, and improved comprehensibility (Table 1; Supporting Information S1 for detailed case descriptions; Videos 1 and 2). Speech impairment in PSP is thought to arise from widespread neurodegeneration involving cortical, subcortical, and brainstem regions.3 The midbrain, globus pallidus, striatum, subthalamic nuclei, and locus coeruleus5 are particularly affected in PSP patients, leading to mixed dysarthria with hypokinetic, spastic, and occasionally ataxic components.3 Postmortem studies revealed ~50% reduction in locus coeruleus pigmented neurons in PSP, that correlated with disease severity.3 The locus coeruleus provides widespread noradrenergic innervation to the precentral gyrus (facilitating speech motor execution),3 the pedunculopontine nucleus (playing a role in regulating gait initiation and rhythmicity), the nucleus ambiguus (controlling muscles responsible for vocal fold tension and pitch modulation), and the hypoglossal nucleus (controlling laryngeal and tongue muscles). Duloxetine achieves 30–40% norepinephrine transporter (NET) occupancy at clinical doses (20–60 mg), despite its 9-fold lower affinity for NET compared to serotonin transporter.5 In PSP, duloxetine could counteract noradrenergic and serotonergic deficits by increasing synaptic noradrenaline in surviving locus coeruleus terminals, thereby partially restoring noradrenaline-dependent motor planning, and by augmenting serotonergic signaling in prefrontal-striatal circuits, enhancing cognitive-motor integration.5 Additionally, in the prefrontal cortex duloxetine elevates synaptic dopamine through NET blockade, potentially compensating for fronto-striatal dopamine deficits and improving executive functions and speech initiation in PSP. The observed speech improvements in our patients might reflect either direct influences of duloxetine on cognitive and motor-speech processes involved in verbal production, or an indirect effect mediated through improvement in emotional state, and further research is needed to better understand the underlying mechanisms involved. This question could potentially be addressed by administering duloxetine for speech disturbances in PSP patients who are not experiencing emotional/affective disorders, ideally in a controlled trial setting. Duloxetine's noradrenergic effects enhance psychomotor speed and mental processing independent of depressive symptoms, though distinguishing between cognitive-linguistic improvements and pure motor speech enhancement can be challenging. To our knowledge, this is the first report of beneficial effects of serotonin-norepinephrine reuptake inhibitor treatment on PSP-related speech disturbances. These observations emerged serendipitously during routine clinical management of patients, and should be confirmed by prospective, before-and-after treatment, testing of psychomotor, language (including writing), and speech functions, which was not done in our study. The diagnostic certainty of PSP cases could also be improved by employing newly-emerging fluid/tissue biomarkers and advanced neuroimaging, which were not available for our patients. Given the significant disability caused by speech disturbances in PSP patients, further systematic investigation is warranted to evaluate the effectiveness of duloxetine in larger, controlled cohorts. A. Conception, B. Execution, C. Processing, D. Writing of the first draft, E. Review and Critique. O.T.: A, B, C, D N.D.: D M.Y. Ch.: E S.-Y.L.: C, D, E Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. Ethical Compliance Statement: This study is a case series describing treatment responses. Formal institutional review board/ethics committee approval was not obtained, as per local regulations policies for such descriptive reports. This work was conducted in accordance with the principles of the Declaration of Helsinki and other applicable ethical standards. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. All patients (except case 3 who provided only oral consent) provided both oral and written informed consent for inclusion in this report and for dissemination of associated case details and videos, with the assurance that personal identifiers would be anonymized. The data that supports the findings of this study are available in the supplementary material of this article. Supplementary Materials S1. Detailed description of cases presented in Table 1, including clinical course and imaging. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.